Managing Curing Type 1 Diabetes

Jeremy Warshauer PGY-2

Internal Medicine

UT Southwestern

Objectives

bull Overview of type 1 diabetes

bull Bionic Pancreas

bull Islet Transplantation

bull Stem Cell Therapy

Prevalence

bull In 2012 291 million Americans or 93 of the population had diabetes

ndash 125 million American children and adults have type 1 diabetes

bull $245 billion in 2012 impact on economy

Normal Islet Cells

httpwwwbritannicacomEBcheckedtopic329670islets-of-Langerhans

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

bull Beta cell regeneration and transplantation

bull Immune research

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

Artificial or bionic pancreas

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Objectives

bull Overview of type 1 diabetes

bull Bionic Pancreas

bull Islet Transplantation

bull Stem Cell Therapy

Prevalence

bull In 2012 291 million Americans or 93 of the population had diabetes

ndash 125 million American children and adults have type 1 diabetes

bull $245 billion in 2012 impact on economy

Normal Islet Cells

httpwwwbritannicacomEBcheckedtopic329670islets-of-Langerhans

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

bull Beta cell regeneration and transplantation

bull Immune research

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

Artificial or bionic pancreas

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Prevalence

bull In 2012 291 million Americans or 93 of the population had diabetes

ndash 125 million American children and adults have type 1 diabetes

bull $245 billion in 2012 impact on economy

Normal Islet Cells

httpwwwbritannicacomEBcheckedtopic329670islets-of-Langerhans

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

bull Beta cell regeneration and transplantation

bull Immune research

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

Artificial or bionic pancreas

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Normal Islet Cells

httpwwwbritannicacomEBcheckedtopic329670islets-of-Langerhans

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

bull Beta cell regeneration and transplantation

bull Immune research

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

Artificial or bionic pancreas

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

bull Beta cell regeneration and transplantation

bull Immune research

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

Artificial or bionic pancreas

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

bull Beta cell regeneration and transplantation

bull Immune research

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

Artificial or bionic pancreas

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

T1DM

α-cell dysfunction

autoimmune β-cell destruction insulin deficiency

Artificial or bionic pancreas

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

ldquoInsulin is not a cure for diabetes it is a treatment It enables the diabetic to burn sufficient carbohydrates so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of liferdquo

ndash Sir Frederick Grant Bantingduring his Nobel lecture on September 15 1925

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

From JDRF

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Bionic Pancreas

bull Addresses dysfunctional alpha cells and insulin deficiency

bull Embraces technology CGMS insulin and glucagon pumps

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

α-cell dysfunction

Diabetes Care Volume 37 May 2014

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

4-10x

Old way

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Bionic Pancreas

288x

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Bionic Pancreas Setup

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Bionic Pancreas improved glucose control

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

How much did the bionic pancreas help

bull Average blood glucose reduced

ndash 159 mgdL to 133 mgdL (A1C = 62)

bull Hypoglycemia reduced

ndash 37 to 15 of the time with a blood glucose lt60mgdL

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

How much did they improve

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Is this really a cure

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Problems with Bionic Pancreas

bull Invasive

bull Possibility of technology malfunction

bull No stable preparation of glucagon

bull Insulin time of onset

bull Not physiologic

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

α-cell dysfunction

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Underlying problem with insulin injections

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Islet transplantation

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Edmonton Protocol -immunosuppresion

bull Glucocorticoid-free immunosuppressive therapy

bull Daclizumab

bull Tacrolimus

bull Sirolimus

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

11131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121111312111131211113121

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Edmonton Protocol ndash a long term solution

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Why doesnrsquot everybody get this

bull Patient needs unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

bull Remaining challengesndash expansion of the islet donor supply

ndash improving islet isolation techniques

ndash strategies to improve engraftment

ndash mediating the anti-inflammatory response post-transplant

ndash improving recipient immunosuppression regimens

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Prevelance

Diabetes Metabolic Syndrome and Obesity Targets and Therapy 20147 submit your manuscript | wwwdovepresscom

Dovepress

Dovepress

213

Islet transplantation for type 1 diabetes

from 2007ndash2010 as evidenced by retained C-peptide levels

reduction of HbA1c

and reduced islet reinfusion rates19 This

success in part can be attributed to shifts in immunosuppres-

sion strategies However improvements to islet engraftment

and subsequent survival are critical in achievement of durable

insulin-independence

Within North America few islet transplant centers are

currently active despite the substantial transplant activity

of international islet transplant centers This is reflected in

the classification of islet transplantation as an experimental

therapy in the United States resulting in a lack of available

funds to conduct and support large scale clinical trials

Currently two pivotal Phase III clinical trials are being con-

ducted in specialized islet transplantation centers through

the Clinical Islet Transplant (CIT) Consor tium (CIT-06 and

CIT-07 NCT00468117 and NCT00434811 respectively) in

an effort to support the US Food and Drug Administration

biological license application mandate Successful licensure

will inevitably recognize islet transplantation as a clinical

therapy expanding its therapeutic benefit for patients with

T1DM in the United States

The University of Albertarsquos Clinical Islet Transplant

Program continues to be the most active center participating

within the CITR In 2013 alone 66 islet transplants were

conducted at the Edmonton site The Edmonton group also

reports that of over 200 patients transplanted with more than

400 intraportal islet preparations 79 of recipients continue

to show full or partial islet graft function20 The median

duration of insulin independence is 346 and 11 months

for subjects with full or partial graft function respectively

whereas the duration of C-peptide is 533 and 704 months

respectively for those same patients20ndash22

Prior to the Edmonton Protocol insulin independence

was an uncommon achievement Though clinical success

has improved markedly over the past 14 years further

obstacles must be overcome if islet transplantation is to be

more broadly applied in the T1DM population Such remain-

ing challenges include expansion of the islet donor supply

improving islet isolation techniques strategies to improve

engraftment mediating the anti-inflammatory response

post-transplant and improving recipient immunosuppres-

sion regimens Several clinical trials are currently under

active investigation to address these obstacles in an attempt

to improve this important therapy (Table 1)

Clinical islet transplantation obstacles and refine me nt sDonor selection and availabilityThe number of pancreas donors required to treat one recipient

limits the number of transplants that can occur A component

of islet transplantation that may improve clinical outcomes is

donor selection Retrospective studies at single centers have

identified several donor-related variables that may contribute

to islet isolation outcomes These variables include donor

80

60

Edmonton

North America

International

40

20

Year

Islet transplant recipients per

year registered with CITR

Nu

mb

er

of

isle

t tr

an

sp

lan

t re

cip

ien

ts

0

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Figure 1 Number of islet transplant recipients from 1999ndash2013 in Edmonton North America and International Islet Transplant Centers

Notes This data is kindly reproduced with express permission from the CITR Coordinating Center and Investigators The Collaborative Islet Transplant Registry 2011

Seventh Annual Report Reported data is unavailable from 2010ndash2013 for North America and International Islet Transplant Centers15

Abbreviation CITR Collaborative Islet Transplant Registry

From the Clinical Islet Transplantation (CIT) Consortium

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Stem cell Therapy

bull 2 Key features

ndash Ability to renew themselves through cell divisionwhile remaining undifferentiated

ndash When given the appropriate signals stem cells can differentiate into many specialized cell types

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Encapsulation

bull Protect against immune rejection ndash Encaptradevice by Viacyte

httpviacytecomproductsvc-01-diabetes-therapy

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

Conclusions

bull A cure is in site but there are several obstacles that still must be overcome

ndash Immune modulation

ndash Not enough supply

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12

References

bull Bruni A et al (2014) Islet cell transplantation for the treatment of type 1 diabetes recent advances and future challenges Diabetes Metab Syndr Obes 7 211-223

bull Derr R et al (2003) Is HbA(1c) affected by glycemic instability Diabetes Care 26(10) 2728-2733

bull Kudva Y C et al (2014) Closed-loop artificial pancreas systems physiological input to enhance next-generation devices Diabetes Care 37(5) 1184-1190

bull Peyser T et al (2014) The artificial pancreas current status and future prospects in the management of diabetes Ann N Y Acad Sci 1311 102-123

bull Pagliuca F W et al (2014) Generation of functional human pancreatic beta cells in vitro Cell 159(2) 428-439

bull Russell S J et al (2014) Outpatient glycemic control with a bionic pancreas in type 1 diabetes N Engl J Med 371(4) 313-325

bull Shapiro A M et al (2006) International trial of the Edmonton protocol for islet transplantation N Engl J Med 355(13) 1318-1330

bull Unger R H and L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes ProcNatl Acad Sci U S A 107(37) 16009-16012

bull Unger R H and A D Cherrington (2012) Glucagonocentric restructuring of diabetes a pathophysiologic and therapeutic makeover J Clin Invest 122(1) 4-12