insulin therapy in type 1 diabetes update

8/14/2019 Insulin Therapy in Type 1 Diabetes Update

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Insulin Therapy in Type 1

Diabetes Mellitus

Pro f. Dr. MONA EL SAMAHY

Professo r of Pediatr ics ,

Head o f Diabetes Un it

Ain Shams Universi ty, Cairo, Egypt.


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Why are We Concerned about Diabetes?

Egyp t wi l l be the 10th. World w ide

India

ChinaUSAIndonesiaPakistanBrazilBangladeshJapanPhilippines

Egypt

Country

2030

79.4

42.330.321.313.911.311.18.97.8

6.7

People withdiabetes(millions)

India

ChinaUSAIndonesiaJapanPakistanRussian Fed.BrazilItaly

Bangladesh

Country

2000

31.7

20.817.78.46.85.24.64.64.3

3.2

People withdiabetes (millions)

1

23456789

10

Ranking

Wild S et al. Diabetes Care 2004;27:104753

The worldw ide diabetes market is exper iencing expo nent ial growth , especial ly

with respect to typ e 2 diabetes, which has been descr ibed as a global epidemicv


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Microvascularcomplications

Myocardial

infarction

HbA1c

37%

14%

Lowering HbA1c reduces the risk of complications

Deaths related todiabetes

21%

1%

Stratton IM, et al. BMJ2000; 321:405412.


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Treat To Target Guidelines

Need For Progressive Treatment Strategy

PG=plasma glucose.

1.American Diabetes Association. Diabetes Care 2005;28(suppl 1):S1436.2.American Association of Clinical Endocrinologists. Endocr Pract 2002;8(suppl 1):4384.3.International Diabetes Federation. Diabet Med 1999;16:71630.

*12 hours postprandial; **2 hours postprandial.

Glucose control Healthy ADA1 AACE2 IDF3

HbA1c (%)


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Treatment

Ideal therapy

Should include the following:

* Insulin.

* Diet.

* Exercise.

* Psychological management.

* Health education.

* Home glucose monitoring.


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Before Insulin.Whats After?

Before insulin wasdiscovered in 1921,everyone with type 1

diabetes died withinweeks to years of its onset

JL on 12/15/22 and 2 mos later


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Insulin Therapy in Type 1 Diabetes

is a must


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Insulin is the 1ry mode of therapy in type 1diabetes

Insulin treatment must be started as soonas possible after diagnosis to preventmetabolic decompensation and diabetic

ketoacidosis


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Most children are prescribed human insu l inbecause of their availability through modernmanufacturing techniques using recombinantDNA technology and because of their low

immunogenicityPorc ine or bovinepreparations may be cheaper

and more readily available in some parts of theworld. They are not inferior in clinical efficacy to

human insulin. They may have greaterimmunogenicity and high titer antibodies mayalter pharmacodynamics by acting as insulinbinding proteins


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Insulin concentrations:The most widely available insulin concentration is 100IU/ml. It must be given by insulin syringes calibrated tothe concentration of insulin being used

Injection sites:

1- Front of the thigh/ lateral thigh

2- Abdomen

3- Buttocks4- Lateral aspect of arm


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Storage of insulin :

. Insulin must never be frozen

. Unused insulin should be stored

in a refrigerator (2-8C). Direct sunlight damages insulin

. After opening, an insulin vial

should be discarded after 3months if kept at (2-8C)


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Problems with injections

1- Local hypersensitivity reactions

2- Lipohypertrophy

3- Lipoatrophy4- Painful injections

5- Leakage of insulin

6- Bruising and bleeding7- Bubbles in insulin


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Insulin Preparations

Short Acting Insulin (Regular)

Rapid - Acting Analogues

Intermediate - Acting (NPH) Insulin

Premixed Insulin

Long - Acting Insulin

Long Acting Analogues


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Premixed insulins are popular in somecountries particularly for prepubertalchildren on twice daily regimen.Although they reduce potential errorsin drawing up insulin they remove theflexibility offered by separate

adjustment of the two types


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Pharmacokinetics of Current Insulin


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EffectiveOnset Peak Duration

Insulin lispro


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Principles of insulin therapy

To provide sufficient insulin throughout the 24hours to cover basal requirements.

To deliver higher bolus of insulin in an attempt tomatch the glycemic effect of meals.


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Insulin regimens

Two injections daily of a mixture of short andintermediate acting insulin (before breakfast andthe main evening meal)

Three injections daily using a mixture of short andintermediate acting insulin before breakfast,short acting insulin alone before an afternoonsnack or main evening meal, intermediate acting

insulin before bed


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Basal-bolus regimen of short acting insulin 20-30min before main meals, intermediate or longacting insulin at bed time

Basal-bolus regimen of rapid acting insulinanalogue immediately before main meals,intermediate or long acting insulin at bed time,probably before breakfast and occasionally at

lunch time


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Treatment


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Ideal Insulin Regimens Type 1 DM

Minimizes nocturnal

hypos OptimizeFBS

Minimizes late morning andafternoon hypos

Basal-Bolus Regimen

The challenge is to

Come as close as possible to normoglycemia and reduce hypoglycemia.


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Intensive Insulin Therapy

Intensive glycemic control is the therapeutic


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Intensive glycemic control is the therapeuticapproach

That aims to achieve near normal glycemia.

Reduce the risk of microvascular complications

with intensive insulin therapy is associated

with increase risk of hypoglycemia [specially

nocturnal 55%].


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Daily insulin dosage

Dosage depend on many factors such as: age,wt, stage of puberty, exercise, nutritional in take,results of blood glucose monitoring, etc

In the partial remission phase the daily insulindose is 1 IU/kg/day


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Physiologic insulin delivery: About half of insulin dose is basal, unrelated to meals

About half of insulin dose is required to utilize ingested

carbohydrate, distributed approximately in proportion to

carbohydrates in meals or snacks Total dose in adults ~ 0.7- 0.9 U/kg/day, in adolescents up to

1.5 U/kg/day

Distinguish between revising the regimen and

adjusting individual doses: Revising the regimen means changing the usual dose on a

recurring basis

Adjusting individual dose means one time only


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Revising the regimen:

Change basal dose according to overnight BG profile (e.g. if BGrises, increase dose)

Change usual meal dose according to BG profile between meals

or post-prandial BG With practice, many patients can learn to revise the regimen

Adjusting individual doses:

Each meal dose should be adjusted for current BG level (e.g. +1unit/50 mg/dl)

Each meal dose may be adjusted for expected or plannedcarbohydrate intake (e.g. +/- 1 unit/15 gm carbohydrate)

Give written individual dose change schedules as a sliding scaleor algorithm


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Indications for Revising Insulin Regimen

HbA1c > 7%

SMBG results erratic, or outside target range

Frequent hypoglycemia

Severe hypoglycemia without warning

Recurrent severe hypoglycemia

Symptoms of hyperglycemia

NEW INSULINS


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NEW INSULINS

1) Ins ul in analogu es

Rapid -act ing analogues.

Lon g-act ing analogues.

2) Oral insu l in.

3) Inh aled insul in.


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Rapid Acting Analogues

Li it ti f R l H I li (RHI)


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Limitations of Regular Human Insulin (RHI)

Properties of RHI:

SC injection does not appropriately match the postprandial hyperglycaemic peak.

Slow onset of action with subcutaneous (SC) injection which lead to:

Late postprandial hypoglycaemia, if the meal is delayed.

Nocturnal hypoglycaemia.

Requires administration 3045 minutes before any meal.

Wittlin SD, et al. In: Leahy JL, Cefalu W T, eds. Insulin Therapy:2002:7385

Id l R id A ti A l


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Ideal Rapid - Acting Analogue

Similar physiological properties to human insulin, with faster absorption & onset

of action

Faster absorption & higher concentration after SC. Injection compared to

conventional insulin , thus more physiological action reduce post prandial

glucose to greater extent. Give peak plasma concentration within 30 60 min.

Rapid return to basal level by 180 min ( no delayed peak concentration)means

less incidence of hypoglycemia

Reduced tendency for self association or rapid dissociation.

Improve patient convenience (pre & post meal).

Achieve the best glycemic control (post prandial control). Diabetes care

1990 1991 & The Lancet 1997

R id A ti A l


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Rapid Acting Analogues

Appearance: CLEAR Onset: 15 minutes

Peak: one hour

Duration: 2-4 hours

Examples:

Lispro (Humalog: Insulin analog)

Insulin Aspart (Novolog)

Administration: subcutaneous Usually given 5 minutes before the meal:

Peak coincides with postprandial rise in BS

St t f i li Li B28 B29


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A-chain

7 20

282930

1

19

116 7

21

1

B-chain

B29

Pro

B28

Lys

Structure of insulin Lispro (LysB28, ProB29)

Novo Rapid


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Novo-Rapid

Glu

ThrLys

Thr TyrPhe Phe Gly Arg

Glu GlyCys

ValLeu

TyrLeuAla

ValLeu

HisSer

GlyCysLeuHislnsnalhe1

Asn CysTyr

AsnGluLeuGln

TyrLeu

SerCysleerhrysCys

GlnGluValIle

GlyA21

B28B30

Asp Pro

Asp


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B9 ASP, B27ASP

B10 ASP

B28 LYS B29 PRO Insulin lispro

B28ASP Insulin Aspart

B3Lys, B29Glu: HMR 1964

Insulin glulisine (Apidra)

RapidActing

INSULIN ANALOGUES

monomeric

X


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Structure Difference

How Insulin Glulisine is different?

Rapid-acting Insulin Glulisine Apidra


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A chain

B chain

Gly

1

5

1

5

1015

20

SS

20

1510

Gly

Gln

Ile Gln

Cys

Phe

His

His

Leu

S

S

S

S

Phe

25

30ProLys

Thr

Ala

Modified Human Insulin

Insulin Glulisine:Replacement of Asparagine B3 withlysine and lysine B29 with glutamic

acid

GluLys

= Subst i tu t ion

Asn

Rapid-acting Insulin Glulisine Apidra

Apidra (insulin glulisine [rDNA origin] injection) USPI. Sanofi Aventis 2004; EU SPC. Sanofi Aventis.

Insulin glulisine APIDRA


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Zinc free reduce the formation of stable hexamers and obtain the fast

acting properties (quick onset of action).

The Only Rapid Insulin Analogue

Without Zinc

An alternative stabilizer than zinc was needed.

Improved physical stability in solution.

Inhibits the denaturation resulting from thermal &

mechanical stress.

Improved in-use stability.

No influence on the time-action profile of insulin glulisine.

With Polysorbate 20 Stabilizer

APIDRA(insulin glulisine)

f


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Rapid Onset of action

The two substitutions favourmonomer formation and facilitaterapid absorption from the tissue

following subcutaneous injection.

Hollemen F, et al. N Engl J Med 1997;337:17683 (adapted from Brange 1988)

Insulin Glulisine Apidra


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Provid es Rapid Onset & Sho rt durat ion of act ion

Drugs of Today 2005, 41 (7): 433-440Becker RHA, et al. Diabetes 2003;52:471-P

Time (minutes)

60 0 60 120 180 240 300 360 420 480 540

0

2

4

6

8

10

12

14

Glucoseinfusionrate

(mg/kg/min)

Dosage=0.3 U/kg

Insulin glulisine

Insulin lispro

RHI

Rapid-Acting Analogs and RHI in Obese


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p g gSubjects

Frick AD et al. ADA 64th Scientific Sessions, 2004. Abstract 526.

0 120 240 360 480 600

Time, min

0

1

2

3

4

5

6Glulisine

Lispro

Regular human insulin

N=18

BMI=30 kg/m2 to 40 kg/m2

Dosage=0.3 U/kg GIR=Glucose Infusion Rate

GIR,m

g.kg-1.m

in-1

60

*

*

* p< .05 GIR-t20%

vs RHI and Lispro


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Long acting analogues

The need for a 24 hour basal insulin


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The need for a 24 hour basal insulin

To achieve near normal glycemia exogenous insulinmust be delivered in a way that closely mimic normalphysiologic insulin secretion:

a) Continuous low level [basal insulin sec.]

b) Stimulated sec. after meals [prandial insulin]

Reduce hepatic glucose production (more effectiveapproach for glycemic control)

Maintain glucose level for brain and other vital organsdependent on proper glucose utilization


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The Challenge is, The way the pancreas does it


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1. Lantus (insulin glargine) Approved Product Information2. McKeage K et al. Drugs. 2001;61:1599-1624.3. Kramer W. Exp Clin Endo crinol Diabetes. 1999;107(suppl 2):S52-S61.

Novel Basal Insulin

24-hour peakless profile of insulin glargineallows once-daily administration

Structure of Insulin Glargine


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g

Modifications to human insulin chain

Substitution of glycine at position A21

Addition of two arginines at position B30 Unique release pattern from injection site

1

1

15105

5 10 15 20

20 Asn

25 30

Gly

Arg Arg

Substitution

Extension

Absorption of Insulin Glargine


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p g

Clear Solution

PH 4.0pH 7.4

Precipitation

Dissolution

Capillary Membrane

Insulin in Blood

Hexamers Dimers Monomers

10-3 M 10-5M 10-8 M

Sc Injection of Insulin

Glargine

Microprecipitates

at neutral PH 7.4

depotof

Insulin Glargine

Slow dissolution of free

Glargine Hexamers

Continuously releasedover 24 hours

Once daily dose

Insulin Glargine as an ideal basal insulin


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Insulin Glargine as an ideal basal insulin

Reliable, constant basal insulin concentration to control basal

metabolism.

Prolonged duration of action (24hours) compared with NPH

human insulin (14.5 hours).

Once-daily dosing

Safety Smooth peakless time-action profile

Lower risk of clinically hypoglycemic events

Clear Soluble with less interpersonal variation. Consistent absorption from arm, leg and abdomen unlike

other insulin formulations

Basal Insulin Profiles

Gl I f i R t


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0 4 8 12 16 20 24

Glucose Infusion Rates

Lepore et al. Diabetes49: 2142-2148, 2000

Glucosein

fusion

(mg/kg

/min)

4

3

2

1

0Glargine

NPHUltralente

Hours

Which type Of Basal Insulin?Look at all available basal insulins


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Look at all available basal insulins

Lepore M, et al. Diabetes 2000;49:21428.Adapted from Plank J, et al. Diabetes Care 2005;28:110712.

Plank et al 2005 (n=12)

Glucose infusionrate (mg/kg/min)

Glucose infusionrate (mol/kg/min)

0

2

4

Time (hours)

1

3

0

8

16

4

12

20

24

0 4 8 12 16 20 24

sc injection0.3 IU/kg or CSII 0.3 IU/kg/24/h

Ultralente

CSII

NPH

Insulinglargine

0

4

8

Time (hours)

2

6

0

30

10

20

40scinjection

NPH0.3 IU/kg

Insulin detemir0.4 IU/kg

Glucose infusionrate (mg/kg/min)

Glucose infusionrate (mol/kg/min)

0 4 8 12 16 20 24

216 12

RESULTS


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72

108

144

180

216

4

6

8

10

12

mg/dl

Glargine (N=24)Detemir MeanSD

0 2 4 6 8 10 12 14 16 18 20 22 24

048

12162024

01733

506784100

Subje

cts(N)

Subje

cts(%)

(Subjects with plasma glucose > 150 mg/dl)by time of study

mmol/l

PLASMA GLUCOSEs.c. insulin0.35 U/Kg

Time (hours)Porcellati F et al., Diabetes 55 (Suppl.1): A130, 2006

Ideal Insulin Regimens Type 1 DM


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Minimizes nocturnalhypos

OptimizeFBS

Minimizes late morning andafternoon hypos

Basal-Bolus Regimen

The challenge is to

Come as close as possible to normoglycemia and reduce hypoglycemia.

Delivery System


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y y

Disadvantages of conventional subcutaneous injection: Discomfort Inconvenience Systemic delivery Inconsistent pharmacokinetics Irreversible after injection

Insulin pumps

Insulin pen

Systems in clinical testing: Inhaled formulation


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Insulin Pen Development

Development for reusable pens


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OptiSet disposable pen

Alpha disposable pen

Omega Lite electronic

reusable pen


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Easy to teachSimple and quick

Easy to useJust dial and dose

Easy to inject 1,2Easy-to-push, soft

and gentle injection1

1. Clarke A, Spollett G. Expert Opin. Drug Deliv 2007; 4(2):165-174.2. Haak T, et al. Clin Ther (2007) 29: (4) 2007.

Easy Accurate Efficacy

S l STAR i 100% t i th l b t 1 t ISO3 d


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SoloSTAR is 100% accurate in the laboratory1 to ISO3 doseaccuracy standards

SoloSTAR is 100% accurate when used by patients2

In a dose accuracy study with 60 patients, each delivering 6different doses, SoloSTAR was 100% accurate2 to ISO3laboratory dose accuracy standards

Lantus % of delivereddoses within

ISO standard

Passes ISO

standard

60 x 10 u 100%60 x 40 u 100%

60 x 80 u 100%

Apidra % of delivereddoses within

ISO standard

Passes ISO

standard

60 x 5 u 100%60 x 15 u 100%

60 x 30 u 100%

1 Clarke A, Spollett G Expert Opinion in Drug Delivery 2007; 4(2): 165-1742 Hermanns N, Diabetologie und Stoffwechsel, 2008, 3 (Supplementum 1)3 Pen-injectors for medical use, EN ISO 11608-1:2000

In a random sample hospitalized diabetic patients delivered very precisely insulindoses using both Lantus SoloStar and Apidra SoloStar 2


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Pulmonary Approach


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Insulin delivered through the oralcavity can also be considered to haveits uptake in the pulmonary bed.However, the idea of pulmonarydelivery of insulin is not a new idea,

as the first report of inhaled insulinwas noted in 1925.

The high permeability of the lungslarge surface area makes it an idealroute for the administration of

insulin. The lung has hundreds ofmillions of alveoli that are richlyvascularised and where drugabsorption takes place

Exubera Inhale CorporationDry powder insulin inhaled

Inhaled Insulin


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The rationale:

We know that medicine can beabsorbed from the lung (e.g. AsthmaRx)

How big is the lung?

The pluses:

It works (insulin is absorbed)

Insulin is absorbed in similar fashion to

Humalog (Lyspro) Consistent & reproducible action of the

insulin

~ action to Humalog/Novo-rapid

Oralin - Generex Corp.oral mucus membraneinsulin application

Inhaled Insulin


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The negatives:

Dose is ten times greater than normal insulin dose (only 10 percent isabsorbed)

Where is the rest going (?swallowed, ?absorbed)

Buccal absorption is better

Still need an injection of basal insulin

Increased absorption if have upper respiratory tract infection orsmoker

Increased absorption if smoker

? Lung toxicity (2 of 4 studies showed impaired lung function)

2 patients found to have pulmonary fibrosis (by CT: ? Therealready)

How do we titrate the dose?

Intranasal Approach


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Delivery of insulin using an intranasal approach was first

suggested over 65 years ago, but it was not until the 1980s

that this approach was seriously evaluated. Feasibility has

been demonstrated, as intranasal insulin (60 or 120U)

given pre-meal to 17 patients with type 2 diabetes andcompared with placebo resulted in reductions in

postprandial glucose at both 60 and 120 minutes.

Jet Injectors


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This approach is appealing because of the lack ofneedles,but the discomfort associated with jetinjectors is not reported to be less than that observedwith injections.


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Low-Frequency Ultrasound


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It has been estimated that the permeability achieved by 1hour of sonophoresis performed three times daily may allowfor a typical daily dose of insulin (about 36U) to be deliveredtransdermally.

Transfersomes


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Transfersomes are lipid vesicles made of soybean ofdeformability, which makes them flexible enough to passthrough pores much smaller than themselves.

Gastrointestinal Delivery


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Insulin molecules lend to be too large and hydrophilic tocross the mucosa. Uptake of insulin via the

gastrointestinal tract is limited by an extremely low

bioavailability (i.e. 0.5%).

An additional limitation is the extensive enzymatic and

chemical degradation of insulin within the enzymatic

barrier of the gastrointestinal tract mucosa.

Buccal Delivery


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Oral insulin delivery that relies upon uptake by thebuccal mucosa and oropharynx appears to be feasiblefor more widespread clinical testing, as insulinappears to be rapidly absorbed into the systemiccirculation with this approach.

Buccal insulin, therefore, has also demonstrated proofof concept; unfortunately, the studies to datedemonstrating efficacy are presented as abstractsonly, and safety and adverse effect profiles for thisapproach have not been presented for large numbersof subjects.

Insulin therapy in type 2 Diabetes


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The emergence oftype 2 diabetes inchildhood and adolescence is alarming,especially as these patients progress to

chronic complications, potentially at a veryyoung age pausing a public healthproblem.

Proposed algorithm for the management of youthwith T2DM (Silva Arslanian, 2007).


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The recent advances indiabetes technologyincluding:

newer and more powerful oral agents

insulin analogs that provide a more physiological

delivery ofinsulin insulininfusion devices

accurate and less invasive methods of assessingglycemic control

[offer great promise that improved, if not ideal, glycemiccontrol and associated health-related benefits might beachieved, thus reducing or preventing the long-term

complications of diabetes (Kenneth etal.,2005)]


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insulin therapy in type 1 diabetes update

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