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Type 1 and Type 2 Diabetes

Disease Overview

▪ David Escalante M.D.,

Endocrinology Diabetes and

Metabolism

▪ Assistant Professor of

Medicine, University of

Kentucky

▪ Private Practitioner at

Appalachia Health Service

Jellico, Tennessee

2

3

b- and a-Cells in the Pancreas of Normal Individuals

b-Cells a-Cells

▪ Comprise about 70%–80% of

the endocrine mass of the

pancreas1,2

▪ Comprise about 15% of the

endocrine mass of the

pancreas1

▪ Located in the central portion

of the islet1,2

▪ Located in the periphery

of the islet1

▪ Produce insulin and amylin3▪ Produce glucagon1

▪ Insulin released in response to

elevated blood glucose levels1

▪ Glucagon released in response

to low blood glucose levels1

1. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21–39.

2. Rhodes CJ. Science. 2005;307:380–384.

3. Kahn SE et al. Diabetes. 1998;47:640–645.

Pathophysiology

of Type 1 Diabetes

4

Type 1 Diabetes Mellitus

• Characterized by absolute insulin deficiency

• Pathophysiology and etiology

– Result of pancreatic beta cell destruction

• Prone to ketosis

– Total deficit of circulating insulin

– Autoimmune

– Idiopathic

5

Type of Diabetes in Youth by

Race/Ethnicity and Etiology

6AA, African American; AI, American Indian; API, Asian/Pacific Islander; IR, insulin resistant; IS, insulin sensitive; NHW, non-Hispanic white.

Dabelea D, et al. Diabetes Care. 2011;34:1628-1633.

62.9

43.732.5 33.3

16.1

54.5

19.8

21.3

18 15.1

12.9

19.5

11.1

6.6

9.4 10.8

3.2

10.1

6.2

28.340.1 40.8

67.8

15.9

0%

20%

40%

60%

80%

100%

NHW Hispanic AA API AI Total

Non-autoimmune + IR

Non-autoimmune + IS

Autoimmune + IR

Autoimmune + IS

SEARCH for Diabetes in Youth Study

(N=2291)

Dis

trib

uti

on

of

eti

olo

gic

ca

teg

ori

es

by

ra

ce

/eth

nic

ity

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Type 1 Diabetes Pathophysiology

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Inflammation

T cell

TNF-a IFN-g

FasL

Autoimmune Reaction

Macrophage

b-cell

CD8+ T cell

TNF-a

IL-1

NO

Class IMHC

Dendritic cell

b-cell Destruction

Class IIMHC

CD8, cluster of differentiation 8; FasL, Fas ligand; IFN-g, interferon g; IL-1, interleukin 1; MHC,

major histocompatibility complex; NO, nitric oxide; TNF-a, tumor necrosis factor a.

Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.

• b-cell destruction

– Usually leading to

absolute insulin

deficiency

• Immune mediated

• Idiopathic

Pathophysiologic Features of

Type 1 Diabetes

• Chronic autoimmune disorder– Occurs in genetically susceptible individuals

– May be precipitated by environmental factors

• Autoimmune response against– Altered pancreatic b-cell antigens

– Molecules in b-cells that resemble a viral protein

• Antibodies– Approximately 85% of patients: circulating islet cell

antibodies

– Majority: detectable anti-insulin antibodies

– Most islet cell antibodies directed against GAD within pancreatic b-cells

8GAD, glutamic acid decarboxylase.

Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.

Major Metabolic Effects of Insulin and

Consequences of Insulin Deficiency

Insulin effects: inhibits breakdown of triglycerides (lipolysis) in adipose tissue

• Consequences of insulin deficiency: elevated FFA levels

Insulin effects: inhibits ketogenesis

• Consequences of insulin deficiency: ketoacidosis, production of ketone bodies

Insulin effects in muscle: stimulates amino acid uptake and protein synthesis, inhibits protein degradation, regulates gene transcription

• Consequences of insulin deficiency: muscle wasting

16 17

Clinical Presentation of

Type 2 Diabetes

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• Age ≥45 years

• Family history of T2D or

cardiovascular disease

• Overweight or obese

• Sedentary lifestyle

• Non-Caucasian ancestry

• Previously identified IGT, IFG,

and/or metabolic syndrome

• PCOS, acanthosis nigricans, or

NAFLD

• Hypertension (BP >140/90 mmHg)

• Dyslipidemia (HDL-C <35 mg/dL

and/or triglycerides >250 mg/dL)

• History of gestational diabetes

• Delivery of baby weighing

>4 kg (>9 lb)

• Antipsychotic therapy for

schizophrenia or severe bipolar

disease

• Chronic glucocorticoid exposure

• Sleep disorders

– Obstructive sleep apnea

– Chronic sleep deprivation

– Night shift work

Risk Factors for Prediabetes and

Type 2 Diabetes

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BP, blood pressure; HCL-C, high density lipoprotein cholesterol; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NAFLD,

nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes.

Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

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Development of Type 2 Diabetes

Depends on Interplay Between Insulin

Resistance and β-Cell Dysfunction

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Insulin resistance

Insulin resistance

Abnormalβ-Cell

Function

Relative insulin

deficiency

Gerich JE. Mayo Clin Proc. 2003;78:447-456.

Type 2 diabetes

Normalβ-Cell

Function

Compensatory hyperinsulinemia

No diabetes

Genes &

environment

Genes &

environment

Etiology of β-cell Dysfunction

21Poitout V, Robertson RP. Endocrine Rev. 2008;29:351-366.

Genetic predisposition

Lean phenotype Obese phenotype

IGT, IFG Elevated FFA

Oxidative stress and glucotoxicity

Cellular lipid synthesis and glucolipotoxicity

Progressive b-cell failure and type 2 diabetes

Initial glucolipoadaptation (increased FFA usage)

Hyperglycemia

Glucolipotoxicity and glucotoxicity

EMBS, estimated metabolic body size; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.

Weyer C et al. J Clin Invest. 1999;104:787-794.

Progression to Type 2 Diabetes:

“Falling Off the Curve”

22

0

100

200

300

400

500

0 1 2 3 4 5

Glucose disposal (insulin sensitivity)

(mg/kg EMBS/min)

DIA

IGT

NGT

Progressors

NGT

NGTNGT

Nonprogressors

Pathophysiology of

Type 2 Diabetes

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Organ System Defect

Major Role

Pancreatic beta cells Decreased insulin secretion

Muscle Inefficient glucose uptake

LiverIncreased endogenous glucose

secretion

Contributing Role

Adipose tissue Increased FFA production

Digestive tract Decreased incretin effect

Pancreatic alpha cells Increased glucagon secretion

Kidney Increased glucose reabsorption

Nervous system Neurotransmitter dysfunction

DeFronzo RA. Diabetes. 2009;58:773-795

Tissues Involved in T2D

Pathophysiology

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Organ System Normal Metabolic Function Defect in T2D

Major Role

Pancreatic beta cells Secrete insulin Decreased insulin secretion

Muscle Metabolizes glucose for energy Inefficient glucose uptake

Liver

Secretes glucose during fasting periods to maintain brain

function; main site of gluconeogenesis (glucose production

in the body)

Increased endogenous glucose

secretion

Contributing Role

Adipose tissue (fat)

Stores small amounts of glucose for its own use. When fat

is broken down, glycerol is released, which is used by the

liver to produce glucose

Increased FFA production

Digestive tractDigests and absorbs carbohydrates and secretes incretin

hormonesDecreased incretin effect

Pancreatic alpha cells

Secrete glucagon, which stimulates hepatic glucose

production between meals and also helps suppress insulin

secretion during fasting periods

Increased glucagon secretion

Kidney

Reabsorbs glucose from renal filtrate to maintain glucose

at steady-state levels; also an important site for

gluconeogenesis (glucose production)

Increased glucose reabsorption

BrainUtilizes glucose for brain and nerve function

Regulates appetiteNeurotransmitter dysfunction

T2D, type 2 diabetes.

DeFronzo RA. Diabetes. 2009;58:773-795

Natural History of Type 2

Diabetes

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Figure courtesy of CADRE.

Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349;

UKPDS Group. Diabetes. 1995;44:1249-1258

Fasting glucose

Type 2 diabetes

Years from

diagnosis0 5–10 –5 10 15

Prediabetes

Onset Diagnosis

Postprandial glucose

Macrovascular complications

Microvascular complications

Insulin resistance

Insulin secretion

b-Cell function

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Dashed line = extrapolation based on Homeostasis Model Assessment (HOMA) data.

Data points from obese UKPDS population, determined by HOMA model.

Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.

b-cell Loss Over Time

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UKPDS

Type 2 Diabetes

b-C

ell

Fu

nc

tio

n (

%)

Years from Diagnosis

25 –

100 –

75 –

0 –

50 –

l

-12

l

-10

l

-6l

-2

l

0

l

2

l

6

l

10

l

14

PostprandialHyperglycemia

Impaired Glucose

Tolerance

Müller WA, et al. N Engl J Med. 1970;283:109-115.

Normal Glucose Homeostasis and Pre- and

Postmeal Insulin and Glucagon Dynamics

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Premeal Postmeal

Insulin Insulin

Glucagon

HGP

Glucagon

HGP

Just enough glucose to meet metabolic needs between meals

Modest postprandial increase with

prompt return to fasting levels

Glucose (mg %)

Glucagon (pg/mL)

Time (min)

-60 0 60 120 180 240

Meal120

90

60

30

0

140

130

120

110

100

90

Insulin (µU/mL)

360

330

300

270

240

110

80

Normal (n=11)

Hyperglycemia in Type 2 Diabetes Results from

Abnormal Insulin and Glucagon Dynamics

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Premeal Postmeal

Insulin Insulin

Glucagon

HGP

Glucagon

HGP

FPG PPGGlucose (mg %)

Insulin (µU/mL)

Glucagon (pg/mL)

Time (min)

-60 0 60 120 180 240

Meal120

90

60

30

0

140

130

120

110

100

90

360

330

300

270

T2D (n=12)

Normal (n=11)

240

110

80

T2D, type 2 diabetes.

Müller WA, et al. N Engl J Med. 1970;283:109-115.

Acute Insulin Response Is

Reduced in Type 2 Diabetes

29IRI, immunoreactive insulin.

Pfeifer MA, et al. Am J Med. 1981;70:579-588.

Pla

sm

a IR

I

(µU

/ml)

Time (minutes)

20 g glucose infusion

2nd phase1st

-300

20

40

60

80

100

0 30 60 90 120

120Normal (n=85)

Type 2 diabetes (n=160)

Defective Insulin Action

in Type 2 Diabetes

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Le

g G

luc

os

e U

pta

ke

(mg

/kg

le

g w

t p

er

min

)

Time (minutes)

0

P<0.01

12

1801401006020

8

4

0

To

tal

Bo

dy

Glu

co

se

Up

tak

e

(mg

/kg

• m

in)

T2DNormal

0

7

6

5

4

3

2

1

T2D, type 2 diabetes.

DeFronzo RA. Diabetes. 2009;58:773-795; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.

FPG, fasting plasma glucose; HGP, hepatic glucose production; T2D, type 2 diabetes.

DeFronzo RA, et al. Metabolism. 1989;38:387-395.

Elevated Fasting Glucose in

Type 2 Diabetes Results From

Increased HGP

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Ba

sa

l H

GP

(mg

/kg

• m

in)

FPG (mg/dL)

2.0

2.5

3.0

3.5

4.0

100 200 300

r=0.85

P<0.001

Control

T2D

0

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*P≤.05.

Nauck M, et al. Diabetologia. 1986;29:46-52.

The Incretin Effect Is Diminished

in Type 2 Diabetes

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Normal Glucose Tolerance

(n=8)

Type 2 Diabetes

(n=14)IV Glucose

Oral Glucose

0 60 120 180

240

Pla

sm

a G

luco

se (

mg

/dL

)

180

90

0

0 60 120 180

Pla

sm

a G

luco

se (

mg

/dL

) 240

180

90

0

**

* **

* * *

0 60 120 180

C-P

ep

tid

e (

nm

ol/L

)

Time (min)

30

20

10

00 60 120 180

C-p

ep

tid

e (

nm

ol/L

)

Time (min)

30

20

10

0

Actions of GLP-1 and GIP

GLP-1

• Released from L cells in ileum and colon

• Stimulates insulin release from b-cell in a glucose-dependent manner

• Potent inhibition of gastric emptying

• Potent inhibition of glucagon secretion

• Reduction of food intake and body weight

• Significant effects on b-cell growth and survival

GIP

• Released from K cells in duodenum

• Stimulates insulin release from b-cell in a glucose dependent manner

• Minimal effects on gastric emptying

• No significant inhibition of glucagon secretion

• No significant effects on satiety or body weight

• Potential effects on b-cell growth and survival

33Drucker DJ. Diabetes Care 2003;26:2929-2940.

Renal Glucose Reabsorption

in Type 2 Diabetes

• Sodium-glucose cotransporters 1 and 2

(SGLT1 and SGLT2) reabsorb glucose in the

proximal tubule of kidney

– Ensures glucose availability during fasting periods

• Renal glucose reabsorption is increased in

type 2 diabetes

– Contributes to fasting and postprandial

hyperglycemia

– Hyperglycemia leads to increased SGLT2 levels,

which raises the blood glucose threshold for

urinary glucose excretion34

Wright EM, et al. J Intern Med. 2007;261:32-43.

90% of glucose

SGLT1

(180 L/day) (90 mg/dL) = 162 g glucose per day

10% of glucose

Glucose

No Glucose

S1

S3

Normal Renal Handling of

Glucose

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SGLT2

Abdul-Ghani MA, et al. Endocr Pract. 2008;14:782-790.

Increased SGLT2 Protein Levels

Change Glucose Reabsorption

and Excretion Thresholds

36TmG, glucose transport maximum.

Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790.

27090

Re

na

l G

luc

os

e R

ea

bs

orp

tio

n

TmG

180

TmG

Blood Glucose Concentration

(mg/dL)

Reabsorption

increases

27090 180

Blood Glucose Concentration

(mg/dL)

Excretion

threshold

increases

Re

na

l G

luc

os

e E

xc

reti

on

Reabsorption Excretion

Hypothalamic Dopaminergic

Tone and Autonomic Imbalance

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In diabetes:

Low dopaminergic tone in

hypothalamus in early

morning

Sympathetic tone

HPA axis tone

Hepatic gluconeogenesis

FFA and TG

Insulin resistance

Inflammation/hypercoagulation

Impaired glucose metabolism

Hyperglycemia

Insulin resistance

Adverse cardiovascular pathology

37Fonseca V. Dopamine Agonists in Type 2 Diabetes. New York, NY: Oxford University Press; 2010.

Cincotta AH. In: Hansen B, Shafrir E, eds. Insulin Resistance and Insulin Resistance Syndrome. New York, NY: Taylor

& Francis; 2002:271-312.

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ADDICTION

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DSM-5

Changes to DSM in new edition: no longer dichotomy between abuse and dependence

Addiction now the preferred term instead of dependence.

Addiction now seen as a continuum.

Substance use disorder requires 2 of following:

tolerance inability to stop

withdrawal problems excessive spending or effort

use more than intended to obtain

reduced involvement continued use

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What is addiction?

• heroin addiction

• cocaine addiction

• alcohol addiction (“alcoholism”)

• marijuana addiction

• amphetamine addiction

• nicotine addiction

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What is addiction?

• sex addiction??

• gambling addiction??

• food addiction??

• shopping addiction????

• internet addiction????

• cell phone addiction????

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Why do some people

become addicted while

others do not?

Vulnerability

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True or False

Prescription medications are the most abuse substances in

the United States?

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44

True or False

It is safer to abuse prescription medications than street

drugs?

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True or False

Most people who abuse prescription drugs get them from a drug

dealer?

46

Where do People Obtain Prescription Drugs?

70% of people who abuse

prescription medicine get them from

a FRIEND or RELATIVE47

DA Neurotransmiter

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DA Pathway

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DOPAMINE RECEPTOR

1) Decreased in DM2

2) Control Food Intake

3) Energy Expenditure

4) Glucose Metabolism

5) Increase Resistance

6) Control Insulin Secretion (acute +, chronic -)

7) Insulin and DA ReUptake (acute +, chronic -)

8) Increase Liver Production Glucose

9) Lipid Metabolism Increase Lipolysis, FFA

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Dopamine Related

1) Schizophrenia/ Depression

2) Restless Leg Syndrome

3) ADHD

4) Prolactinoma

5) Nausea, Vomiting

6) Parkinson and other Movement disorders

7) Obesity?

8) Metabolic Syndrome?

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Pharmacologic Use

1) Movement Disorders

2) Prolactinomas

3) Nausea, Vomiting

4) Motility Disorders

5) Mood Disorders

6) Psychotic Disorders

7) ADHD

8) Pain

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ALCOHOL

1) Increase in CARB intake

2) Increased Hypoglycemia

3) Decrease hypoglycemia awareness

4) Confusion over hypoglycemia

5) Chronic use increase nerve damage

6) Blurry vision Vasodilation of eye vessels

7) Decrease activity of secretague

8) Dyslipidemia

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SMOKING

1) Increase Vascular Disease

2) Increase Cancer

3) Decrease Control

4) Increase Renal Disease

5) Increase Neuropathic Pain

6) Increased Amputations

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STIMULANTS

1) Hyperglycemia

2) Hypoglycemia

3) Weight Loss

4) Insulin Resistance

5) Increase MI and CVA

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Benzodiazepine

1) Insulin Resistance

2) Increase Sedentary Life

3) Increase Metabolic Syndrome

4) Weight Gain

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Narcotics

1) Increase Insulin Resistance

2) Decrease Insulin Secretion

3) Change in appetite

4) Memory Change

5) Mood change

6) Weight Change

7) Bowel Habit Change

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CANABIS

1) Decrease in Glucose in Intoxication

2) Increase in Fat Deposition

3) Increase Appetite

4) Short Term Memory Loss with Decrease compliance

5) Decrease coordination

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ANTIPSYCHOTICS

1) Increase Insulin Resistance

2) Decrease Insulin secretion

3) Increase Weight Mainly Central

4) Dyslipidemia

5) Increase Prolactin

6) Increase DM

7) Cardiovascular Disease

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ACTION POINTS

1) Avoid Dopamine Altering Medication

2) Aggressive Life Intervention to Minimize Effects

3) Pharmacologic Therapy

4) Seek Professional and Spiritual Help

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▪ OPEN DISCUSION