Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal...

32

Transcript of Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal...

Page 1: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.
Page 2: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Inside the Islet

Exploring Issues in Type 2 Diabetes

Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis

Page 3: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Learning Objectives

After participating in this educational activity, you will be able to: Describe the role of islet cells ( and β) in maintaining normal

glucose homeostasis. Understand disturbances in β-cell function, glucagon secretion, and

hepatic glucose production in type 2 diabetes. Describe the progressive nature of β-cell dysfunction and its role in

the pathogenesis of type 2 diabetes.

Page 4: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

- and -Cells in the Pancreas of Normal Individuals

Produce glucagon1 Produce insulin and amylin3

Glucagon released in response to low blood glucose levels1

Insulin released in response to elevated blood glucose levels1

Comprise about 15% of the endocrine mass of the pancreas1

Comprise about 70%–80% of the endocrine mass of the pancreas1,2

Located in the periphery of the islet1

Located in the central portion of the islet1,2

-Cells-Cells

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.

Page 5: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

N=11.Adapted with permission from Woerle HJ et al. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.

Insulin Increases and Glucagon Falls in Response to Meals in Normal Subjects

Minutes After Meal Ingestion

–60 0 60 120 180 240 300 360

180

126

72

mg/

dL (

-

)

Glucose

400

200

0

pM (

-

)

Insulin105

75

45

ng/L ( - )

Glucagon

Page 6: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

The Normal β-Cell Insulin Response to Intravenous (IV) Glucose Is Biphasic

2nd phase

N=17 subjects. Hyperglycemic clamp technique was used.Adapted with permission from Pratley RE et al. Diabetologia. 2001;44:929–945. © Springer-Verlag, 2001.

0

100

200

300

400

500

0 20 40 60 80 100 120

Time, min

Pla

sma

Insu

lin

, p

mo

l/L 1st

phase

Page 7: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Relationship Between Insulin Sensitivity and Insulin Response in Apparently Healthy Subjects

Men

Women

2,000

1,500

1,000

500

00 5 10 15 20 25

95th

50th5th

AIRglucose=first-phase insulin response. Insulin response examined following intravenous administration of glucose.N=93 apparently healthy subjects aged <45 yrs.Adapted from Vidal J, Kahn SE. In: Genetics of Diabetes Mellitus. Kluwer Academic Publishers; 2001;109–131. Figure 2. With kind permission from Springer Science and Business Media.

AIR

glu

cose

, pM

Insulin Sensitivity Index, Si x 10–5 min–1/pM

Page 8: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Compensatory β-Cell Insulin Secretion With Increasing Insulin Resistance

95th50th5th

• In subjects without diabetes, insulin secretion is modulated by the prevailing degree of insulin sensitivity.

• For glucose tolerance to remain constant when insulin sensitivity varies, a proportionate and reciprocal alteration in insulin output has to occur.

AIRmax=measure of the β-cell secretory capacity. β-cell secretory capacity to nonglucose secretagogue arginine was used to characterize the relation between insulin release and glucose level.N=43 subjects with varying degrees of obesity, aged <45 years, fasting plasma glucose <115.2 mg/dL. Adapted from Kahn SE et al. Diabetes. 1993;42:1663–1672. Modified with permission from The American Diabetes Association. Copyright © 1993 American Diabetes Association.

0

1,000

2,000

3,000

4,000

5,000

0 5 10 15 20 25

AIR

max

, p

M

Men

Women

Insulin Sensitivity Index, Si x 10–5 min–1/pM

Page 9: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Net

Hep

atic

Glu

cose

Out

put,

µm

oL •

kg–1

• m

in–1

Hepatic Sinusoidal Insulin, pmol/L

Net

Hep

atic

Glu

cose

Out

put,

µ

moL

• k

g–1 •

min

–1

Hepatic Sinusoidal Glucagon,ng/L

Experiment carried out in overnight fasted conscious dogs.Adapted from Cherrington AD. Copyright © 1999 American Diabetes Association. From Diabetes, 1999;48:1198–1214. Reprinted with permission from The American Diabetes Association.

Insulin vs Net Hepatic Glucose Output

Glucagon vs Net Hepatic Glucose Output

Fixed basal glucagon level

0

20

40

60

0 240 480 720

0

20

40

60

0 200 400 600

Hepatic Glucose Production in Dogs Is Regulated by Insulin and Glucagon

Fixed basal insulin level

Page 10: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Insulin and Glucagon Regulate Normal Glucose Homeostasis

Glucose output Glucose uptake

Glucagon(α-cell)

Insulin(β-cell)

Pancreas

Liver Muscle

Porte D Jr et al. Clin Invest Med. 1995;18:247–254.Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Blood glucose

Page 11: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Role of Selected Organs in Normal Glucose Homeostasis

Glu

cag

on

Fat

Plasma Glucose

Pancreas

Liver

α β

Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Brain

Muscle

Insu

lin

Insulin-dependent glucose uptake

Insulin

Insulin-independent glucose uptake

Page 12: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Summary: Normal Glucose Homeostasis Involves Pancreatic Islet Cells in Normal Subjects

Insulin from β-cells

Blood glucose homeostasis

Ingestion of food

Pancreas

-cells -cells

Glucagon from α-cells

Glucose production by

liver

Glucose uptake by

adipose and muscle tissue

Release of gut hormones

GI tract

Glucose dependent

Glucose dependent

Page 13: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Summary of the Role of the Pancreatic Islet in Normal Glucose Homeostasis

Pancreatic α- and β-cells play several key roles in maintaining normal glucose homeostasis by regulating insulin and glucagon.1

The normal β-cell insulin response is biphasic, with a first (early) phase and a second (late) phase.2

In response to glucose loading, insulin levels increase and glucagon levels fall to maintain normal glucose homeostasis.3

To maintain normal glucose homeostasis, any change in insulin sensitivity is balanced by a reciprocal and proportionate change in β-cell function.4

1. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.2. Pratley RE, Weyer C. Diabetologia. 2001;44:929–945. 3. Woerle HJ et al. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.4. Kahn SE et al. Diabetes. 1993;42:1663–1672.

Page 14: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 Diabetes

Page 15: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Glucose output Glucose uptake

Glucagon(α-cell)

Insulin(β-cell)

Pancreas

Liver

Hyperglycemia

Muscle

Islet cell dysfunction

1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

The Pathophysiology of Type 2 Diabetes Includes Islet Cell Dysfunction and Insulin Resistance1,2

*

* Reduced effect of insulin indicating insulin resistance

Page 16: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

First-Phase Insulin Response to IV Glucose Is Lost in Type 2 Diabetes

Normal Type 2 Diabetes

n=9 normal; n=9 type 2 diabetes.Adapted from Pfeifer MA et al. Am J Med. 1981;70:579–588. With permission from Excerpta Medica, Inc.

0

20

40

60

80

100

120

–30 0 30 60 90 120

Time, min

0

20

40

60

80

100

120

–30 0 30 60 90 120

Time, min

Pla

sma

Insu

lin

, µ

U/m

L

Pla

sma

Insu

lin

, µ

U/m

L

Page 17: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Some Abnormalities of β-Cell Function in Type 2 Diabetes

Disrupted pulsatile insulin response1

proinsulin/insulin ratio1

β-cell responsiveness to

glucose 2,3

insulin production4

– insulin

– insulin granules

β-Cell dysfunction

1. Buchanan TA. Clin Ther. 2003;25(suppl B):B32–B46.2. Buse JB et al. In: Larsen PR et al. Williams Textbook of Endocrinology. 10th ed. Saunders; 2003;1427–1483.3. Ward WK et al. J Clin Invest. 1984;74:1318–1328. 4. Marchetti P et al. J Clin Endocrinol Metab. 2004;89:5535–5541.

Page 18: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Patients With Type 2 Diabetes Have Decreased β-Cell Responsiveness to Glucose

n=11 control; n=11 type 2 diabetes.ISR=insulin secretory rate; BMI=body mass index.Adapted with permission from Byrne MM et al. Am J Physiol Endocrinol Metab. 1996;270:E572–E579.

Type 2 diabetes

Control

0

5

10

15

20

25

30

50 100 150 200 250 300

Glucose, mg/dL

ISR

/BM

I,p

mo

l x

m2 /

(min

x k

g)

Page 19: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

N=277 Pima Indians; NGT=normal glucose tolerance; IGT=impaired glucose tolerance; T2DM=type 2 diabetes;EMBS=estimated metabolic body size.Changes in β-cell function, measured as acute insulin response to glucose (AIRglucose) relative to changes in insulin sensitivity, measured by clamp technique at a low insulin concentration (M-low).Adapted with permission from Weyer C et al. J Clin Invest. 1999;104;787–794.

AIR

glu

cose

, μU

/mL

M-Low, mg/kg EMBS/min

0

100

200

300

400

500

0 1 2 3 4 5

T2DM

IGT

NGT

NGTNGT

NGT

Nonprogressors

Progressors

The Relationship Between Insulin Secretion and Insulin Action During the Development of Type 2 Diabetes

Page 20: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes

–60 0 60 120 180 240

360

330

300

270

240

110

80

140

130

120

110

100

90

120

90

60

30

0

Glucose, mg %

Insulin, μ/mL

Glucagon, μμ/mL

Meal

(minutes)

Type 2 diabetes

Normal patients

n=12 normal; n=12 type 2 diabetes.

Adapted with permission in 2005 from Müller WA et al. N Engl J Med. 1970;283:109–115.

Copyright © 1970 Massachusetts Medical Society. All rights reserved.

Page 21: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

P<0.001

Fasting

Fasting and Postprandial Glucagon Levels Are Elevated in Patients With Impaired Glucose Intolerance and Type 2 Diabetes

P<0.001

Postprandial

NGT=normal glucose tolerance, n=33; IGT=impaired glucose tolerance, n=15; T2DM=type 2 diabetes mellitus, n=54.Toft-Nielson M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.

Fa

sti

ng

Pla

sm

a G

luc

ag

on

, p

mo

l/L

Po

stp

ran

dia

l G

luc

ag

on

at

24

0 m

in,

pm

ol/

L

Page 22: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Lack of Suppression of Glucagon Causes Postprandial Hyperglycemia in Type 2 Diabetes

*

72

108

144

180

216

–60 0 60 120 180 240 300 360

Time, min

Glu

cose

, m

g/d

L

Nonsuppressed glucagon

Suppressed glucagon

*P<0.001. N=9 (7 men, 2 women).Reprinted with permission from Shah P et al. J Clin Endocrinol Metab. 2000;85:4053–4059. Copyright © 2000, The Endocrine Society.

Page 23: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

The abnormalities in β-cell function typically include:

A. Decreased insulin production and increased proinsulin/insulin ratio

B. Abnormal pulsatile insulin response

C. Decreased β-cell responsiveness to glucose

D. All of the above

What Are the Abnormalities in β-Cell Function Seen in Type 2 Diabetes?

Page 24: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Summary of Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 Diabetes

Islet cell dysfunction and insulin resistance play important roles in the pathophysiology of type 2 diabetes.1

In type 2 diabetes:– First-phase insulin response by β-cells is lost.2

– There is abnormal β-cell function and decreased β-cell responsiveness to glucose.3

– Endogenous glucose production is elevated.4

– Fasting and postprandial glucagon secretion are elevated.4,5

1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.2. Ward WK et al. Diabetes Care. 1984;7:491–502. 3. Kahn SE. Diabetologia. 2003;46:3–19.4. Basu A et al. J Invest Med. 2004;52:366–374.5. Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.

Page 25: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

The Development and Progression of Type 2 Diabetes

Page 26: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Patients at High Risk of Type 2 Diabetes Have Inadequate β-Cell Compensation for Degree of Insulin Resistance

0

100

200

300

400

500

600

700

0 1 2 3 4 5 6 7

Type 2 diabetes

Older subjects

IGT

AIR

glu

cose

, pm

ol/L

Insulin Sensitivity Index, Si x 10–5 min–1/pmol/L

75th

50th

25th

5th

Relatives of type 2

diabetes

IGT=Impaired glucose tolerance, n=21; type 2 diabetes, n=10; older subjects, n=13; relatives, n=14.Percentile lines based on data from 93 healthy subjects.AIRglucose=first-phase insulin response.Adapted from Vidal J, Kahn SE. In: Genetics of Diabetes Mellitus. Kluwer Academic Publishers; 2001;109–131. Figure 3. With kind permission from Springer Science and Business Media.

Page 27: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Inadequate Insulin Secretion and Insulin Action Occur Early in the Development of Type 2 Diabetes

AIRglucose=acute insulin response; M-high=maximally insulin-stimulated glucose disposal.*P<0.05; **P<0.01. Adapted with permission from Weyer C et al. J Clin Invest. 1999;104:787–794.

0

50

250

NGT

AIR

glu

cose

, µ/m

L

150

100

200

IGT T2DM

Overall Time EffectP<0.0001

NGTM

-Hig

h,

mg

/kg

EM

BS

/min

IGT T2DM

300

0

2

10

6

4

8

12

Overall Time EffectP<0.0001

*

**

**

**

Longitudinal study over 5.1 ± 1.4 years; N=17 Pima Indians in whom glucose tolerance deteriorated from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes (T2DM).

Page 28: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

0

0

40

60

80

HO

MA

% B

20

2 4 6

Years From Diagnosis

0

0

40

60

HO

MA

% S

20

2 4 6

β-Cell Function Insulin Sensitivity

HOMA=Homeostasis Model Assessment; HOMA % B=β-cell function; HOMA % S=Insulin sensitivity.N=432. 10-year follow-up of the Belfast Diet Study. Data from Group 2 shown: newly diagnosed T2DM subjects who required additional treatment (due to secondary failure to diet therapy) at 5–7 years. Reproduced with permission from Levy J et al. Diabet Med. 1998;15:290–296. © 1998 Blackwell Publishing.

-Cell Function Declines After Diagnosis, Whereas Insulin Sensitivity Remains Relatively Stable

Years From Diagnosis

Page 29: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Years

A1C

, %

Diet/conv Rx (n=297)Metformin (n=251)SU/intensive (n=695)

Years

Progressive Impairment of -Cell Function and Deterioration of Glycemic Control in Type 2 Diabetes

-Cell Function Declines Over Time

-C

ell f

un

ctio

n, %

β

Diet/conv Rx (n=376)Metformin (n=159)SU/intensive (n=511)

0 1 2 3 4 5

100

75

50

25

06

A1C Increases Over Time

0 1 2 3 4 5

10

9

8

7

6

5

6

Diet/conv Rx=conventional therapy (diet alone); UKPDS=United Kingdom Prospective Diabetes Study; SU/intensive=sulfonylurea or insulin.N=4,209 newly diagnosed patients with type 2 diabetes.Reprinted from UK Prospective Diabetes Study Group 16. Copyright © 1995 American Diabetes Association. From Diabetes. 1995;44:1249–1258. Reprinted with permission from The American Diabetes Association.

Page 30: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

What Are Some Determinants of -Cell Mass?

Some determinants of -cell mass include:

A. Cell proliferation rate

B. Rate of cell death (apoptosis)

C. Regeneration of β-cells (neogenesis)

D. All

Page 31: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Some β-Cell Abnormalities in Type 2 Diabetes

-cell mass1,2

-cell apoptosis1

Impaired β-cell proliferation2,3

Impaired β-cell neogenesis2,3

β-Cell abnormalities

1. Butler AE et al. Diabetes. 2003;52:102–110.2. Donath MY, Halban PA. Diabetologia. 2004;47:581–589.3. Rhodes CJ. Science. 2005;307:380–384.

Page 32: Inside the Islet Exploring Issues in Type 2 Diabetes Role of Pancreatic Islets in Maintaining Normal Glucose Homeostasis.

Inside the Islet: Exploring Issues in Type 2 Diabetes

In summary: The pathophysiology of type 2 diabetes includes islet cell dysfunction,

insulin resistance, and increased hepatic glucose output.1–3

Elevated hepatic glucose production in type 2 diabetes results from the combination of excess glucagon and diminished insulin.1

Early and progressive β-cell dysfunction is integral to the development of type 2 diabetes and to the deterioration of glucose control over time.1

1. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.2. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.3. Del Prato S, Marchetti P. Diabetes Technol Ther. 2004;6:719–731.

© 2006 Merck & Co., Inc. All rights reserved. 20551162(1)-01/06-JAN.