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.
- 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.
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
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
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
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
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
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
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
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
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.
Islet Cell Dysfunction and Abnormal Glucose Homeostasis in Type 2 Diabetes
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
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
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.
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)
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
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.
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
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.
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?
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.
The Development and Progression of Type 2 Diabetes
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.
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).
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
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.
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
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.
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.
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