Type 2 Diabetes: Pathophysiology
and Opportunities for Treatment
Tyler Aguinaldo, MD
Director, Center for Diabetes & Metabolism
Santa Clara Valley Medical Center
April 16, 2009
Objectives
• Review epidemiology of diabetes and pre-diabetes.
• Distinguish diabetes type 1 and type 2
• Describe the role of pancreatic islet cells ( and β) in
•
•
maintaining normal glucose homeostasis.
Understand disturbances in insulin resistance, β-cell
function, glucagon secretion, hepatic glucose
production and incretin hormones in type 2 diabetes.
Summarize treatment options in type 2 diabetes.
Number (in Millions) and Percent of
Civilian/Noninstitutionalized Persons with
Diagnosed Diabetes, U.S., 1980–2006
http://www.cdc.gov/diabetes/statistics/prev/national/fi
gpersons.htm
National Diabetes Statistics, 2007
Prevalence of Diagnosed and Undiagnosed Diabetes in the
United States, All Ages, 2007:
Total: 23.6 million people — 7.8 percent
— have diabetes.
Diagnosed: 17.9 million people
Undiagnosed: 5.7 million people
of the population
Prevalence of Impaired Fasting Glucose in People Aged 20
Years or Older, United States, 2007
In 2003 to 2006, 25.9
percent of U.S. adults aged 20
years or older had IFG —35.4 percent of adults aged 60 years
or older, yields an estimated 57 million American adults aged 20
years or older with IFG
http://diabetes.niddk.nih.gov/dm/pubs/statistics/#allages
4
5
The global diabetes epidemic 2000―2010
and beyond: prevalence of diabetes
14.2
17.5
+23%
26.5
84.5
32.9
132.3
+24%
+57%
URGENT NEED FOR ACTION
9.4
15.6
14.1
22.5
+50%
1.0
+44%
Wild S, et al. Diabetes Care 2004;27:1047―53.
Adapted from Zimmet P, et al. Nature 2001;414:782―7.
1.3
2000:
2010:
2025:
2030:
151
220
300
366
million
million + ~50%
million + ~100%
million + ~145%
+33%
NHANES: Glycemic Control in the U.S.
20.8M
Patients
12.6M Treated With
Oral Agents or Insulin
6.2M
Undiagnosed
2M D&E
Yet Average A1C
Is Increasing
7.9
62%
A1C >7%
12.6M
Rx Treated
38%
NHANES
1999–2000
A1C <7%
AACE A1C Goal = 6.5%
ADA A1C Goal = <7%
CDC 2005, NHANES 1999–2002
7.7
NHANES
1988–1994
Criteria for the Diagnosis of Diabetes
Two Main Classes of Diabetes Mellitus
• Type 1 Diabetes:
– Insulin deficiency (usually auto-immune)
– Accounts for 5-10% of total diabetes
• Type 2 Diabetes:
– Multi-factorial:
• Insulin resistance
• Relative insulin deficiency
• Dysregulation of glucagon
• Abnormalities in incretin hormones
– Accounts for 90-95% of total diabetes
– Associated with “Metabolic Syndrome”
Type 1 DM
• Younger
• More lean
• Insulin-deficient
• Low triglycerides
Type 2 DM
• Older
• Overweight
• Insulin-resistant
• High TG’s/Low HDL-C
11
b- and -Cells in the Pancreas of Normal Individuals
b-Cells
-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.
12
Insulin Increases and Glucagon Falls in Response to
Meals in Normal Subjects
mg/dL ( - )
180
Glucose
126
72
400
105
Glucagon
200
75
0
45
–60
0
60
120
180
240
300
ng/L ( - )
pM ( - )
Insulin
360
Minutes After Meal Ingestion
N=11.
Adapted with permission from Woerle HJ et al. Am J Physiol Endocrinol Metab. 2003;284:E716–E725.
13
Insulin and Glucagon Regulate Normal
Glucose Homeostasis
Fasting state
Glucagon
(alpha cell)
Fed state
Pancreas
Insulin
(beta cell)
Glucose uptake
Glucose output
 Blood glucose

Liver
Muscle
Adipose
tissue
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams
& Wilkins; 2005:145–168.
14
The Normal β-Cell Insulin Response to
Intravenous (IV) Glucose Is Biphasic
Plasma Insulin, pmol/L
500
400
2nd
phase
1st
phase
300
200
100
0
0
20
40
60
80
100
120
Time, min
N=17 subjects. Hyperglycemic clamp technique was used.
Adapted with permission from Pratley RE et al. Diabetologia. 2001;44:929–945. © Springer-Verlag, 2001.
15
Relationship Between Insulin Sensitivity and Insulin
Response in Apparently Healthy Subjects
AIRglucose, pM
2,000
Men
Women
1,500
1,000
500
95th
50th
5th
0
0
5
10
15
20
25
Insulin Sensitivity Index, Si x 10–5 min–1/pM
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.
16
Islet Cell Dysfunction and Abnormal Glucose
Homeostasis in Type 2 Diabetes
17
The Pathophysiology of Type 2 Diabetes Includes Islet
Cell Dysfunction and Insulin Resistance1,2
Islet cell dysfunction
Glucagon
(α-cell)
* Reduced effect of insulin
indicating insulin resistance
Pancreas
Insulin
(β-cell)
Glucose output
*
Glucose uptake
Hyperglycemia
Liver
Muscle
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.
18
•Insulin resistance: A state in which a given
concentration of insulin is associated with a
subnormal glucose response (1)
•Syndrome X, Insulin Resistance Syndrome:
Insulin resistance and compensatory
hyperinsulinemia associated with glucose
intolerance, hypertension, dyslipidemia, CVD.
1-Moller DE & Flier JS, N Engl J Med 1991 Sep 26;325(13):938-48.
2- Reaven G, Banting Lecture 1988
19
20
Natural History of DM 2
Years from -10
diagnosis
-5
Onset
0
5
10
15
Diagnosis
Insulin resistance
Insulin secretion
Postprandial glucose
Fasting glucose
Microvascular complications
Macrovascular complications
Pre-diabetes
Type 2 diabetes
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789;
Nathan DM. N Engl J Med. 2002;347:1342-1349
21
First-Phase Insulin Response to IV Glucose Is Lost in
Type 2 Diabetes
100
120
Plasma Insulin, µU/mL
Plasma Insulin, µU/mL
120
Normal
80
60
40
20
Type 2 Diabetes
100
80
60
40
20
0
0
–30 0
30 60 90 120
Time, min
–30 0
30 60 90 120
Time, min
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.
22
Inadequate Insulin Secretion and Insulin Action Occur
Prior to the Development of Type 2 Diabetes
Overall Time Effect
P<0.0001
300
12
250
10
M-High,
mg/kg EMBS/min
AIRglucose, µ/mL
Overall Time Effect
P<0.0001
*
200
**
150
100
50
0
**
**
8
6
4
2
0
NGT
IGT
T2DM
NGT
IGT
T2DM
 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).
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.
23
The Relationship Between Insulin Secretion and Insulin
Action During the Development of Type 2 Diabetes
500
AIRglucose, μU/mL
400
Nonprogressors
300
NGT
NGT
NGT
NGT
200
IGT
Progressors
100
T2DM
0
0
1
2
3
4
5
M-Low, mg/kg EMBS/min
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.
24
Insulin and Glucagon Dynamics in Response to Meals
Are Abnormal in Type 2 Diabetes
360
Glucose,
mg %
Meal
330
300
270
Type 2 diabetes
240
Normal patients
110
80
120
Insulin,
μ/mL
90
60
30
0
140
130
Glucagon,
μμ/mL
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.
120
110
100
90
–60
0
60
120
180
240
(minutes)
25
Pathophysiology of 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.
26
Treatment Options in Type 2 Diabetes
1. Why treat diabetes?
2. Therapeutic Lifestyle Changes
3. Oral medications
4. Insulin
5. Newer agents (incretins)
6. Gastric Bypass
27
Higher Blood Sugar
Causes More Complications
15
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
Relative Risk
13
11
9
7
5
3
1
6
7
8
9
HbA1c (%)
Endocrinol Metab Clin North Am. 1996;25:243-254.
10
11
12
Intensive Therapy Group
Various Endpoints in the UKPDS
Complication
Reduction in Risk
All microvascular
– Retinopathy progression
– Microalbuminuria
25%
21%
33%
P<0.01
P<0.02
P<0.0001
Myocardial infarction
16%
P=0.052
All diabetes-related
endpoints studied
12%
P<0.03
UKPDS Group. Lancet. 1998;352:837-853
Intensive initial treatment with insulin,
sulfonylurea in type 2 DM reduces microvascular
and macrovascular complications and death
Therapeutic Lifestyle Changes (TLC)
Diet
Exercise
Major Targeted Sites of Oral Drug Classes
Pancreas
Beta-cell
dysfunction
Sulfonylureas
Liver
Hepatic glucose
overproduction
Biguanides
Meglitinides
↓Glucose level
Gut
Muscle
and fat
Insulin
resistance
TZDs
TZDs
Biguanides
Reduced
glucose
absorption
Alphaglucosidase
inhibitors
TZD = thiazolidinediones.
DeFronzo RA. Ann Intern Med. 1999;131:281–303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed.
Philadelphia: Saunders; 2003:1427–1483.
Modern insulin syringes, pens, delivery
devices, rapid-acting insulin analogs
Insulin delivery systems on the horizon...
•Inhaled insulin – Came and went….
Incretin Overview
 An incretin is a hormone with the following
characteristics1:
– It is released from the intestine in response to ingestion of
food, particularly glucose.
– The circulating concentration of the hormone must be
sufficiently high to stimulate the release of insulin.
– The release of insulin in response to physiological levels of
the hormone occurs only when glucose levels are elevated
(glucose-dependent).
Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
36
The Incretin Effect in Subjects With & W/O DM2
Control Subjects
(n=8)
0.6
Incretin
Effect
80
60
0.4
20
0.1
0
0
0
60
120
180
Time, min
60
0.5
0.4
0.3
40
nmol/L
0.2
nmol / L
0.3
40
0.6
The incretin effect
is diminished
in type 2 diabetes.
0.5
IR Insulin, mU/L
80
IR Insulin, mU/L
Patients With Type 2 Diabetes
(n=14)
0.2
20
0.1
0
0
0
60
120
180
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
37
GLP-1 and GIP Are Incretin Hormones
GLP-1
GIP
 Is released from L cells in ileum and
colon1,2
 Is released from K cells in duodenum1,2
 Stimulates insulin response from
beta cells in a glucose-dependent
manner1
 Stimulates insulin response from
beta cells in a glucose-dependent
manner1
 Inhibits gastric emptying1,2
 Has minimal effects on gastric
emptying2
 Reduces food intake and
body weight2
 Has no significant effects on satiety or
body weight2
 Inhibits glucagon secretion from
alpha cells in a glucose-dependent
manner1
 Does not appear to inhibit glucagon
(may
secretion from alpha cells1,2
GLP-1: glucagon-like peptide-1
even stimulate glucagon!)
GIP: glucose-dependent insulinotropic
Polypeptide (formerly gastric inhibitory
Polypeptide!)
1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
38
pmol/L
pmol/L
*
*
*
*
*
*
0
250
200
150
100
50
0
*
*
*
*
*
*
40
30
20
10
0
20
20
15
15
10
5
0
–30
*
*
*
10
*
5
Infusion
0
60
120
pmol/L
Glucagon
*
250
200
150
100
50
mU/L
Insulin
15.0
12.5
10.0
7.5
5.0
2.5
0
Placebo
mg/dL
Glucose
mmol/L
Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon
Levels in Patients With Type 2 Diabetes
GLP-1
*P <0.05
Patients with type 2
diabetes (N=10)
When glucose levels
approach normal values,
insulin levels decreases.
When glucose levels
approach normal values,
glucagon levels rebound.
0
180
240
Minutes
Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.
39
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal
GIP and
GLP-1
release
GIP-(1–42)
GLP-1(7–36)
Intact
DPP-4
Enzyme
Rapid Inactivation
GIP-(3–42)
GLP-1(9–36)
Metabolites
Half-life*
GLP-1 ~ 2 minutes
GIP ~ 5 minutes
GIP and GLP-1
Actions
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.
40
41
The Beginning
• Exenatide
– Synthetic version of salivary protein (exendin-4) found in
the Gila monster
– More than 50% amino acid sequence identity with human GLP-1
 Binds to known human GLP-1 receptors on b cells (in vitro)
 Resistant to DPP-IV inactivation
Site of DPP-IV Inactivation
• Following injection, exenatide is measurable in plasma
for up to 10 hours
Adapted from Nielsen LL, et al. Regul Pept. 2004;117:77-88.
Adapted from Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:173-181.
Exenatide Lowered A1C
Large Phase 3 Clinical Studies
Type 2 Diabetes
Placebo BID
5 µg Exenatide BID
10 µg Exenatide BID
MET
0.5
SFU
0.5
MET + SFU
0.5
0.2
0.1
 A1C (%)
0.1
0
-0.5
-1
-0.4
*
0
0
-0.5
-0.5
-0.5
*
- 0.8
*
-1
-0.6
*
-0.9
*
-1
ITT; N = 1446; Mean ± SE; *P<0.005
Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100; Data from Buse JB, et al. Diabetes Care. 2004;
27:2628-2635; Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.
-0.8
*
Summary
Pancreas2,3
GI tract
Ingestion
of food
Glucose-dependent
insulin from beta cells
(GLP-1 and GIP)
Release of gut
hormones —
Incretins1,2
Active
GLP-1 & GIP
X
DPP-4
Enzyme
Inactive GLP-1
and GIP
2,4
Glucose
uptake
by muscles
β-cells
α-cells
Blood
glucose
Glucagon
from alpha cells
(GLP-1)
Glucose
production
by liver
Glucose dependent
Active incretins physiologically regulate glucose by modulating insulin secretion
in a glucose-dependent manner.
GLP-1 also modulates glucagon secretion in a glucose-dependent manner.
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
44
Clinical Pharmacology of JANUVIA (sitagliptin phosphate):
Pharmacodynamics:
 JANUVIA led to inhibition of DPP-4 activity for a 24-hour
period in patients with type 2 diabetes, resulting in:
 2- to 3-fold  in levels of active GLP-1 and GIP
  glucagon concentrations
  responsiveness of insulin release to glucose
  fasting glucose and  glucose excursion after an
oral glucose load or a meal
 In healthy subjects, JANUVIA did not lower blood
glucose or cause hypoglycemia
45
Diabetes and Bariatric Surgery
• Buchwald et al (2004), in a meta-analysis of
22,094 patients undergoing gastric bypass
surgery for morbid obesity found:
• 1417 of 1846 patients with diabetes (76.8%)
experienced complete resolution of their
diabetes
• (Defined as ability to discontinue all diabetes-
related medications and maintain blood glucose
levels within the normal range)
Summary
• 1. Type 2 Diabetes (DM 2) is a multi-factorial
disorder that is increasing in prevalence.
• 2. Insulin resistance, beta-cell & alpha-cell
dysfunction and abnormal incretin function all
contribute to the metabolic derangements seen
in pre-diabetes and DM2.
• 3. Diabetes is associated with increase in both
microvascular and macrovascular complications
• 4. Many therapeutic options exist to target the
pathophysiologic features of DM 2, reduce
hyperglycemia and can prevent/delay
complications.
Thanks! Questions?