- Type 2 diabetes results from insulin resistance and pancreatic islet cell dysfunction, leading to high blood glucose levels. Over time this causes further deterioration in beta cell function and increasing insulin resistance. - Both fasting plasma glucose levels and post-prandial glucose levels contribute to overall hyperglycemia, but their relative contributions depend on the patient's HbA1c level. Higher HbA1c levels correlate more with post-prandial glucose levels. - The incretin hormones GLP-1 and GIP are released from the intestine after eating to stimulate insulin secretion, suppress glucagon release, and decrease hepatic glucose production and peripheral glucose uptake, helping to lower blood glucose levels. Their actions are impaired in

1. Review Of The Pathophysiology
Of Type 2 Diabetes And The Key
Role Of Incretin Hormones

2. Major Pathophysiologic Defects in
Type 2 Diabetes
Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
Hepatic
glucose
output
Insulin
resistance
Glucose uptake
Glucagon
(α cell)
Insulin
(β cell)
LiverLiver
Hyperglycemia
Islet-Cell Dysfunction
MuscleMuscle
AdiposeAdipose
tissuetissue
PancreasPancreas
LiverLiver

3. Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2
diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier.
Development and Progression of
Type 2 Diabetes and Related Complicationsa
a
Conceptual representation.
Insulin levelInsulin level
Insulin resistanceInsulin resistance
Hepatic glucoseHepatic glucose
productionproduction
PostprandialPostprandial
glucoseglucose
Fasting plasmaFasting plasma
glucoseglucose
BBetaeta-cell function-cell function
Progression of Type 2 Diabetes Mellitus
Impaired Glucose Tolerance
Diabetes Diagnosis
Frank Diabetes
4–7 years
Development of Macrovascular Complications
Development of Microvascular Complications

4. Relative Contribution of FPG and PPG to Overall
Hyperglycemia Depending on HbA1c Quintiles
n = 58 n = 58 n = 58 n = 58n = 58
0
20
40
60
80
100
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
Postprandial glucose Fasting glucose
HbA1c
Contribution,%
Monnier L et al. Diabetes Care. 2003;26:881–885.
Copyright 2003 American Diabetes Association from Diabetes Care, Vol. 26, 2003; 881-885.
Reprinted with permission from The American Diabetes Association.

5. Incretins Modulate Insulin and Glucagon to
Decrease Blood Glucose During Hyperglycemia
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Brubaker PL et al. Endocrinology 2004;145:2653–2659; Zander M et al. Lancet 2002;359:824–930; Ahren B. Curr Diab Rep 2003;3:365–372; Buse JB et al. In:
Williams Textbook of Endocrinology,11th ed. Philadelphia: Saunders; 2008:1329–1389; Drucker DJ. Diabetes Care 2003;26:2929–2940.
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day;
their levels increase in response to a meal.
Release of
active incretins
GLP-1 and GIPa
 Blood glucose in
fasting and
postprandial states
Ingestion
of food
 Glucagon
from alpha cells
(GLP-1)
 Hepatic
glucose
production
GI tract
DPP-4
enzyme
Inactive
GLP-1
 Insulin from
beta cells
(GLP-1 and GIP)
Glucose-dependent
Glucose-dependent
Pancreas
Inactive
GIP
Beta cellsBeta cells
Alpha cellsAlpha cells
 Peripheral
glucose
uptake

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