Review Of The Pathophysiology Of Type 2 Diabetes And The Key

Role Of Incretin Hormones

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 glucoseoutput

Insulin resistance

Glucose uptake

Glucagon(α cell)

Insulin(β cell)

LiverLiver

Hyperglycemia

Islet-Cell Dysfunction

MuscleMuscle

Adipose Adipose tissuetissue

PancreasPancreas

LiverLiver

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

aConceptual representation.

Insulin levelInsulin level

Insulin resistanceInsulin resistance

Hepatic glucose Hepatic glucose productionproduction

PostprandialPostprandial glucoseglucose

Fasting plasma Fasting 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

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

Co

ntr

ibu

tio

n, %

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.

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 ofactive incretinsGLP-1 and GIPa

Blood glucose in fasting and

postprandial states

Ingestion of food

Glucagonfrom alpha cells

(GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

Insulin from beta cells

(GLP-1 and GIP)

Glucose-dependent

Glucose-dependent

Pancreas

InactiveGIP

Beta cellsBeta cellsAlpha cellsAlpha cells

Peripheral glucose uptake

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