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ß-Cell Deficit Due to Increased Apoptosis in the Human Islet Amyloid Polypeptide Transgenic (HIP) Rat Recapitulates the Metabolic Defects Present in Type 2 Diabetes

From the Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, California

Address correspondence and reprint requests to Dr. Peter C. Butler, Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 900A Weyburn Pl., Los Angeles, CA 90095. E-mail: pbutler{at}mednet.ucla.edu

Abbreviations: IAPP, islet amyloid polypeptide; IFG, impaired fasting glucose

Type 2 diabetes is characterized by defects in insulin secretion and action and is preceded by impaired fasting glucose (IFG). The islet anatomy in IFG and type 2 diabetes reveals an 50 and 65% deficit in ß-cell mass, with increased ß-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Defects in insulin action include both hepatic and extrahepatic insulin resistance. The relationship between changes in ß-cell mass, ß-cell function, and insulin action leading to type 2 diabetes are unresolved, in part because it is not possible to measure ß-cell mass in vivo, and most available animal models do not recapitulate the islet pathology in type 2 diabetes. We evaluated the HIP rat, a human IAPP transgenic rat model that develops islet pathology comparable to humans with type 2 diabetes, at age 2 months (nondiabetic), 5 months (with IFG), and 10 months (with diabetes) to prospectively examine the relationship between changes in islet morphology versus insulin secretion and action. We report that increased ß-cell apoptosis and impaired first-phase insulin secretion precede the development of IFG, which coincides with an 50% defect in ß-cell mass and onset of hepatic insulin resistance. Diabetes was characterized by 70% deficit in ß-cell mass, progressive hepatic and extrahepatic insulin resistance, and hyperglucagonemia. We conclude that IAPP-induced ß-cell apoptosis causes defects in insulin secretion and ß-cell mass that lead first to hepatic insulin resistance and IFG and then to extrahepatic insulin resistance, hyperglucagonemia, and diabetes. We conclude that a specific ß-cell defect can recapitulate the metabolic phenotype of type 2 diabetes and note that insulin resistance in type 2 diabetes may at least in part be secondary to ß-cell failure.

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