β-cell deficit due to increased apoptosis in the human islet amyloid polypeptide transgenic (HIP) rat recapitulates the metabolic defects present in type 2 diabetes

Aleksey V. Matveyenko, Peter C. Butler

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103 Scopus citations

Abstract

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 β-cell mass, with increased β-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 β-cell mass, β-cell function, and insulin action leading to type 2 diabetes are unresolved, in part because it is not possible to measure β-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 β-cell apoptosis and impaired first-phase insulin secretion precede the development of IFG, which coincides with an ∼50% defect in β-cell mass and onset of hepatic insulin resistance. Diabetes was characterized by ∼70% deficit in β-cell mass, progressive hepatic and extrahepatic insulin resistance, and hyperglucagonemia. We conclude that IAPP-induced β-cell apoptosis causes defects in insulin secretion and β-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 β-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 β-cell failure.

Original languageEnglish (US)
Pages (from-to)2106-2114
Number of pages9
JournalDiabetes
Volume55
Issue number7
DOIs
StatePublished - Jul 1 2006

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Keywords

  • IAPP, islet amyloid polypeptide
  • IFG, impaired fasting glucose

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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