Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: Interactions with metformin

Aleksey V Matveyenko, Sarah Dry, Heather I. Cox, Artemis Moshtaghian, Tatyana Gurlo, Ryan Galasso, Alexandra E. Butler, Peter C. Butler

Research output: Contribution to journalArticle

196 Scopus citations


OBJECTIVE-We sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes. RESEARCH DESIGN AND METHODS-HIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and β-cell mass, function, and turnover were measured in each group. RESULTS-Sitagliptin plus metformin had synergistic effects to preserve β-cell mass in HIP rats. Metformin more than sitagliptin inhibited β-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. β-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis. CONCLUSIONS-The combination of metformin and sitagliptin had synergistic actions to preserve β-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.

Original languageEnglish (US)
Pages (from-to)1604-1615
Number of pages12
Issue number7
StatePublished - Jul 2009
Externally publishedYes


ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

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