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

Diabetes. 2009 Jul;58(7):1604-15. doi: 10.2337/db09-0058. Epub 2009 Apr 29.

Abstract

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 beta-cell mass, function, and turnover were measured in each group.

Results: Sitagliptin plus metformin had synergistic effects to preserve beta-cell mass in HIP rats. Metformin more than sitagliptin inhibited beta-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. beta-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 beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / genetics
  • Amyloid / metabolism*
  • Animals
  • Animals, Genetically Modified
  • Arginine / pharmacology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Disease Models, Animal
  • Glucose Clamp Technique
  • Humans
  • Hyperglycemia / drug therapy
  • Hyperinsulinism / metabolism
  • Hypoglycemic Agents / therapeutic use*
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Metformin / therapeutic use*
  • Pyrazines / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Sitagliptin Phosphate
  • Triazoles / therapeutic use*

Substances

  • Amyloid
  • Hypoglycemic Agents
  • Islet Amyloid Polypeptide
  • Pyrazines
  • Triazoles
  • Metformin
  • Arginine
  • Sitagliptin Phosphate