Beneficial Endocrine but adverse Exocrine effects of Sitagliptin in the HIP rat model of Type 2 Diabetes, interactions with Metformin.

  1. Aleksey V. Matveyenko (amatveyenko{at}mednet.ucla.ed)1,
  2. Sarah Dry2,
  3. Heather I. Cox1,
  4. Artemis Moshtaghian1,
  5. Tatyana Gurlo1,
  6. Ryan Galasso1,
  7. Alexandra E Butler1 and
  8. Peter C. Butler1
  1. 1. Larry Hillblom Islet Research Center, Division of Endocrinology, David Geffen School of Medicine, UCLA
  2. 2. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA

    Abstract

    Objective. We sought to establish the extent and by which mechanisms sitagliptin and metformin singly and in combination modify islet disease progression in human IAPP transgenic rats (HIP rats), a model for T2DM.

    Research Design and Methods HIP rats were treated with sitagliptin (SIT), metformin (MET), sitagliptin and metformin (SIT+MET) or no drug as controls for the 12 weeks. Fasting blood glucose, insulin sensitivity, beta cell mass, function and turnover were measured in each group.

    Results. SIT+MET had synergistic effects to preserve beta cell mass in HIP rats. MET more than SIT inhibited beta cell apoptosis. MET enhanced hepatic insulin sensitivity, SIT enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. Beta cell function was partially preserved by SIT + MET. However SIT 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, beta cell function and enhance insulin sensitivity in the HIP rat model of T2DM. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation.

    Footnotes

      • Received January 12, 2009.
      • Accepted April 8, 2009.