Inhibition of Dipeptidyl Peptidase IV With Sitagliptin (MK0431) Prolongs Islet Graft Survival in Streptozotocin-Induced Diabetic Mice

  1. Su-Jin Kim1,
  2. Cuilan Nian1,
  3. Doris J. Doudet2 and
  4. Christopher H.S. McIntosh1
  1. 1Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
  2. 2Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  1. Corresponding author: Dr. C.H.S. McIntosh, Department of Cellular and Physiological Sciences, the Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, B.C., V6T 1Z3, Canada. E-mail: mcintoch{at}interchange.ubc.ca

Abstract

OBJECTIVE—Dipeptidyl peptidase-IV (DPP-IV) inhibitors have been introduced as therapeutics for type 2 diabetes. They partially act by blocking degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus increasing circulating levels of active hormones. In addition to their insulinotropic actions, GLP-1 and GIP also promote β-cell proliferation and survival, and DPP-IV inhibitors exert similar effects in rodent type 2 diabetes models. The study objective was to establish whether DPP-IV inhibitor treatment prolonged survival of transplanted islets and to determine whether positron emission tomography (PET) was appropriate for quantifying the effect of inhibition on islet mass.

RESEARCH DESIGN & METHODS—Effects of the DPP-IV inhibitor MK0431 (sitagliptin) on glycemic control and functional islet mass in a streptozotocin (STZ)-induced type 1 diabetes mouse model were determined with metabolic studies and microPET imaging.

RESULTS—The type 1 diabetes mouse model exhibited elevated plasma DPP-IV levels that were substantially inhibited in mice on an MK0431 diet. Residual β-cell mass was extremely low in STZ-induced diabetic mice, and although active GLP-1 levels were increased by the MK0431 diet, there were no significant effects on glycemic control. After islet transplantation, mice fed normal diet rapidly lost their ability to regulate blood glucose, reflecting the suboptimal islet transplant. By contrast, the MK0431 group fully regulated blood glucose throughout the study, and PET imaging demonstrated a profound protective effect of MK0431 on islet graft size.

CONCLUSIONS—Treatment with a DPP-IV inhibitor can prolong islet graft retention in an animal model of type 1 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 25 February 2008. DOI: 10.2337/db07-1639.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1639.

  • C.H.S.M. has acted as a consultant for Boehringer Ingleheim, Merck, and Takeda and has received research funding from Priobiodrug and OSI.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 19, 2008.
    • Received November 19, 2007.
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