Article

Diabetologia

, Volume 55, Issue 2, pp 404-412

First online:

Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice

  • Y. TakedaAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University
  • , Y. FujitaAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University Email author 
  • , J. HonjoAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University
  • , T. YanagimachiAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University
  • , H. SakagamiAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University
  • , Y. TakiyamaAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University
  • , Y. MakinoAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University
  • , A. AbikoAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University
  • , T. J. KiefferAffiliated withDepartment of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia
    • , M. HanedaAffiliated withDivision of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University

Abstract

Aims/hypothesis

Incretins stimulate insulin secretion in a glucose-dependent manner but also promote pancreatic beta cell protection. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new glucose-lowering treatment that blocks incretin degradation by DPP-4. We assessed whether DPP-4 inhibition suppresses the progression to hyperglycaemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated how DPP-4 inhibition affects islet function and morphology.

Methods

The DPP-4 inhibitor, des-fluoro-sitagliptin (SITA), was administered to mice during and after STZ injections, and in some mice also before STZ.

Results

In control mice, STZ resulted in hyperglycaemia associated with impaired insulin secretion and excess glucagon secretion. In SITA-treated STZ mice, these metabolic abnormalities were improved, particularly when SITA administration was initiated before STZ injections. We observed beta cell loss and dramatic alpha cell expansion associated with decreased insulin content and increased glucagon content after STZ administration. In SITA-treated mice, islet architecture and insulin content were preserved, and no significant increase in glucagon content was observed. After STZ exposure, beta cell apoptosis increased before hyperglycaemia, and SITA treatment reduced the number of apoptotic beta cells. Interestingly, alpha cell proliferation was observed in non-treated mice after STZ injection, but the proliferation was not observed in SITA-treated mice.

Conclusions/interpretation

Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation.

Keywords

Alpha cell proliferation Beta cell death Dipeptidyl peptidase-4 Glucagon Glucose-dependent insulinotropic polypeptide Glucagon-like peptide-1 Insulin Streptozotocin