Abstract

Objective: The endopeptidase dipeptidyl peptidase-IV (DPP-IV) has been shown to N-terminally truncate the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), thus ablating their ability to potentiate glucose-stimulated insulin secretion (GSIS). Increasing the circulating levels of incretins through administration of DPP-IV inhibitors has therefore been introduced as a therapeutic approach for the treatment of Type 2 diabetes (T2DM). DPP-IV inhibitor treatment has also been shown to preserve islet mass in rodent models of T1DM. The current study was initiated in order to define the effects of the DPP-IV inhibitor Sitagliptin (MK0431) on transplanted islet survival in non-obese diabetic (NOD) mice, an auto-immune T1DM model.

Research Design and Methods: Effects of MK0431 on islet graft survival in diabetic NOD mice were determined with metabolic studies and microPET imaging, and its underlying molecular mechanisms were assessed.

Results: Treatment of NOD mice with MK0431, prior to and post islet transplantation, resulted in prolongation of islet graft survival whereaspost-treatment alone showed only small beneficial effects compared to non-treated controls. Subsequent studies demonstrated that MK0431 pre-treatment resulted in decreased insulitis in diabetic NOD miceand reduced in vitro migration of isolated splenic CD4⁺ T lymphocytes. Furthermore, in vitro treatment of splenic CD4⁺ T cellswith DPP-IV resulted in increased migration, as well as activation of protein kinase A (PKA)and Rac1.

Conclusions: Treatment with MK0431 therefore reduced the effect of autoimmunity on graft survival partially by decreasing the homing of CD4⁺ T cells into pancreatic β-cells, through a pathway involving cAMP/PKA/Rac1 activation.