Inhibition of Dipeptidyl Peptidase IV (DPP-IV) with Sitagliptin (MK0431) Prolongs Islet Graft Survival in Streptozotocin (STZ)-induced Diabetic Mice

Abstract

Objective: Dipeptidyl peptidase-4 (DPP-IV) inhibitors have been introduced as therapeutics for type 2 diabetes (T2DM). 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 T2DM 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 and Methods: Effects of the DPP-IV inhibitor MK0431 (sitagliptin) on glycemic control and functional islet mass in a streptozotocin (STZ)-induced type 1 diabetes (T1DM) mouse model was determined with metabolic studies and microPET imaging.

Results: The T1DM 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-diabetic mice and, although active GLP-1 levels were increased by the MK0431 diet, there were no significant effects on glycemic control. Following islet transplantation, mice fed normal diet rapidly lost their ability to regulate blood glucose, reflecting the sub-optimal 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 DPP-IV inhibitor can prolong islet graft retention in an animal model of T1DM.