OBJECTIVE-The endopeptidase dipeptidyl peptidase-IV (DPP-IV) has been shown to NH 2 -terminally truncate incretin hormones, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1, thus ablating their ability to potentiate glucose-stimulated insulin secretion. 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. DPP-IV inhibitor treatment has also been shown to preserve islet mass in rodent models of type 1 diabetes. The current study was initiated to define the effects of the DPP-IV inhibitor sitagliptin (MK0431) on transplanted islet survival in nonobese diabetic (NOD) mice, an autoimmune type 1 diabetes model.
RESEARCH DESIGN AND METHODS-Effects of MK0431on islet graft survival in diabetic NOD mice were determined with metabolic studies and micropositron emission tomography imaging, and its underlying molecular mechanisms were assessed.RESULTS-Treatment of NOD mice with MK0431 before and after islet transplantation resulted in prolongation of islet graft survival, whereas treatment after transplantation alone resulted in small beneficial effects compared with nontreated controls. Subsequent studies demonstrated that MK0431 pretreatment resulted in decreased insulitis in diabetic NOD mice and reduced in vitro migration of isolated splenic CD4 ϩ T-cells. Furthermore, in vitro treatment of splenic CD4ϩ T-cells with DPP-IV resulted in increased migration and activation of protein kinase A (PKA) and Rac1. T he incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), exert a number of actions that improve glucose homeostasis, including potentiation of glucose-stimulated insulin secretion (GSIS), promotion of -cell proliferation and survival, and inhibition of glucagon secretion (1-7). Because GIP and GLP-1 are rapidly degraded by the endopeptidase dipeptidyl peptidase IV (DPP-IV; CD26), it has not been possible to directly take advantage of their beneficial actions for the treatment of type 2 diabetes (8,9). Therefore, a number of strategies have been explored to circumvent this problem, including the development of small molecule (10,11) and DPP-IVresistant peptide (12,13) incretin receptor agonists, and DPP-IV inhibitors (14,15). Members of two classes of compounds have recently been approved by the Food and Drug Administration as type 2 diabetes therapeutics: the DPP-IV-resistant GLP-1 receptor agonist (incretin mimetic) exenatide (Byetta) and the DPP-IV inhibitor sitagliptin (Januvia).
CONCLUSIONS-TreatmentAlthough DPP-IV inhibitors have been extensively studied in treatment of type 2 diabetes, little is known about their potential for treatment of type 1 diabetes. Infusion of GLP-1 was shown to reduce glycemic excursions in type 1 diabetic patients, and this result was attributed to reduced glucagon levels and delayed gastric emptying (16,17). In preclinical studies, the DPP-IV inhibitor isoleucine thiazolidide w...