Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes.
Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic beta-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic beta-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA(1c), and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive beta-cells in islets, leading to the normalization of beta-cell mass and beta-cell-to-alpha-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.
Mu
James
J
Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
Woods
John
J
Zhou
Yun-Ping
YP
Roy
Ranabir Sinha
RS
Li
Zhihua
Z
Zycband
Emanuel
E
Feng
Yue
Y
Zhu
Lan
L
Li
Cai
C
Howard
Andrew D
AD
Moller
David E
DE
Thornberry
Nancy A
NA
Zhang
Bei B
BB
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000188:drug therapy / Q000378:metabolism; D005913:Glipizide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011719:Pyrazines; D013453:Sulfonylurea Compounds; D014230:Triazoles; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D000068900:Sitagliptin Phosphate; D005913:Glipizide