title: 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.
abstract: 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.
authors.affiliation: Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mu
authors.forename: John
authors.initials: J
authors.lastname: Woods
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.forename: Ranabir Sinha
authors.initials: RS
authors.lastname: Roy
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Emanuel
authors.initials: E
authors.lastname: Zycband
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
mesh_terms: 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*
chemical_list: 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