Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes.
Inhibition of dipeptidyl peptidase-4 (DPP-4) activity has been shown to improve glycemic control in patients with type 2 diabetes by prolonging and potentiating the actions of incretin hormones. This study is designed to determine the effects of the DPP-4 inhibitor sitagliptin on improving islet function in a mouse model of insulin resistance and insulin secretion defects. ICR mice were pre-treated with high fat diet and a low dose of streptozotocin to induce insulin resistance and impaired insulin secretion, respectively. Diabetic mice were treated with sitagliptin or the sulfonylurea agent glipizide as admixture to high fat diet for ten weeks. Sustained reduction of blood glucose, HbA(1c), circulating glucagon and improvement in oral glucose tolerance were observed in mice treated with sitagliptin. In contrast, glipizide improved glycemic control only during the early weeks and to a lesser degree compared to sitagliptin, and had no effect on circulating glucagon levels or glucose tolerance. The improvement in glycemic control in sitagliptin-treated mice was associated with a significant increase in glucose-dependent insulin secretion in both perfused pancreas and isolated islets. Importantly, in contrast to the lack of effect by glipizide, sitagliptin significantly restored beta and alpha cell mass as well as alpha/beta cell ratio. These data indicate that DPP-4 inhibition by sitagliptin provided better overall improvement of glycemic control compared to glipizide in the high fat diet/streptozotocin induced diabetic mouse model. The ability of sitagliptin to enhance islet cell function may offer insight into the potential for disease modification.
Mu
James
J
Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA. yingjun_mu@merck.com
Petrov
Aleksandr
A
Eiermann
George J
GJ
Woods
John
J
Zhou
Yun-Ping
YP
Li
Zhihua
Z
Zycband
Emanuel
E
Feng
Yue
Y
Zhu
Lan
L
Roy
Ranabir Sinha
RS
Howard
Andrew D
AD
Li
Cai
C
Thornberry
Nancy A
NA
Zhang
Bei B
BB
D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004041:Dietary Fats / Q000008:administration & dosage; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005913:Glipizide / Q000378:metabolism / Q000627:therapeutic use*; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006442:Glycated Hemoglobin / Q000032:analysis; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size; D011719:Pyrazines / Q000378:metabolism / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000378:metabolism / Q000627:therapeutic use*; D014280:Triglycerides / Q000032:analysis
D001786:Blood Glucose; D004041:Dietary Fats; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005913:Glipizide; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D019394:Ki-67 Antigen; D008055:Lipids; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles; D014280:Triglycerides; C545245:Dpp4 protein, mouse