Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model.

Abstract

BACKGROUND:

Stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice.

METHOD AND RESULTS:

C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), and 8-hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide-1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice.

CONCLUSIONS:

The results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress.

• Authors: Maimaiti Yisireyili, Kyosuke Takeshita, Motoharu Hayashi, Hongxian Wu, Yasuhiro Uchida, Koji Yamamoto, Ryosuke Kikuchi, Chang-Ning Hao, Takayuki Nakayama, Xian Wu Cheng, Tadashi Matsushita, Shigeo Nakamura, Toyoaki Murohara
• Journal: Psychoneuroendocrinology (Psychoneuroendocrinology) Vol. 73 Pg. 186-195 (11 2016) ISSN: 1873-3360 [Electronic] England
• PMID: 27509090 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Piperidines
• Uracil
• Dipeptidyl Peptidase 4
• alogliptin

Topics

• Adipose Tissue (metabolism)
• Animals
• Dipeptidyl Peptidase 4 (metabolism)
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Disease Models, Animal
• Inflammation (blood, drug therapy, etiology, metabolism)
• Insulin Resistance
• Male
• Mice
• Mice, Inbred C57BL
• Piperidines (pharmacology)
• Stress, Psychological (complications)
• Thrombophilia (drug therapy, etiology)
• Uracil (analogs & derivatives, pharmacology)