Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler.

Abstract

Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.

• Authors: Naohide Kanemoto, Takashi Okamoto, Koji Tanabe, Takahiro Shimada, Hitomi Minoshima, Yuya Hidoh, Masashi Aoyama, Takashi Ban, Yusuke Kobayashi, Hikaru Ando, Yuki Inoue, Motohiro Itotani, Seiji Sato
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 2172 (05 15 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31092829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoglycemic Agents
• Uncoupling Agents

Topics

• Administration, Oral
• Animals
• Blood Pressure (drug effects)
• CHO Cells
• Cricetulus
• Diabetes Mellitus (blood, drug therapy)
• Disease Models, Animal
• Fatty Liver (drug therapy, etiology, pathology)
• Female
• Hep G2 Cells
• Humans
• Hypertension (drug therapy, etiology, mortality)
• Hypoglycemic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Kidney (drug effects)
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Mitochondria (drug effects, metabolism)
• Oxidative Phosphorylation (drug effects)
• Rats
• Rats, Sprague-Dawley
• Stroke (drug therapy, etiology, mortality)
• Survival Analysis
• Uncoupling Agents (pharmacokinetics, pharmacology, therapeutic use)