Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler
Year: 2019
Type: article
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.
Source: Nature Communications
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
Institutions: Otsuka (Japan), Otsuka Pharmaceutical Factory (Japan)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funder: Otsuka Pharmaceutical
OpenAlex ID: W2945783425