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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.

INSTRUMENT(S): Flow Injection Analysis MS - Positive (FIA-MS (Positive))

PROVIDER: MTBLS836 | MetaboLights | 2019-05-24

REPOSITORIES: MetaboLights

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	KIT3-0-1211_1029054599_01_0_1_1_01_10000001.raw	Raw
	KIT3-0-1211_1029054599_01_0_1_2_01_10000001.raw	Raw
	KIT3-0-1211_1029054599_01_0_1_3_01_10000001.raw	Raw
	KIT3-0-1211_1029054599_02_0_1_1_10_11000011.raw	Raw
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Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler.

Kanemoto Naohide N Okamoto Takashi T Tanabe Koji K Shimada Takahiro T Minoshima Hitomi H Hidoh Yuya Y Aoyama Masashi M Ban Takashi T Kobayashi Yusuke Y Ando Hikaru H Inoue Yuki Y Itotani Motohiro M Sato Seiji S

Nature communications 20190515 1

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 e ...[more]

PMID: 31092829

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