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.

International Ring Trial of a High Resolution Targeted Metabolomics and Lipidomics Platform for Serum and Plasma Analysis

“…9 The AbsoluteIDQ p400HR assay quantifies over 400 metabolites from eleven analyte groups: amino acids, biogenic amines, acylcarnitines, monosaccharides (hexose), diglycerides, triglycerides, lysophosphatidylcholines, phosphatidylcholines, sphingomyelins, ceramides, and cholesteryl esters. 10 The kit includes calibration standards, internal standards, and quality control (QC) samples. Selective analyte detection is accomplished by the Q Exactive Orbitrap™ family of high-resolution, accurate-mass mass spectrometers (Thermo Fisher Scientific).…”

Hungry for your alanine: when liver depends on muscle proteolysis

“…They also place hepatic energy metabolism at the center of the connection among fasting, insulin resistance, and NAFLD. Indeed, novel mild mitochondrial uncouplers identified hepatic energy metabolism as a target for treating obesity, type 2 diabetes, and NAFLD (23,24).…”

Fluorescein Derivatives as Antibacterial Agents Acting via Membrane Depolarization

“…The main arguments in favor of Mitchell's chemiosmotic theory were based on the ability of uncouplers to cause the collapse of the membrane potential by carrying protons across membranes. At present, there is a revival of interest in uncouplers because of the growing evidence of their broad-spectrum therapeutic efficacy [1][2][3][4][5][6][7][8][9], including antibacterial potency [10][11][12][13][14][15][16][17][18][19], which was actually found very early [20]. To this end, a series of esters of fluorescein were obtained and studied at our laboratory, manifesting themselves as rather effective mitochondrial uncouplers [21][22][23].…”