Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model

Abstract

Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice.

Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice

“…Of note, our experimental design using succinate to fuel mitochondria in the presence of Rotenone specifically detected ROS production at mitochondrial Complex III (cytochrome C reductase). Based on recent studies, an additional contribution of ROS generation by reverse electron flow at Complex I (NADH‐dehydrogenase) is also feasible, as demonstrated in skeletal muscle (Brand, in press) and liver (Vial et al., ).…”

Maternal exercise modifies body composition and energy substrates handling in male offspring fed a high‐fat/high‐sucrose diet

“…Rats were killed 15 min after injection, and gastrocnemius muscle and liver were rapidly removed and frozen. Protein kinase B (PKB) phosphorylation level, as an indicator of insulin pathway activation, was determined by western blotting (Vial et al 2015). Tissues were lysed in PBS buffer containing 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS supplemented with 5 mM EDTA, 1 mM Na 3 VO 4 , 20 mM NaF, 1 mM DTT and protease inhibitors cocktail (Sigma P2714, Saint Quentin Fallavier, France).…”

iRhom2 serves as a facilitator in obesity by enhancing adipose inflammation and insulin resistance

“…S2 A-D). Of note, previous evidences have demonstrated that prolonged HFD feeding intake is able to promote insulin resistance and glucose intolerance (23)(24)(25). When obesity aspects were investigated, phenotypes of obesity and lipid accumulation in liver were significantly observed in HFD-fed WT mice compared with HFD-treated iRhom2 KO mice ( Fig.…”