Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

Abstract

Metformin is the main drug of choice for treating type 2 diabetes, yet the therapeutic regimens and side effects of the compound are all undesirable and can lead to reduced compliance. The aim of this study was to elucidate the mechanism of action of two novel compounds which improved glucose handling and weight gain in mice on a high-fat diet. Wildtype C57Bl/6 male mice were fed on a high-fat diet and treated with novel, anti-diabetic compounds. Both compounds restored the glucose handling ability of these mice. At a cellular level, these compounds achieve this by inhibiting complex I activity in mitochondria, leading to AMP-activated protein kinase activation and subsequent increased glucose uptake by the cells, as measured in the mouse C2C12 muscle cell line. Based on the inhibition of NADH dehydrogenase (IC50 27µmolL−1), one of these compounds is close to a thousand fold more potent than metformin. There are no indications of off target effects. The compounds have the potential to have a greater anti-diabetic effect at a lower dose than metformin and may represent a new anti-diabetic compound class. The mechanism of action appears not to be as an insulin sensitizer but rather as an insulin substitute.

Why All the Fuss about Oxidative Phosphorylation (OXPHOS)?

“…134 In light of this, complex I inhibitors RTC1 and RTB70 show antidiabetic effects by efficiently restoring glucosehandling abilities in models of high-fat-fed mice. 135 Although more mechanistic studies and animal models are needed to further elucidate the function of complex I inhibitors in diabetes, this study provides the rationale for a new therapeutic area for OXPHOS inhibitors.…”

Forchlorfenuron-Induced Mitochondrial Respiration Inhibition and Metabolic Shifts in Endometrial Cancer

“…[ 32 , 40 , 41 ]. FCF also triggered a metabolic shift toward glycolysis ( Figure 4 F–H, Figure 6 E and Figure 8 ), possibly acquiring compensatory cytoprotection during this energy crisis [ 42 , 43 ]. Our observations on HIF-1α and glucose uptake appear to be a direct consequence of impaired mitochondrial function due to FCF.…”