Insulin resistance and the mitochondrial link. Lessons from cultured human myotubes

In order to better understand the impact of reduced mitochondrial function for the development of insulin resistance and cellular metabolism, human myotubes were established from lean, obese, and T2D subjects and exposed to mitochondrial inhibitors, either affecting the electron transport chain (Antimycin A), the ATP synthase (oligomycin) or respiratory uncoupling (2,4-dinitrophenol). Direct inhibition of the electron transport chain or the ATP synthase was followed by increased glucose uptake and lactate production, reduced glycogen synthesis, reduced lipid and glucose oxidation and unchanged lipid uptake. The metabolic phenotype during respiratory uncoupling resembled the above picture, except for an increase in glucose and palmitate oxidation. Antimycin A and oligomycin treatment induced insulin resistance at the level of glucose and palmitate uptake in all three study groups while, at the level of glycogen synthesis, insulin resistance was only seen in lean myotubes. Primary insulin resistance in diabetic myotubes was significantly worsened at the level of glucose and lipid uptake. The present study is the first convincing data linking functional mitochondrial impairment per se and insulin resistance. Taken together functional mitochondrial impairment could be part of the pathophysiology of insulin resistance in vivo.