IRS1 and Insulin resistance: To determine whether mitochondrial dysfunction induced by mtDNA depletion causes insulin resistance in hepatocytes, we analyzed the expression and insulin-stimulated phosphorylation of insulin signaling intermediates, such as IRS-1, Akt2, and glycogen synthase kinase-3β (GSK3β), in the mtDNA-depleted SK-Hep1 hepatocytes.