Impaired mitochondrial metabolism and reduced amphibolic Krebs cycle activity in diabetic rat hepatocytes

Oxidation of [2,3(14)C] and [1,4(14)C] succinate carbons in the mitochondrial Krebs cycle (KC) was used as a probe to investigate the effect of insulin and diabetes on mitochondrial metabolism in isolated rat hepatocytes. The data presented show that mitochondrial oxidation of succinate carbons and their incorporation into protein and lipid was markedly lower in diabetic and insulin treated diabetic rat hepatocytes. Unlike controls, diabetic rat hepatocytes were unresponsive to in vitro insulin addition. Amphibolic channeling of [2,3(14)C] succinate carbons into amino acid fraction was reduced in hepatocytes from diabetic rats, however, more of these carbons were diverted into the gluconeogenesis pathway. These data suggest that the diminished level of anabolic activities in the diabetic rat hepatocytes may be due to impairment in the KC reactions and a subsequent reduction in amphibolic channeling of metabolic intermediates.