Mitochondrial regulation of hepatic glucose production in type 2 diabetes

Insulin resistance and resultant hyperglycemia during type 2 diabetes (T2D) contribute to vascular disease, driving T2D morbidity and mortality. In T2D patients, fasting blood glucose levels directly correlate with rates of hepatic gluconeogenesis (GNG), the de novo synthesis of glucose. GNG requires carbon substrate and reducing equivalents. Major gluconeogenic substrates include lactate and the amino acids glutamine and alanine. In T2D, hepatic uptake of these precursors increases. For GNG, they must first be imported into mitochondria and incorporated into the TCA cycle. However, mitochondria must export carbon substrate and reducing equivalents to the cytosol. Previous studies in ex vivo models suggest the mitochondrial dicarboxylate carrier (DIC) exports mitochondrial malate to contribute both carbon substrate and reducing equivalents for GNG. However, the role of DIC has not been tested in vivo. Given this, we hypothesized that hepatic DIC disruption would limit GNG to attenuate hyperglycemia and insulin resistance in a mouse model of T2D. To test our hypothesis, we generated liver-specific DIC knockout (DIC-LivKO) mice. We found that hepatic DIC disruption decreased, but did not eliminate, glucose production from lactate/pyruvate and glutamine. In addition, we found that hepatic aspartate is increased in DIC-LivKO mice, suggesting it is an alternative export substrate. The mitochondrial aspartate-glutamate carrier 2 (AGC2) exports aspartate in the liver. Hepatic AGC2 deletion suppressed glucose production from lactate/pyruvate. Finally, we found that hepatic DIC disruption in western diet fed mice ameliorated hyperglycemia and insulin resistance by decreasing hepatic glucose production from lactate/pyruvate. Overall, these studies show DIC supports hepatic GNG. Thus, DIC may be an attractive therapeutic target for suppressing excessive GNG in T2D.