The tuberous sclerosis complex model Eker (TSC2+/−) rat exhibits hyperglycemia and hyperketonemia due to decreased glycolysis in the liver

• TSC2 heterozygosis mutation Eker rats show the hyperketonemia and hyperglycemia.
• Hyperketonemia was observed without higher levels of serum NEFA and insulin.
• The ratio of serum βOHB/AcAc was decreased in Eker rats.
• βOHB was inhibited due to resistant on glycolysis.

Tuberous sclerosis complex (TSC) presents as benign tumors that affect the brain, kidneys, lungs and skin. The inactivation of TSC2 gene, through loss of heterozygosity is responsible for tumor development in TSC. Since TSC patients are carriers of heterozygous a TSC2; mutation, to reveal the risk factors which these patients carry prior to tumor development is important. In this experiment, Eker rat which carry a mutation in this TSC2 gene were analyzed for their metabolic changes. Wild-type (TSC2+/+) and heterozygous mutant TSC2 (TSC2+/−) Eker rats were raised for 100 days. As a result, the Eker rats were found to exhibit hyperglycemia and hyperketonemia. However the high ketone body production in the liver was observed without accompanying increased levels of plasma free fatty acids or insulin. Further, production of the ketone body β-hydroxybutyrate was inhibited due to the low NADH/NAD+ ratio resulting from the restraint on glycolysis, which was followed by inhibition of the malate-aspartate shuttle and TCA cycle. Therefore, we conclude that glycolysis is restrained in the livers of TSC2 heterozygous mutant rats, and these defects lead to abnormal production of acetoacetate.