Hyperhomocysteinemia stimulates hepatic glucose output and PEPCK expression.

Homocysteine is an intermediate in the sulfur amino acid metabolism. Recent studies suggested that there might be links between hyperhomocysteinemia and insulin resistance. In the present study, we investigated the effect of homocysteine on glucose metabolism. We demonstrated that the levels of insulin were significantly higher in mice with hyperhomocysteinemia than those in the normal mice after administration of glucose. The effect of insulin on glucose output was significantly blocked in the homocysteine-treated hepatocytes. In addition, the expression of phosphoenolpyruvate carboxykinase (PEPCK) gene was elevated in the liver of mice with hyperhomocysteinemia and primary mouse hepatocytes treated with homocysteine. The action of homocysteine was suppressed by H89, a protein kinase A (PKA) inhibitor. Thus, hyperhomocysteinemia may be considered as a risk factor that contributes to the development of insulin resistance with respect to elevated glucose output and upregulation of PEPCK, probably via the PKA pathway. Our study provides a novel mechanistic explanation for the development of insulin resistance in hyperhomocysteinemia.