Inhibition of hepatic gluconeogenesis in type 2 diabetes by metformin: complementary role of nitric oxide.

Metformin is the first-line treatment for type 2 diabetes mellitus. Type 2 diabetes mellitus is associated with decreased nitric oxide bioavailability, which has significant metabolic implications, including enhanced insulin secretion and peripheral glucose utilization. Similar to metformin, nitric oxide also inhibits hepatic glucose production, mainly by suppressing gluconeogenesis. This review explores the combined effects of metformin and nitric oxide on hepatic gluconeogenesis and proposes the potential of a hybrid metformin-nitric oxide drug for managing type 2 diabetes mellitus. Both metformin and nitric oxide inhibit gluconeogenesis through overlapping and distinct mechanisms. In hepatic gluconeogenesis, mitochondrial oxaloacetate is exported to the cytoplasm via various pathways, including the malate, direct, aspartate, and fumarate pathways. The effects of nitric oxide and metformin on the exportation of oxaloacetate are complementary; nitric oxide primarily inhibits the malate pathway, while metformin strongly inhibits the fumarate and aspartate pathways. Furthermore, metformin effectively blocks gluconeogenesis from lactate, glycerol, and glutamine, whereas nitric oxide mainly inhibits alanine-induced gluconeogenesis. Additionally, nitric oxide contributes to the adenosine monophosphate-activated protein kinase-dependent inhibition of gluconeogenesis induced by metformin. The combined use of metformin and nitric oxide offers the potential to mitigate common side effects. For example, lactic acidosis, a known side effect of metformin, is linked to nitric oxide deficiency, while the oxidative and nitrosative stress caused by nitric oxide could be counterbalanced by metformin's enhancement of glutathione. Metformin also amplifies nitric oxide -induced activation of adenosine monophosphate-activated protein kinase. In conclusion, a metformin-nitric oxide hybrid drug can benefit patients with type 2 diabetes mellitus by enhancing the inhibition of hepatic gluconeogenesis, decreasing the required dose of metformin for maintaining optimal glycemia, and lowering the incidence of metformin-associated lactic acidosis.