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

Farahani, Arman1; Farahani, Aryan1; Kashfi, Khosrow2; Ghasemi, Asghar1,*

Author Information

1Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA

*Correspondence to: Asghar Ghasemi, PhD, Ghasemi@sbmu.ac.ir or Ghasemi.asghar@gmail.com.

Funding:This work was supported by Shahid Beheshti University of Medical Sciences, No. 43011564-1; and in part by the National Institutes of Health, USA, Nos. R01GM123508 and 2U54MD017979-01A1 (both to KK).

Abstract

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.

摘要

二甲双胍是2型糖尿病的一线治疗药物。2型糖尿病与一氧化氮生物利用度降低有关，而一氧化氮具有重要的代谢调节作用，包括增强胰岛素分泌和外周葡萄糖利用。与二甲双胍类似，一氧化氮也能抑制肝脏葡萄糖生成，主要通过抑制糖异生作用实现。本综述探讨了二甲双胍和一氧化氮对肝脏糖异生的联合作用，并提出了一种二甲双胍-一氧化氮杂合药物用于治疗2型糖尿病的潜力。二甲双胍和一氧化氮通过重叠但又有区别的机制抑制糖异生。在肝脏糖异生过程中，线粒体草酰乙酸通过多种途径（包括苹果酸途径、直接途径、天冬氨酸途径和延胡索酸途径）转运至细胞质。一氧化氮和二甲双胍对草酰乙酸转运的影响具有互补性：一氧化氮主要抑制苹果酸途径，而二甲双胍则强效抑制延胡索酸途径和天冬氨酸途径。此外，二甲双胍能有效阻断乳酸、甘油和谷氨酰胺的糖异生作用，而一氧化氮主要抑制丙氨酸诱导的糖异生。一氧化氮还参与二甲双胍诱导的、依赖于腺苷酸活化蛋白激酶的糖异生抑制作用。二甲双胍和一氧化氮的联合使用具有减轻常见副作用的潜力。例如，二甲双胍已知的副作用乳酸性酸中毒与一氧化氮缺乏有关，而一氧化氮引起的氧化应激和亚硝化应激则可能被二甲双胍增强的谷胱甘肽作用所抵消。二甲双胍还能增强一氧化氮诱导的腺苷酸活化蛋白激酶激活。总之，二甲双胍-一氧化氮杂合药物可通过增强对肝脏糖异生的抑制、减少维持最佳血糖所需的一甲双胍剂量以及降低二甲双胍相关性乳酸性酸中毒的发生率，使2型糖尿病患者受益。