Background:

Metformin HCl is one of the most effective and widely used therapeutics for treatment of type 2 diabetes. It selectively lowers the hepatic gluconeogenesis without rising insulin production, causing weight gain or hypoglycemia. [1]

AMPK (5'AMP-activated protein kinase) acts as a metabolic master switch regulating several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids and the biogenesis of GLUT4 (glucose transporter 4) and mitochondria.

In hepatocytes, AMPK was activated by metformin, followed by decreased ACC (acetyl-CoA carboxylase) activity, induction of fatty acid oxidization and suppression of lipogenic enzyme expression.[2] Metformin also inhibited mGPD (mitochondrial lycerophosphate dehydrogenase),a redox shuttle enzyme, leading to an altered hepatocellular redox state, decreased conversion of lactate and reduced hepatic gluconeogenesis. [1]

In rats treated with metformin, hepatic expression of SEREP-1 mRNAs/protein and activity of ACC were reduced. [2] In metformin treated mice, LKB1 in liver was essential for the ability of metformin to reduce blood glucose [3]. In ASO (Antisense oligonucleotide) knockdown of hepatic mGOD in rats, the phenotype was similar to chronic metformin treatment. It abolished mefromin-induced cytosolic redox state, reduction in plasma glucose concentration and EGP inhibition. [1]

参考文献:
1. Madiraju AK, Erion DM, Rahimi Y et al.? Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.? Nature. 2014 Jun 26;510(7506):542-6.
2. Zhou G, Myers R, Li Y et al.? Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001 Oct;108(8):1167-74.
3. Shaw RJ, Lamia KA, Vasquez D et al.? The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005 Dec 9;310(5754):1642-6.