The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective

Abstract

Metformin therapy lowers blood glucose in type 2 diabetes by targeting various pathways including hepatic gluconeogenesis. Despite widespread clinical use of metformin the molecular mechanisms by which it inhibits gluconeogenesis either acutely through allosteric and covalent mechanisms or chronically through changes in gene expression remain debated. Proposed mechanisms include: inhibition of Complex 1; activation of AMPK; and mechanisms independent of both Complex 1 inhibition and AMPK. The activation of AMPK by metformin could be consequent to Complex 1 inhibition and raised AMP through the canonical adenine nucleotide pathway or alternatively by activation of the lysosomal AMPK pool by other mechanisms involving the aldolase substrate fructose 1,6-bisphosphate or perturbations in the lysosomal membrane. Here we review current interpretations of the effects of metformin on hepatic intermediates of the gluconeogenic and glycolytic pathway and the candidate mechanistic links to regulation of gluconeogenesis. In conditions of either glucose excess or gluconeogenic substrate excess, metformin lowers hexose monophosphates by mechanisms that are independent of AMPK-activation and most likely mediated by allosteric activation of phosphofructokinase-1 and/or inhibition of fructose bisphosphatase-1. The metabolite changes caused by metformin may also have a prominent role in counteracting G6pc gene regulation in conditions of compromised intracellular homeostasis.

Keywords: AMPK; Liver metabolism; gluconeogenesis; metformin; phosphofructokinase-1.

Figure 2

Crossover plots of metabolites of gluconeogenesis and glycolysis in liver or isolated hepatocytes. (A) Effects of AICAR (500 μM) in hepatocytes incubated with 10 mM lactate + 1 mM pyruvate [61]. (B) Effects of mitochondrial inhibitors (DCMU, dichlorophenyl dimethylurea) [69] or phenformin [70], in rat hepatocytes incubated with 10 mM lactate + 1 mM pyruvate (red) or effects of metformin on rat liver in vivo [6] (blue).

Figure 1

Liver concentrations of intermediates of glycolysis and gluconeogenesis. (A) Metabolic intermediates of glycolysis and gluconeogenesis. (B) Concentrations of key metabolites in rat liver in the fed and fasted state; data from Bergmeyer, HU [52]). (C,D) Liver metabolites in fed and fasted rats treated with glucose (2 g/kg, 10 min) or glucagon (1 mg/kg, 2 min); data from [53,54]. (E) Effects of 1 mM oleate on metabolites in hepatocytes from fasted rats, data from [55]. (F) Rat liver metabolites in rested and exercised rats, data from [56]. * p < 0.05 fasted vs. fed

Figure 3

Metabolic pathways linked to glycerol 3-P formation in liver. G3P is generated from glycerol phosphorylation by glycerokinase or from DHAP, an intermediate of glycolysis and gluconeogenesis by cGPD, which catalyses the reversible NADH/NAD linked interconversion of DHAP and G3P; mGPD on the outer surface of the mitochondrial innermembrane catalyses irreversible oxidation of G3P coupled to the transfer of electrons to ubiquinone in the respiratory chain.