Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes

Abstract

Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK ␣2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK ␣2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK ␣2.

Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects

“…In line with work by Musi et al [2], we found that enzyme activity of AMPK, measured in samples taken prior to insulin administration in the clamp study, was increased in muscles of patients receiving long-term metformin treat- Fig. 2 Effects of long-term metformin treatment on phosphorylation/activation of PKB in diabetic muscle.…”

“…The mechanism of action of metformin, a widely used agent for treating type 2 diabetes mellitus, is uncertain, but recent studies suggest involvement of 5'-AMP-activated protein kinase (AMPK) [1][2][3], which is activated by metformin in muscle and liver, and which, in serving as a metabolic energy sensor of 5'-AMP/ATP levels, increases energy (ATP) production by: (1) promoting glucose uptake into muscle; and (2) diminishing lipid synthesis and increasing the oxidation of fatty acids in both muscle and liver.…”

“…However, metformin increases the phosphorylation/activity of AMPK in muscles of diabetic subjects [2]. In muscle preparations of rodents and cultured L6 myotubes, substances that activate AMPK -e.g., aminoimidazole-4-carboxamide-1-β-D-riboside (AICAR), which enters cells and mimics 5'-AMP, and dinitrophenol (DNP), which uncouples mitochondrial oxidative phosphorylation, thereby increasing 5'-AMP levels -also activate atypical protein kinase C (aPKC) isoforms, PKC-ζ and PKC-λ.…”

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

“…In addition, in some of these studies the concentration of Metformin was likely supra‐therapeutic. In addition, in particular in individuals where some degree of mitochondrial impairment may already be present, there may be an association between Metformin and increased plasma lactate concentrations 26, 27. However, Metformin has clear efficacy in DM, and may have benefit in other conditions as well 28.…”

Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin

“…The action of metformin in ameliorating hyperglycaemia is linked to its ability to reduce hepatic gluconeogenesis and to improve peripheral insulin sensitivity [1,2]. Metformin promotes glucose uptake in muscle [3,4] and lowers hepatic glucose production [5,6]. In addition, metformin improves lipid metabolism, lowering plasma triglycerides [7,8] and nonesterified fatty acids [9].…”