Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Abstract

Abnormal elevation of hepatic gluconeogenesis is central to the onset of hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). Metformin corrects hyperglycaemia through inhibition of gluconeogenesis, but its mechanism of action is yet to be fully described. SIRT1 and GCN5 (listed as KAT2A in the MGI Database) have recently been identified as regulators of gluconeogenic gene expression through modulation of levels and activity of the coactivators cAMP-response element binding protein-regulated transcription coactivator 2 (TORC2 or CRTC2 as listed in the MGI Database) and peroxisome proliferator-activated receptor-g coactivator-1a (PGC1a or PPARGC1A as listed in the MGI Database). We report that in db/db mice, metformin (250 mg/kg per day; 7 days) increases hepatic levels of GCN5 protein and mRNA compared with the untreated db/db mice, as well as increases levels of SIRT1 protein and activity relative to controls and untreated db/db mice. These changes were associated with reduced TORC2 protein level and decreased gene expression and activation of the PGC1a gene target phosphoenolpyruvate carboxykinase, and lower plasma glucose and insulin. Inhibition of SIRT1 partially blocked the effects of metformin on gluconeogenesis. SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD C . Moreover, levels of GCN5 were dramatically reduced in db/db mice compared with the controls. This indicates that loss of GCN5-mediated inhibition of gluconeogenesis appears to constitute a major mechanism for the onset of abnormally elevated hepatic glucose production in db/db mice. In conclusion, induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin. In addition, these data identify induction of hepatic GCN5 as a potential therapeutic strategy for treatment of T2DM.

Transcriptional co-factors and hepatic energy metabolism

“…TORC2 protein levels were reduced, gene expression and activation of the PGC1-alpha target gene PEPCK was decreased, and plasma glucose and insulin levels were lower. The data suggested the induction of hepatic GCN5 as a potential therapeutic strategy for treatment of type 2 diabetes [83].…”

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…The studies with unknown status are not reported in the particular, metformin upregulates SIRT1, which, in turn, reduces TORC2 and PGC1-a activity and the plasma levels of glucose and insulin. 94 A 16-week double-blind, placebo-controlled, completed, and published study (NCT00570739) demonstrated that the combination therapy with metformin plus colesevelam (a bile acid sequestrant) was able to significantly reduce the concentration of low-density lipoprotein (LDL) particles and improved the atherogenic plasma lipoprotein profile of patients with early T2DM (Table 2). 95 The dietary polyphenol resveratrol (one of the first activators of SIRT1 to be identified) exerts an anti-diabetic activity by regulating the activity of AMPK and PGC1a.…”

Jejunal Induction of SI and SGLT1 Genes in Rats by High-Starch/Low-Fat Diet Is Associated with Histone Acetylation and Binding of GCN5 on the Genes

“…A recent study reported that GCN5 expression in the liver was induced by the drug metformin (29). Metformin is used in diabetes to improve insulin sensitivity and inhibit gluconeogenesis.…”