General Information:

Id: 6,456 (click here to show other Interactions for entry)
Diseases: Cancer
Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Viollet B et al.(2012) Cellular and molecular mechanisms of metformin: an overview Clin. Sci. 122: 253-270 [PMID: 22117616]

Interaction Information:

Comment AMPK involvement in the antidiabetic effect of metformin was initially supported by a study showing that the glucose-lowering effect of the drug was greatly decreased in mice lacking hepatic LKB1. LKB1/AMPK signalling has been reported to regulate the phosphorylation and nuclear exclusion of CRTC2 [CREB (cAMP-response-element-binding protein)-regulated transcription co-activator 2; also referred to as TORC2 (transducer of regulated CREB-binding protein 2)]. CRTC2 has been identified as a pivotal regulator of hepatic glucose output in response to fasting by directing transcriptional activation of the gluconeogenic programme. Non-phosphorylated CRTC2 translocates to the nucleus, where it associates with phosphorylated CREB to drive the expression of PGC-1alpha (PPAR-gamma co-activator-1alpha) and its subsequent gluconeogenic target genes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6- phosphatase). Phosphorylation of Ser171 on CRTC2 by AMPK and/or AMPK-related kinases, including SIKs (salt-inducible kinases), is critical for determining the activity, cellular localization and degradation of CRTC2, thereby inhibiting the gluconeogenic programme. However, since CRTC2 is O-glycolysated at Ser171 in insulin-resistance states, making phosphorylation impossible, it is unlikely that metformin regulates gluconeogenesis through CTRC2 phosphorylation. A possible alternative mechanism for the inhibitory action of metformin on TORC2-mediated gluconeogenesis has been proposed, involving an increase of hepatic SIRT1 (sirtuin 1) activity, an NAD + -dependent protein deacetylase, through AMPK-mediated induction of NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme for NAD + biosynthesis. SIRT1 has been reported to deacetylate CRTC2, resulting in the loss of protection from COP1 (constitutive photomorphogenesis 1)-mediated ubiquitination and subsequent degradation.
Formal Description
Interaction-ID: 61187

drug/chemical compound

Metformin

increases_activity of

gene/protein

SIRT1

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