Metformin lowers both basal and postprandial plasma glucose. It works mainly by suppressing excessive hepatic glucose production (through a reduction in gluconeogenesis) [Article:11118008]. Other potential pharmacodynamic roles of Metformin metformin include: an increase in glucose uptake, increase in insulin signaling, decrease in fatty acid and triglyceride synthesis, and an increase in fatty acid beta-oxidation. Metformin may also increase glucose utilization in peripheral tissues, and possibly reduce food intake and intestinal glucose absorption. As metformin does not stimulate endogenous insulin secretion, it does not cause hypoglycemia or hyperinsulinemia, side effects associated with other anti-diabetic drugs.
The molecular mechanisms underlying metformin action appear to be complex and remain a topic of much debate. However, there is general agreement that metformin administration results in phosphorylation of AMPK in the liver, which in turn may lead to many of the pharmacologic effects of metformin including inhibition of glucose and lipid synthesis. Although the specific route of AMPK phosphorylation is not yet clear, molecular components LKB1/STK11 and ATM have been demonstrated to play a role in the phosphorylation of AMPK in the presence of metformin [Articles:21163246, 21163246]. However, ATM, LKB1 and AMPK are not the direct targets of metformin [Article:16952573]. Although the direct target has not been elucidated, metformin has been reported to inhibit complex I of the respiratory chain (encoded by genes NDUFA1 , NDUFA2, NDUFAB1 , NDUFA11 ; NDUFS1 , NDUFS2, NDUFV1, NDUFS6, NDUFS4 , NDUFB4 etc.), suggesting that this inhibition may activate AMPK by increasing cellular AMP:ATP ratios [Articles:19629071, 16952573, 10839993, 10617608]. AMPK is a major cellular regulator of lipid and glucose metabolism. The activated AMPK phosphorylates and inactivates HMG-CoA reductase (HMGCR), MTOR (target of rapamycin); ACC-2 (ACACB); ACC (ACACA), glycerol-3-phosphate acyltransferase (GPAT/PPAT), and carbohydrate response element binding protein (CHREBP) [Articles:11724780, 21163246]. Activation of AMPK by metformin also suppresses expression of SREBP-1 (SREBF1), a key lipogenic transcription factor [Article:11602624]. Phosphorylated AMPK also activates SiRT1 and increases Pgc-1a expression in the nucleus, leading to the downstream activation of mitochondrial biogenesis. A recent publication has also demonstrated that Metformin disrupts the co-activation of PXR with SRC1, resulting in down regulation of CYP3A4 gene expression [Article:21920351]. Finally, activated AMPK results in an increase in glucose uptake in skeletal muscle via an increase in GLUT4 (encoded by gene SLC2A4) translocation activity [Article:17476361]. The overall effect of AMPK activation includes the stimulation of fatty acid (FA) oxidation with inhibition of cholesterol and triglyceride synthesis in the liver and stimulation of FA oxidation and glucose uptake in skeletal muscle as well as a systemic increase in insulin sensitivity [Article:19629071].
Metformin has also been shown to possess tumor suppression ability and emerges as an agent that has the potential to protect from cancer [Article:20557275]. Population studies have shown that metformin is associated with a significant reduction of neoplasias in multiple cancer types (cancer of the breast and prostate, in particular). Metformin may also inhibit the growth of cancer cells. The mechanisms underlying this protective potential of metformin are not well understood. The cell cycle arrest in metformin treated breast cancer cells seems to involve activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1 [Articles:19046439, 18212742]. Metformin was reported to suppress HER2 (ERBB2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1/ RPS6KB1 in human breast carcinoma cells [Article:19106626].
Gong Li, Goswami Srijib, Giacomini Kathleen M, Altman Russ B, Klein Teri E. "Metformin pathways: pharmacokinetics and pharmacodynamics" Pharmacogenetics and genomics (2012).
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