Metformin

From Proteopedia

Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. See also Metformin. The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial glycerol-3-phosphate dehydrogenase (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on gut microbiota.[1][2][3][4] Metformin exerts an anorexiant effect in most people, decreasing caloric intake.[5] Metformin inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin,[6] which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries.[7][8] The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.[9]

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References

1. ↑ LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT, Vatner DF, Gaspar RC, Zhang XM, Cline GW, Nakahara K, Woo S, Shimada A, Hüttemann M, Shulman GI. Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2122287119. PMID:35238637 doi:10.1073/pnas.2122287119
2. ↑ Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia. 2013 Sep;56(9):1898-906. PMID:23835523 doi:10.1007/s00125-013-2991-0
3. ↑ Burcelin R. The antidiabetic gutsy role of metformin uncovered? Gut. 2014 May;63(5):706-7. PMID:23840042 doi:10.1136/gutjnl-2013-305370
4. ↑ Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014 Jun 26;510(7506):542-6. PMID:24847880 doi:10.1038/nature13270
5. ↑ Pappachan JM, Viswanath AK. Medical Management of Diabesity: Do We Have Realistic Targets? Curr Diab Rep. 2017 Jan;17(1):4. PMID:28101792 doi:10.1007/s11892-017-0828-9
6. ↑ Vázquez-Borrego MC, Fuentes-Fayos AC, Gahete MD, Castaño JP, Kineman RD, Luque RM. The Pituitary Gland is a Novel Major Site of Action of Metformin in Non-Human Primates: a Potential Path to Expand and Integrate Its Metabolic Actions. Cell Physiol Biochem. 2018;49(4):1444-1459. PMID:30205369 doi:10.1159/000493448
7. ↑ Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C. Metformin in polycystic ovary syndrome. Ann N Y Acad Sci. 2010 Sep;1205:192-8. PMID:20840272 doi:10.1111/j.1749-6632.2010.05679.x
8. ↑ Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003 Oct 25;327(7421):951-3. PMID:14576245 doi:10.1136/bmj.327.7421.951
9. ↑ Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000 Dec;49(12):2063-9. PMID:11118008 doi:10.2337/diabetes.49.12.2063