Metformin: Mechanisms in Human Obesity and Weight Loss

Overview

Journal Curr Obes Rep

Specialty Endocrinology

Date 2019 Mar 16

PMID 30874963

Citations 133

Authors

Armen Yerevanian

Alexander A Soukas

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: Metformin has multiple benefits for health beyond its anti-hyperglycemic properties. The purpose of this manuscript is to review the mechanisms that underlie metformin's effects on obesity.

Recent Findings: Metformin is a first-line therapy for type 2 diabetes. Large cohort studies have shown weight loss benefits associated with metformin therapy. Metabolic consequences were traditionally thought to underlie this effect, including reduction in hepatic gluconeogenesis and reduction in insulin production. Emerging evidence suggests that metformin-associated weight loss is due to modulation of hypothalamic appetite regulatory centers, alteration in the gut microbiome, and reversal of consequences of aging. Metformin is also being explored in the management of obesity's sequelae such as hepatic steatosis, obstructive sleep apnea, and osteoarthritis. Multiple mechanisms underlie the weight loss-inducing and health-promoting effects of metformin. Further exploration of these pathways may be important in identifying new pharmacologic targets for obesity and other aging-associated metabolic diseases.

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References

Makimattila S, Nikkila K, Yki-Jarvinen H . Causes of weight gain during insulin therapy with and without metformin in patients with Type II diabetes mellitus. Diabetologia. 1999; 42(4):406-12. DOI: 10.1007/s001250051172. View

Yki-Jarvinen H, Nikkila K, Makimattila S . Metformin prevents weight gain by reducing dietary intake during insulin therapy in patients with type 2 diabetes mellitus. Drugs. 1999; 58 Suppl 1:53-4; discussion 75-82. DOI: 10.2165/00003495-199958001-00012. View

El-Mir M, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X . Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000; 275(1):223-8. DOI: 10.1074/jbc.275.1.223. View

Cubeddu L, Bonisch H, Gothert M, Molderings G, Racke K, Ramadori G . Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2000; 361(1):85-91. DOI: 10.1007/s002109900152. View

Owen M, Doran E, Halestrap A . Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000; 348 Pt 3:607-14. PMC: 1221104. View

Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V . Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000; 49(12):2063-9. PMC: 2995498. DOI: 10.2337/diabetes.49.12.2063. View

Glueck C, Fontaine R, Wang P, Subbiah M, Weber K, Illig E . Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001; 50(7):856-61. DOI: 10.1053/meta.2001.24192. View

Witters L . The blooming of the French lilac. J Clin Invest. 2001; 108(8):1105-7. PMC: 209536. DOI: 10.1172/JCI14178. View

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

10.

Bailey C, Wilcock C, Day C . Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992; 105(4):1009-13. PMC: 1908709. DOI: 10.1111/j.1476-5381.1992.tb09093.x. View

11.

Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple J . Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial. 2005; 17(6):455-65. DOI: 10.1111/j.0894-0959.2004.17606.x. View

12.

de Liefde I, van der Klift M, de Laet C, van Daele P, Hofman A, Pols H . Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int. 2005; 16(12):1713-20. DOI: 10.1007/s00198-005-1909-1. View

13.

Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D . Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005; (3):CD002966. DOI: 10.1002/14651858.CD002966.pub3. View

14.

Levri K, Slaymaker E, Last A, Yeh J, Ference J, DAmico F . Metformin as treatment for overweight and obese adults: a systematic review. Ann Fam Med. 2005; 3(5):457-61. PMC: 1466911. DOI: 10.1370/afm.343. View

15.

Shaw R, Lamia K, Vasquez D, Koo S, Bardeesy N, DePinho R . The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005; 310(5754):1642-6. PMC: 3074427. DOI: 10.1126/science.1120781. View

16.

Kim Y, Kim J, Park Y, Park S, Won K, Choi K . Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes. 2006; 55(3):716-24. DOI: 10.2337/diabetes.55.03.06.db05-0917. View

17.

Bonds D, Larson J, Schwartz A, Strotmeyer E, Robbins J, Rodriguez B . Risk of fracture in women with type 2 diabetes: the Women's Health Initiative Observational Study. J Clin Endocrinol Metab. 2006; 91(9):3404-10. DOI: 10.1210/jc.2006-0614. View

18.

Chau-Van C, Gamba M, Salvi R, Gaillard R, Pralong F . Metformin inhibits adenosine 5'-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology. 2006; 148(2):507-11. DOI: 10.1210/en.2006-1237. View

19.

Kahn S, Haffner S, Heise M, Herman W, Holman R, Jones N . Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006; 355(23):2427-43. DOI: 10.1056/NEJMoa066224. View

20.

Golay A . Metformin and body weight. Int J Obes (Lond). 2007; 32(1):61-72. DOI: 10.1038/sj.ijo.0803695. View