Witters LA. The blooming of the French lilac. J Clin Invest. 2001;108(8):1105–7.
Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–76.
Werner EA, Bell J. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc Trans. 1922;121:1790–4.
DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541–9.
American Diabetes A. Standards of medical care in diabetes-2019 abridged for primary care providers. Clin Diabetes. 2019;37(1):11–34.
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):550–4.
Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89.
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427–43.
Saenz A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(3):CD002966.
Golay A. Metformin and body weight. Int J Obes. 2008;32(1):61–72.
Fontbonne A, Charles MA, Juhan-Vague I, Bard JM, Andre P, Isnard F, et al. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group. Diabetes Care. 1996;19(9):920–6.
Paolisso G, et al. Effect of metformin on food intake in obese subjects. Eur J Clin Investig. 1998;28(6):441–6.
Glueck CJ, Fontaine RN, Wang P, Subbiah MTR, Weber K, Illig E, et al. 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.
Levri KM, et al. Metformin as treatment for overweight and obese adults: a systematic review. Ann Fam Med. 2005;3(5):457–61.
•• Diabetes Prevention Program Research, G. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35(4):731–7. Largest and most comprehensive study that identified persistent weight loss with metformin treatment.
• Apovian CM, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–62 Provides the most recent guidelines on pharmacotherapy for obesity.
Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr Pract. 2016;22(Suppl 3):1–203.
de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.
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.
Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJM, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169(6):616–25.
Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49(12):2063–9.
Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998;338(13):867–72.
El-Mir MY, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–8.
He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab. 2015;21(2):159–62.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74.
Shaw RJ, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–6.
Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355–69.
Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin. J Clin Invest. 2010;120(7):2267–70.
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494(7436):256–60.
• Madiraju AK, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542–6. A novel mechanism by which metformin reduces hepatic glucose output by inhibiting the mitochondrial glycerol-phosphate shuttle, altering hepatocellular redox potential.
Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang XM, Zhang D, et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. 2018;24(9):1384–94.
Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6(1):47–53.
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.
Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial. 2004;17(6):455–65.
Owen MR, Doran E, Halestrap AP. 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.
Tokubuchi I, et al. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS One. 2017;12(2):e0171293.
Islam H, Townsend LK, McKie GL, Medeiros PJ, Gurd BJ, Hazell TJ. Potential involvement of lactate and interleukin-6 in the appetite-regulatory hormonal response to an acute exercise bout. J Appl Physiol (1985). 2017;123(3):614–23.
Lam CK, et al. Central lactate metabolism regulates food intake. Am J Physiol Endocrinol Metab. 2008;295(2):E491–6.
Chari M, Lam CKL, Wang PYT, Lam TKT. Activation of central lactate metabolism lowers glucose production in uncontrolled diabetes and diet-induced insulin resistance. Diabetes. 2008;57(4):836–40.
Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011;152(12):4610–9.
Napolitano A, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014;9(7):e100778.
DeFronzo RA, Buse JB, Kim T, Burns C, Skare S, Baron A, et al. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia. 2016;59(8):1645–54.
• Buse JB, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2016;39(2):198–205. Identified the importance of gut-specific effects of metformin. Metformin’s effects were present even when serum levels were minimal.
Lien F, Berthier A, Bouchaert E, Gheeraert C, Alexandre J, Porez G, et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J Clin Invest. 2014;124(3):1037–51.
Kuhre RE, Wewer Albrechtsen NJ, Larsen O, Jepsen SL, Balk-Møller E, Andersen DB, et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab. 2018;11:84–95.
Duca FA, Côté CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med. 2015;21(5):506–11.
Huang YC, et al. Effects of metformin on the cerebral metabolic changes in type 2 diabetic patients. ScientificWorldJournal. 2014;2014:694326.
de Wit S, Corlett PR, Aitken MR, Dickinson A, Fletcher PC. Differential engagement of the ventromedial prefrontal cortex by goal-directed and habitual behavior toward food pictures in humans. J Neurosci. 2009;29(36):11330–8.
Huerta CI, Sarkar PR, Duong TQ, Laird AR, Fox PT. Neural bases of food perception: coordinate-based meta-analyses of neuroimaging studies in multiple modalities. Obesity (Silver Spring). 2014;22(6):1439–46.
• Duan Y, et al. Metformin inhibits food intake and neuropeptide Y gene expression in the hypothalamus. Neural Regen Res. 2013;8(25):2379–88. Identified hypothalamic mechanism by which metformin could inhibit appetite.
Stevanovic D, Janjetovic K, Misirkic M, Vucicevic L, Sumarac-Dumanovic M, Micic D, et al. Intracerebroventricular administration of metformin inhibits ghrelin-induced hypothalamic AMP-kinase signalling and food intake. Neuroendocrinology. 2012;96(1):24–31.
Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24(1):49–57.
Labuzek K, et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep. 2010;62(5):956–65.
Vaisse C, Halaas JL, Horvath CM, Darnell JE, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet. 1996;14(1):95–7.
Lv WS, Wen JP, Li L, Sun RX, Wang J, Xian YX, et al. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res. 2012;1444:11–9.
Aubert G, Mansuy V, Voirol MJ, Pellerin L, Pralong FP. The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. Metabolism. 2011;60(3):327–34.
Kim YW, Kim JY, Park YH, Park SY, Won KC, Choi KH, et al. Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes. 2006;55(3):716–24.
Stark R, Ashley SE, Andrews ZB. AMPK and the neuroendocrine regulation of appetite and energy expenditure. Mol Cell Endocrinol. 2013;366(2):215–23.
Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LGD, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest. 2007;117(8):2325–36.
• Chau-Van C, et al. Metformin inhibits adenosine 5′-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology. 2007;148(2):507–11. Explored mechanism of metformin’s effects on hypothalamic neurons. It showed that unlike peripheral AMPK, neuronal AMPK is suppressed by metformin.
McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426–35.
Gontier E, Fourme E, Wartski M, Blondet C, Bonardel G, le Stanc E, et al. High and typical 18F-FDG bowel uptake in patients treated with metformin. Eur J Nucl Med Mol Imaging. 2008;35(1):95–9.
Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992;105(4):1009–13.
• Dujic T, et al. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with type 2 diabetes. Diabet Med. 2016;33(4):511–4. Population study that suggested that concentrations of metformin in the gut lumen affects risk of experiencing GI side effects from metformin.
Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CNA, Pearson ER. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64(5):1786–93.
Cubeddu LX, Bönisch H, Göthert M, Molderings G, Racké K, Ramadori G, et al. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn Schmiedeberg's Arch Pharmacol. 2000;361(1):85–91.
Schiffman SS. Influence of medications on taste and smell. World J Otorhinolaryngol Head Neck Surg. 2018;4(1):84–91.
Lee N, Duan H, Hebert MF, Liang CJ, Rice KM, Wang J. Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem. 2014;289(39):27055–64.
Maruvada P, Leone V, Kaplan LM, Chang EB. The human microbiome and obesity: moving beyond associations. Cell Host Microbe. 2017;22(5):589–99.
Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99–103.
Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63(5):727–35.
Cani PD, de Vos WM. Next-generation beneficial microbes: the case of Akkermansia muciniphila. Front Microbiol. 2017;8:1765.
Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016;7(3):189–200.
Zhang X, Zhao Y, Xu J, Xue Z, Zhang M, Pang X, et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015;5:14405.
Bauer PV, et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 2018;27(1):101–117 e5.
• Wu H, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23(7):850–8. Explored impacts of metformin with the microbiome. It showed through transplantation studies that metformin alters microbiome composition that is associated with improved metabolic status.
Collaborators GBDO, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13–27.
Bouchard DR, Dionne IJ, Brochu M. Sarcopenic/obesity and physical capacity in older men and women: data from the Nutrition as a Determinant of Successful Aging (NuAge)-the Quebec longitudinal Study. Obesity (Silver Spring). 2009;17(11):2082–8.
Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010;5(1):e8758.
Kim HJ, Lee SJ, Chun KH, Jeon JY, Han SJ, Kim DJ, et al. Metformin reduces the risk of cancer in patients with type 2 diabetes: an analysis based on the Korean National Diabetes Program Cohort. Medicine (Baltimore). 2018;97(8):e0036.
Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338–45.
Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11(5):390–401.
• Wu L, et al. An ancient, unified mechanism for metformin growth inhibition in C elegans and cancer. Cell. 2016;167(7):1705–1718 e13. Mechanistic paper showing that metformin extends lifespan and inhibits growth of cancer cells by altering mitochondrial function, mTOR, and nucleocytoplasmic transport through the nuclear pore complex.
Castillo-Quan JI, Blackwell TK. Metformin: restraining nucleocytoplasmic shuttling to fight cancer and aging. Cell. 2016;167(7):1670–1.
D'Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009;136(2):284–95.
Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153(1):228–39.
Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23(6):1060–5.
Long DE, Peck BD, Martz JL, Tuggle SC, Bush HM, McGwin G, et al. Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial. Trials. 2017;18(1):192.
Li Y, et al. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep. 2013;1(1):57–64.
• Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57. Guideline paper from the American Association for the Study of Liver Disease (AASLD) on the management of nonalcoholic fatty liver disease.
Lavrentaki A, et al. Mechanisms of disease: the endocrinology of obstructive sleep apnoea. Eur J Endocrinol. 2018.
Lin D, et al. The relationship between metformin and obstructive sleep apnea. J Sleep Med Disord. 2015;2(4).
Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, et al. 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.
de Liefde II, et al. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int. 2005;16(12):1713–20.
Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C, et al. The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int. 2013;24(10):2659–70.
Nordklint AK, Almdal TP, Vestergaard P, Lundby-Christensen L, Boesgaard TW, Breum L, et al. The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial. Osteoporos Int. 2018;29(11):2517–26.
Schwartz AV. Diabetes, bone and glucose-lowering agents: clinical outcomes. Diabetologia. 2017;60(7):1170–9.
Bliddal H, Leeds AR, Christensen R. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons - a scoping review. Obes Rev. 2014;15(7):578–86.
Lu CH, et al. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: a nationwide, retrospective, matched-cohort study in Taiwan. PLoS One. 2018;13(1):e0191242.
Chen D, Xia D, Pan Z, Xu D, Zhou Y, Wu Y, et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis. 2016;7(10):e2441.
Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol. 2013;20(5):437–44.
Lu DY, Huang CC, Huang PH, Chung CM, Lin SJ, Chen JW, et al. Metformin use in patients with type 2 diabetes mellitus is associated with reduced risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. BMC Cardiovasc Disord. 2014;14:187.
Xin G, Wei Z, Ji C, Zheng H, Gu J, Ma L, et al. Metformin uniquely prevents thrombosis by inhibiting platelet activation and mtDNA release. Sci Rep. 2016;6:36222.