How does metformin work to treat type 2 diabetes?

The 2023 Standards of Care in Diabetes guidelines from the American Diabetes Association (ADA) recommend metformin (brand names Fortamet, Glumetza, discontinued brand names Glucophage, Riomet) as first line treatment for adults and children ten years and older with type 2 diabetes.¹

Metformin is a biguanide drug that works to reduce both basal and postprandial plasma glucose through reducing glucose production by the liver, increasing sensitivity to insulin, and decreasing transport of glucose from the intestinal lumen to the blood circulation.^2,3 The main cause of elevated blood glucose in fasting patients with diabetes is an increased rate of hepatic gluconeogenesis, which is why metformin is particularly effective at regulating plasma glucose levels.⁴

While the exact molecular targets of metformin that mediate its effects remain unknown, multiple pathways have been studied. Hypotheses for the reduction in hepatic gluconeogenesis include that metformin inhibits complex I of the mitochondrial electron transport chain^5,6 and inhibits mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2) activity, thereby impacting redox regulation of the gluconeogenic process.^7,8 Metformin does not affect insulin production or secretion, although fasting insulin levels and day-long plasma insulin response may decrease with metformin use.^2,3 Modulation of insulin sensitivity instead appears to be mediated by metformin-induced increases in glucagon-like peptide 1 (GLP1) secretion by the intestine via a adenosine monophosphate-activated protein kinase (AMPK) activation-dependent mechanism.⁹ Metformin has also been shown to cause a short-term reduction in sodium-glucose transport protein 1 (SGLT1) on the apical membrane of enterocytes in the jejunum, contributing to the observed reduction in absorption of dietary glucose from the intestinal lumen.⁹

References

1. ElSayed NA, Aleppo G, Aroda VR, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. Jan 1 2023;46(Suppl 1):S140-s157. doi:10.2337/dc23-S009
2. Glucophage (metformin hydrochloride) tablets, for oral use & Glucophage XR (metformin hydrochloride) extended-release tablets, for oral use. [Package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018.
3. Riomet (metformin hydrochloride) oral solution. [Package insert]. Cranbury, NJ: Sun Pharmaceutical Industries; 2018.
4. Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest. Oct 1992;90(4):1323-7. doi:10.1172/jci115997
5. 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. Jun 15 2000;348 Pt 3(Pt 3):607-14.
6. El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. Jan 7 2000;275(1):223-8. doi:10.1074/jbc.275.1.223
7. Madiraju AK, Qiu Y, Perry RJ, et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. Sep 2018;24(9):1384-1394. doi:10.1038/s41591-018-0125-4
8. Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. Jun 26 2014;510(7506):542-6. doi:10.1038/nature13270
9. Zubiaga L, Briand O, Auger F, et al. Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes. iScience. Apr 21 2023;26(4):106057. doi:10.1016/j.isci.2023.106057