Introduction:

Metformin, a biguanide, is a well-documented drug used commonly in Type 2 Diabetes Mellitus for over half a century. Metformin’s efficacy in diabetic populations remains indisputable. However, the exact mechanism of action is controversial with increasing evidence now indicating the presence of certain AMP-activated protein kinase (AMPK) independent pathways. This information has been changing the perception that Metformin solely reduces hepatic gluconeogenesis physiologically via an AMPK dependent mechanism at the molecular level. Developments over the last couple of decades have helped discover new targets and pathways that Metformin favorably influences to bring about improvements in not just Diabetes but various age-related diseases as well. It is now widely accepted that Metformin brings about its action by acting on various molecular targets and modulating a variety of different pathways and processes. And though we have been using this drug for almost 60 years, new actions continue to be discovered, broadening the range of conditions where Metformin could be used.

Future Research

● Decipher the exact mechanism(s) of action of Metformin

● Explore more on Metformin’s effects in the gut

● Validate its safety in non-diabetic populations if used in other age-related diseases

References

An, H., & He, L. (2016). Current understanding of metformin effect on the control of hyperglycemia in diabetes. Journal of Endocrinology, 228(3), R97–R106. https://doi.org/10.1530/joe-15-0447

Cokorinos, E. C., Delmore, J., Reyes, A. R., Albuquerque, B., Kjøbsted, R., Jørgensen, N. O., Tran, J.-L., Jatkar, A., Cialdea, K., Esquejo, R. M., Meissen, J., Calabrese, M. F., Cordes, J., Moccia, R., Tess, D., Salatto, C. T., Coskran, T. M., Opsahl, A. C., Flynn, D., … Miller, R. A. (2017). Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice. Cell Metabolism, 25(5), 1147-1159.e10. https://doi.org/10.1016/j.cmet.2017.04.010

Crowley MJ, Diamantidis CJ, McDuffie JR, et al. Metformin Use in Patients with Historical Contraindications or Precautions [Internet]. Washington (DC): Department of Veterans Affairs (US); 2016 Sep. APPENDIX A, FDA SAFETY ANNOUNCEMENTS FOR METFORMIN. Available from: https://www.ncbi.nlm.nih.gov/books/NBK409379/

Database resources of the National Center for Biotechnology Information. (2014). Nucleic Acids Research, 43(D1), D6–D17. https://doi.org/10.1093/nar/gku1130

Foretz, M., Hébrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F., & Viollet, B. (2010). Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. Journal of Clinical Investigation, 120(7), 2355–2369. https://doi.org/10.1172/jci40671

Harvard Health Publishing. (2018, December). Type 2 Diabetes Mellitus. Harvard Health https://www.health.harvard.edu/a_to_z/type-2-diabetes-mellitus-a-to-z

Hur, K. Y., & Lee, M.-S. (2015). New mechanisms of metformin action: Focusing on mitochondria and the gut. Journal of Diabetes Investigation, 6(6), 600–609. https://doi.org/10.1111/jdi.12328

Insulin and glucose production in type 2 diabetes. (2019, August). [Illustration]. www.Healthdirect.Gov.Au. https://www.healthdirect.gov.au/type-2-diabetes

Rodbard, H. W., & Jellinger, P. S. (2012). Comment on: Inzucchi et al. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364-1379. Diabetes Care, 35(10), e70. https://doi.org/10.2337/dc12-0768

Rena, G., Hardie, D. G., & Pearson, E. R. (2017). The mechanisms of action of metformin. Diabetologia, 60(9), 1577–1585. https://doi.org/10.1007/s00125-017-4342-z

Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M. F., Goodyear, L. J., & Moller, D. E. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of clinical investigation, 108(8), 1167–1174. https://doi.org/10.1172/JCI13505