Skip to main content
SpringerLink
Log in

Metformin and gut microbiota: their interactions and their impact on diabetes

  • Review Article
  • Published:
Hormones Aims and scope Submit manuscript

Abstract

The ratio of human to bacterial cells in the human body (microbiota) is around 1:1. As a result of co-evolution of the host mucosal immune system and the microbiota, both have developed multiple mechanisms to maintain homeostasis. However, dissociations between the composition of the gut microbiota and the human host may play a crucial role in the development of type 2 diabetes. Metformin, the most frequently administered medication to treat patients with type 2 diabetes, has only recently been suggested to alter gut microbiota composition through the increase in mucin-degrading Akkermansia muciniphila, as well as several SCFA-producing (short-chain fatty acid) microbiota. The gut microbiota of participants on metformin has exerted alterations in gut metabolomics with increased ability to produce butyrate and propionate, substances involved in glucose homeostasis. Thus, metformin appears to affect the microbiome, and an individual’s metformin tolerance or intolerance may be influenced by their microbiome. In this review, we will focus on the effects of metformin in gut microbiota among patients with T2DM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Backhed F (2005) Host-bacterial mutualism in the human intestine. Science 307:1915–1920

    Article  CAS  PubMed  Google Scholar 

  2. Gill SR, Pop M, DeBoy RT et al (2006) Metagenomic analysis of the human distal gut microbiome. Science 312:1355–1359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sender R, Fuchs S, Milo R (2016) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14(8):e1002533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qin J, Li Y, Cai Z et al (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490:55–60

    Article  CAS  PubMed  Google Scholar 

  5. Karlsson FH, Tremaroli V, Nookaew I et al (2013) Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498:99–103

    Article  CAS  PubMed  Google Scholar 

  6. Larsen N, Vogensen FK, van den Berg FWJ et al (2010) Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 5:e9085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang X, Shen D, Fang Z et al (2013) Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One 8:e71108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tilg H, Moschen AR (2014) Microbiota and diabetes: an evolving relationship. Gut 63:1513–1521

    Article  CAS  PubMed  Google Scholar 

  9. Forslund K, Hildebrand F, Nielsen T et al (2015) Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. de la Cuesta-Zuluaga J, Mueller NT, Vanessa Corrales-Agudelo V et al (2017) Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care 40:54–62

    Article  CAS  PubMed  Google Scholar 

  11. Bennett D (2005) Growing pains for metabolomics. Scientist 19(8):25–28

    Google Scholar 

  12. Pedersen HK, Gudmundsdottir V, Nielsen HB et al (2016) Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535:376–381

    Article  CAS  PubMed  Google Scholar 

  13. Perry RJ, Peng L, Barry NA et al (2016) Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 534:213–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee H, Ko G (2014) Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol 80:5935–5943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shin NR, Lee JC, Lee HY et al (2014) An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63:727–735

    Article  CAS  PubMed  Google Scholar 

  16. Napolitano A, Miller S, Nicholls AW et al (2014) Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One 9:e100778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gall WE, Beebe K, Lawton KA et al (2010) α-Hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS One 5:e10883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bonora E, Cigolini M, Bosello O et al (1984) Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in non-diabetic subjects. Curr Med Res Opin 9:47–51

    Article  CAS  PubMed  Google Scholar 

  19. Bailey CJ, Wilcock C, Scarpello JH (2008) Metformin and the intestine. Diabetologia 51:1552–1553

    Article  CAS  PubMed  Google Scholar 

  20. Sekar S, Chandrasekaran A, Rao U, Sastry TP (2011) Comparison of some of the physicochemical characteristics of type 2 diabetic and normal human bones: a sample study. J Diabetes Complicat 25:187–192

    Article  Google Scholar 

  21. DeFronzo RA, Buse JB, Kim T et al (2016) Once-daily delayed release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia 59:1645–1654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Buse JB, DeFronzo RA, Rosenstock J et al (2016) 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 39:198–205

    Article  CAS  PubMed  Google Scholar 

  23. Wu H, Esteve E, Tremaroli V et al (2017) Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. https://doi.org/10.1038/nm.4345

  24. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE (2012) Metformin pathways: pharmacokinetic and pharmacodynamics. Pharmacogenet Genomics 22(11):820–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dresser MJ, Xiao G, Leabman MK, Gray AT, Giacomini KM (2002) Interactions of N-tetraalkylammonium compounds and biguanides with a human renal organic cation tranporter (hOCT2). Pharm Res 19:1244–1247

    Article  CAS  PubMed  Google Scholar 

  26. Kimura N, Masuda S, Tanihara Y et al (2005) Metformin is a superior substrate for renal organic cation tranporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet 20:379–386

    Article  CAS  PubMed  Google Scholar 

  27. Urakami Y, Nakamura N, Takahashi K et al (1999) Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett 461:339–342

    Article  CAS  PubMed  Google Scholar 

  28. Urakami Y, Okuda M, Saito H, Inui K (2000) Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett 473:173–176

    Article  CAS  PubMed  Google Scholar 

  29. Asaka J, Terada T, Okuda M, Katsura T, Inui K (2006) Androgen receptor is responsible for rat organic cation transporter 2 gene regulation but not for rOCT1 and rOCT3. Pharm Res 23:697–704

    Article  CAS  PubMed  Google Scholar 

  30. Leabman MK, Giacomini KM (2003) Estimating the contribution of genes and environment to variation in renal drug clearance. Pharmacogenetics 13:581–584

    Article  CAS  PubMed  Google Scholar 

  31. Mofo Mato EP, Guewo-Fokeng M, Essop MF, Oroma Owira PM (2018) Genetic polymorphisms of organic cation transporter 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes: a systematic review. Medicine 97:27e11349

    Article  CAS  Google Scholar 

  32. Barengolts E, Green SJ, Eisenberg Y et al (2018) Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease. PLoS One 13(3):e0194171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Burton JH, Johnson M, Johnson J, Hsia DS, Greenway FL, Heiman ML (2015) Addition of a gastrointestinal microbiome modulator to metformin improves metformin tolerance and fasting glucose levels. J Diabetes Sci Technol 9:808–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brunkwall L, Orho-Melander M (2017) The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities. Diabetologia 60:943–951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract. Diabetologia 59:426–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Henry RR, Frias JP, Walsh B et al (2018) Improved glycemic control with minimal systemic metformin exposure: effects of metformin delayed-release (metformin DR) targeting the lower bowel over 16 weeks in a randomized trial in subjects with type 2 diabetes. PLoS One 13(9):e0203946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Duca FA, Cote CD, Rasmussen BA et al (2015) Metformin activates a duodenal AMPK-dependent pathway to lower hepatic glucose production in rats. Nat Med 21:506–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Duong JK, Furlong TJ, Roberts DM et al (2013) The role of metformin in metformin-associated lactic acidosis (MALA): case series and formulation of a model of pathogenesis. Drug Saf 36(9):733–746

    Article  CAS  PubMed  Google Scholar 

  39. Maideen NMP, Jumale A, Balasubramaniam R (2017) Drug interactions of metformin involving drug transporter proteins. Adv Pharm Bull 7(4):501–505

    Article  CAS  Google Scholar 

  40. Li Q, Liu F, Zheng TS, Tang JL, Lu HJ, Jia WP (2010) SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin. Acta Pharmacol Sin 31:184–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Endocrinology, Diabetes and Metabolism, Evangelismos General Hospital, 45-47 Ipsilantou str, Athens, Greece

    Natalia G. Vallianou, Theodora Stratigou & Stylianos Tsagarakis

Authors
  1. Natalia G. Vallianou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theodora Stratigou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stylianos Tsagarakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Natalia G. Vallianou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights and informed consent

This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vallianou, N.G., Stratigou, T. & Tsagarakis, S. Metformin and gut microbiota: their interactions and their impact on diabetes. Hormones 18, 141–144 (2019). https://doi.org/10.1007/s42000-019-00093-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42000-019-00093-w

Keywords

Search

Navigation