Effect of Serotonin Transporter 5-HTTLPR Polymorphism on Gastrointestinal Intolerance to Metformin: A GoDARTS Study

Diabetes Care. 2016 Nov;39(11):1896-1901. doi: 10.2337/dc16-0706. Epub 2016 Aug 4.


Objective: The mechanism causing gastrointestinal intolerance to metformin treatment is unknown. We have previously shown that reduced-function alleles of organic cation transporter 1 (OCT1) are associated with increased intolerance to metformin. Considering recent findings that serotonin reuptake transporter (SERT) might also be involved in metformin intestinal absorption, and the role of serotonin in gastrointestinal physiology, in this study we investigated the association between a common polymorphism in the SERT gene and metformin gastrointestinal intolerance.

Research design and methods: We explored the effect of composite SERT 5-HTTLPR/rs25531 genotypes, L*L* (LALA), L*S* (LALG, LAS), and S*S* (SS, SLG, LGLG), in 1,356 fully tolerant and 164 extreme metformin-intolerant patients by using a logistic regression model, adjusted for age, sex, weight, OCT1 genotype, and concomitant use of medications known to inhibit OCT1 activity.

Results: The number of low-expressing SERT S* alleles increased the odds of metformin intolerance (odds ratio [OR] 1.31 [95% CI 1.02-1.67], P = 0.031). Moreover, a multiplicative interaction between the OCT1 and SERT genotypes was observed (P = 0.003). In the analyses stratified by SERT genotype, the presence of two deficient OCT1 alleles was associated with more than a ninefold higher odds of metformin intolerance in patients carrying the L*L* genotype (OR 9.25 [95% CI 3.18-27.0], P < 10-4); however, it showed a much smaller effect in L*S* carriers and no effect in S*S* carriers.

Conclusions: Our results indicate that the interaction between OCT1 and SERT genes might play an important role in metformin intolerance. Further studies are needed to replicate these findings and to substantiate the hypothesis that metformin gastrointestinal side effects could be related to the reduced intestinal serotonin uptake.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / genetics*
  • Genotype
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Male
  • Metformin / adverse effects*
  • Middle Aged
  • Octamer Transcription Factor-1 / genetics
  • Polymorphism, Genetic
  • Serotonin Plasma Membrane Transport Proteins / genetics*


  • Hypoglycemic Agents
  • Octamer Transcription Factor-1
  • POU2F1 protein, human
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Metformin