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

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 transporter (SERT) might also be involved in metformin intestinal absorption, and serotonin role in gastrointestinal physiology, in this study we investigated the association between a common polymorphism in 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 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 (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 over a nine-fold higher odds of metformin intolerance in patients carrying L*L* genotype (OR=9.25, 95% CI 3.18-27.0, P<10-4), however, it showed much smaller effect in L*S* carriers, and no effect in S*S* carriers.
CONCLUSIONS: Our results indicate that 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.