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.
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.
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.