Metformin is the first-line treatment for medical management of Type 2 Diabetes. Up to 25% of
patients experience significant gastrointestinal symptoms and in approximate 5%, side-effects
result in the discontinuation of metformin. It would be of great clinical significance if the
underlying cause of this intolerance was identified.
Recent data has highlighted a metformin transporter in the gut - Organic Cation Transporter
1(OCT1) - as a potential culprit for the variability in metformin tolerance. Across a
diabetic population, up to one in four people were shown to have a single reduced function
allele for OCT1, with approximately 8% having two reduced function alleles. This may increase
the risk of the individual experiencing metformin-associated side-effects, potentially due to
accumulation within the cells lining the intestine. The investigators aim to show that loss
of function of OCT1, either due to genetic variation or drug inhibition of OCT1, may lead to
an increase in the symptoms associated with metformin intolerance.
The study is being undertaken at the Clinical Research Centre in Ninewells Hospital, Dundee.
The investigators will recruit participants from the GoDARTS study (Genetics of Diabetes and
Audit Research Tayside Study). The participants will be healthy controls, i.e. non-diabetic,
and recruited according to their genotype of OCT1 (information from GoDARTS). The volunteers
will then enter a matched cross-over study with two treatment periods. Metformin is taken
during both treatment periods alongside either Omeprazole (a proton pump inhibitor used to
prevent excess stomach acid, known to interact with OCT1) or placebo. The metformin dose is
increased gradually during each period, to a maximum tolerated dose. The investigators expect
to see a lower maximum tolerated dose in individuals with loss of function genotype, or in
those taking concurrent omeprazole compared to placebo. The study will last approximately 9
weeks. Volunteers have 3 visits to the CRC, and weekly phone call interviews.