Genetic Variation in OCT1 and Response to Metformin
Status:
Withdrawn
Trial end date:
2011-06-01
Target enrollment:
Participant gender:
Summary
Type 2 diabetes its microvascular and macrovascular complications have become a major global
health problem. Metformin is often used as first-line therapy for this disorder given that it
is cheap, may cause weight loss and does not have significant side-effects in healthy
patients. On the other hand, as many as one third of all patients with type 2 diabetes
initially treated with metformin never achieve a meaningful response to this intervention.
Recently, genetic variation in the organic cation transporter 1 (Oct1) gene which encodes a
protein, OCT1, mediating metformin uptake by the liver, its primary site of action, has been
shown alter metformin action. In Oct1-deficient mice the glucose-lowering effects of
metformin are completely abolished. Moreover a polymorphism with a 20% minor allele frequency
in Caucasians also alters the effect of metformin on glucose tolerance (the net result of
glucose uptake and glucose release) after ingestion of 75g of glucose. However, it is unknown
if this polymorphism affects suppression of endogenous glucose production or stimulation of
peripheral glucose uptake by metformin, or both, and to what degree. We propose to utilize
established methodology to measure glucose turnover in response to a mixed meal to determine
how common genetic variation in OCT1 alters response to metformin in healthy volunteers. This
will clarify the effect of these variants on response to metformin in humans. The knowledge
gained from this study will help to design future studies examining the role of OCT1 genotype
in determining initial therapy for type 2 diabetes.