The drug metformin is among the most widely prescribed drugs for the treatment of type 2 diabetes and results in an array of therapeutic benefits. Although it has been used for over 30 years, only recently have studies begun to reveal the molecular events responsible for its therapeutic effects. Notably, these studies have shown that metformin acts by phosphorylating the enzyme AMPK, the cellular "energy-sensor", leading to a variety of cellular responses important in diabetic therapy.
A set of mouse and human studies led by Kathleen Giacomini from the University of California, San Francisco and reported in the May 1st issue of the Journal of Clinical Investigation, show that mice lacking organic cation transporter 1 (OCT1) have reduced effects of metformin on AMPK phosphorylation and a decreased ability to control glucose levels. The authors also identified seven mutations in OCT1 in humans that reduce metformin uptake. These studies indicate that OCT1 is important in mediating the therapeutic effects of metformin and that genetic variation in OCT1 in diabetics may contribute to the varied patient responses to this drug.
In an accompanying commentary, Marc Reitman and Eric Schadt from Merck and Rosetta Inpharmatics, respectively, discuss how the identification of individuals that possess specific mutations in certain genes, which are known to affect the action of a particular drug, may eventually help clinicians devise personalized treatment regimes that ensure administration of the right drug for the right person at the right time. They conclude that "tailoring therapeutic choices to the individual should allow lower and better-tolerated doses of drugs that are simultaneously safer and more efficacious. One could eliminate trial-and-error periods of switching among the nine classes of diabetes drugs."
TITLE: Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
AUTHOR CONTACT:
Kathleen M. Giacomini
University of California San Francisco, San Francisco, California, USA.
Phone: (415) 476-1936; Fax (415) 502-4322; E-mail: kathy.giacomini@ucsf.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=30558
ACCOMPANYING COMMENTARY
TITLE: Pharmacogenetics of metformin response: a step in the path toward personalized medicine
AUTHOR CONTACT:
Marc L. Reitman
Merck Research Laboratories, Rahway, New Jersey, USA.
Phone: (732) 594-4609; Fax: (732) 594-3337; E-mail: marc_reitman@merck.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=32133
Journal
Journal of Clinical Investigation