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Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action

Yan Shu1, Steven A Sheardown, Chaline Brown

  • 1Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.

The Journal of Clinical Investigation
|May 4, 2007
PubMed

Insights

Organic cation transporter 1 (OCT1) is crucial for metformin

Area of Science:

  • Pharmacology
  • Genetics
  • Metabolic Diseases

Background:

  • Metformin is a first-line treatment for type 2 diabetes.
  • Organic cation transporter 1 (OCT1) facilitates hepatic metformin uptake.
  • The role of OCT1 in metformin's therapeutic effects, including AMP-activated protein kinase (AMPK) activation, remains unclear.

Purpose of the Study:

  • To investigate the role of OCT1 in metformin's action.
  • To determine if OCT1 polymorphisms affect metformin response.
  • To examine the impact of OCT1 genetic variation on glucose metabolism.

Main Methods:

  • Utilized Oct1-deficient mice and mouse hepatocytes.
  • Assessed metformin's effects on AMPK phosphorylation and gluconeogenesis in vitro.
  • Evaluated glucose-lowering effects of metformin in vivo.
  • Identified and characterized OCT1 polymorphisms with reduced metformin uptake.
  • Conducted clinical studies on glucose tolerance tests in individuals with OCT1 polymorphisms.

Main Results:

  • Oct1 deletion in mice reduced metformin's effects on AMPK phosphorylation and gluconeogenesis.
  • Glucose-lowering effects of metformin were abolished in Oct1-deficient mice.
  • Seven nonsynonymous OCT1 polymorphisms showed reduced metformin uptake, including OCT1-420del.
  • Individuals with reduced-function OCT1 polymorphisms exhibited lower response to metformin in glucose tolerance tests.

Conclusions:

  • OCT1 is essential for metformin's therapeutic efficacy.
  • Genetic variations in OCT1 contribute to inter-individual differences in metformin response.
  • Targeting OCT1 or considering its polymorphisms may personalize metformin therapy.

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