The aim of the study is to evaluate the pharmacodynamic impact of metformin in healthy Caucasian volunteers with and without single polymorphisms M420del or R61C in OCT1, thus the study hypothesis is that metformin only affect the hepatic gluconeogenesis in healthy volunteers with functional OCT1-transporters.

NCT01400191

Conditions

1. Pharmacogenetics of Metformin

Interventions

1. Drug: Metformin

The Inhibitory Effect of Metformin on Gluconeogenesis in Relation to Polymorphisms in Organic Cation Transporter 1 The aim of the study is to evaluate the pharmacodynamic impact of metformin in healthy Caucasian volunteers with and without single polymorphisms M420del or R61C in OCT1, thus the study hypothesis is that metformin only affect the hepatic gluconeogenesis in healthy volunteers with functional OCT1-transporters. --- R61C ---

Inclusion Criteria: - Healthy volunteers - Written consent - Genotyped in OCT1 for (M420del and R61C) Exclusion Criteria: - Daily medication - Alcohol abuse - Pregnancy - Breastfeeding Inclusion Criteria: - Healthy volunteers - Written consent - Genotyped in OCT1 for (M420del and R61C) Exclusion Criteria: - Daily medication - Alcohol abuse - Pregnancy - Breastfeeding Pharmacogenetics of Metformin null --- R61C ---

Inclusion Criteria: - Healthy volunteers - Written consent - Genotyped in OCT1 for (M420del and R61C) Exclusion Criteria: - Daily medication - Alcohol abuse - Pregnancy - Breastfeeding Inclusion Criteria: - Healthy volunteers - Written consent - Genotyped in OCT1 for (M420del and R61C) Exclusion Criteria: - Daily medication - Alcohol abuse - Pregnancy - Breastfeeding Pharmacogenetics of Metformin null --- R61C --- --- R61C ---

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.

NCT00588172

Conditions

1. Type 2 Diabetes

Interventions

1. Drug: Metformin

MeSH:Diabetes Mellitus, Type 2

HPO:Type II diabetes mellitus

Inclusion criteria: - 1. Heterozygous or homozygous for the nsSNPs R61C, G401S, 420Del, G465R, G174S (see supplementary info (3)) or without any nsSNPs that could potentially alter gene function. --- R61C ---