title: Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes.
abstract: OBJECTIVE
  Metformin is the most widely used oral anti-diabetes agent and has considerable benefits over other therapies, yet 20-30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter-individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced-function polymorphisms with common metformin-induced gastrointestinal side effects in Type 2 diabetes.
  
  
  METHODS
  This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss-of-function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced-function alleles with gastrointestinal side effects was analysed using logistic regression.
  
  
  RESULTS
  Forty-three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced-function alleles was significantly associated with over two-fold higher odds of the common metformin-induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07-5.01, P = 0.034).
  
  
  CONCLUSIONS
  In conclusion, we showed for the first time the association between OCT1 variants and common metformin-induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter-individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment.
authors.affiliation: Department of Biochemistry and Clinical Analysis, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: T
authors.initials: T
authors.lastname: Dujic
authors.affiliation: Department of Biochemistry and Clinical Analysis, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: A
authors.initials: A
authors.lastname: Causevic
authors.affiliation: Department of Biochemistry and Clinical Analysis, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: T
authors.initials: T
authors.lastname: Bego
authors.affiliation: Department of Biochemistry and Clinical Analysis, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: M
authors.initials: M
authors.lastname: Malenica
authors.affiliation: Clinic for Endocrinology, Diabetes and Metabolism Diseases, University Clinical Centre of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: Z
authors.initials: Z
authors.lastname: Velija-Asimi
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, School of Medicine, University of Dundee, Dundee, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Pearson
authors.affiliation: Department of Biochemistry and Clinical Analysis, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.|Faculty of Engineering and Natural Sciences, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: S
authors.initials: S
authors.lastname: Semiz
mesh_terms: D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D017522:Bosnia and Herzegovina; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005759:Gastroenteritis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017353:Gene Deletion; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012720:Severity of Illness Index; D012727:Sex Characteristics
chemical_list: D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D008687:Metformin