title: A common variation of the PTEN gene is associated with peripheral insulin resistance.
abstract: OBJECTIVE
  Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated with fasting levels of plasma insulin and glucose, influences in vivo glucose metabolism and insulin signalling. The primary outcome measure was the gene variant's association with peripheral glucose disposal rate and, secondarily, whether this association was explained by altered activities of PTEN targets PI3K and Akt.
  
  
  METHODS
  A total of 183 normoglycaemic Danes, including 158 twins and 25 singletons, were genotyped for PTEN rs11202614, which is in complete linkage disequilibrium with rs2142136 and rs10788575, which have also been reported in association with glycaemic traits and type 2 diabetes (T2D). Hepatic and peripheral insulin sensitivity was measured using tracer and euglycaemic-hyperinsulinaemic clamp techniques; insulin secretion was assessed by intravenous glucose tolerance test; and muscle biopsies were taken during insulin infusion from 150 twins for measurement of PI3K and Akt activities.
  
  
  RESULTS
  The minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single nucleotide polymorphism was not associated with either PI3K or Akt activities.
  
  
  CONCLUSIONS
  A common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling in skeletal muscle.
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Grinder-Hansen
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark; The Danish Diabetes Academy, Odense University Hospital, Sondre Boulevard 29, DK-5000 Odense, Denmark; Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Universitetsparken 1, DK-2100 Copenhagen O, Denmark. Electronic address: rasmus.ribel-madsen@regionh.dk.
authors.forename: R
authors.initials: R
authors.lastname: Ribel-Madsen
authors.affiliation: Section of Molecular Physiology, The August Krogh Centre, Department of Nutrition, Exercise and Sports, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen O, Denmark.
authors.forename: J F P
authors.initials: JF
authors.lastname: Wojtaszewski
authors.affiliation: Novo Nordisk A/S, Vandtårnsvej 108, DK-2860 Soborg, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Poulsen
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark.
authors.forename: L G
authors.initials: LG
authors.lastname: Grunnet
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Vaag
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018454:Spouses; D014427:Twins
chemical_list: D007328:Insulin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Genetics; Insulin resistance; Insulin signalling; PTEN; Skeletal muscle