title: PTEN mutations as a cause of constitutive insulin sensitivity and obesity.
abstract: BACKGROUND
  Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans.
  
  
  METHODS
  We measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.
  
  
  RESULTS
  Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients' insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.
  
  
  CONCLUSIONS
  PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.).
authors.affiliation: Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
authors.forename: Aparna
authors.initials: A
authors.lastname: Pal
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Barber
authors.forename: Martijn
authors.initials: M
authors.lastname: Van de Bunt
authors.forename: Simon A
authors.initials: SA
authors.lastname: Rudge
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lachlan
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Cooper
authors.forename: Helen
authors.initials: H
authors.lastname: Linden
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Levy
authors.forename: Michael J O
authors.initials: MJ
authors.lastname: Wakelam
authors.forename: Lisa
authors.initials: L
authors.lastname: Walker
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005951:Glucose Tolerance Test; D057895:Haploinsufficiency; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000235:genetics*; D009765:Obesity / Q000150:complications / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*
chemical_list: D052242:Adiponectin; D020738:Leptin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human