title: Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity.
abstract: OBJECTIVE
  Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake.
  
  
  METHODS
  Insulin sensitivity in Pten heterozygous (Pten(+/-)) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten(+/-) mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3beta (GSK3beta), a substrate of PKB/Akt, was determined by western immunoblotting.
  
  
  RESULTS
  Following i.p. insulin challenge, blood glucose levels in Pten(+/-) mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten(+/-) mice. Enhanced glucose uptake was observed both in Pten(+/-) myocytes and in skeletal muscle of Pten(+/-) mice by PET. PKB and GSK3beta phosphorylation was enhanced and prolonged in Pten(+/-) myocytes.
  
  
  CONCLUSIONS
  Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten(+/-) mice.
authors.affiliation: The Prostate Centre at Vancouver General Hospital, Vancouver Coastal Health Research Institute, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6.
authors.forename: J T
authors.initials: JT
authors.lastname: Wong
authors.forename: P T W
authors.initials: PT
authors.lastname: Kim
authors.forename: J W
authors.initials: JW
authors.lastname: Peacock
authors.forename: T Y
authors.initials: TY
authors.lastname: Yau
authors.forename: A L-F
authors.initials: AL
authors.lastname: Mui
authors.forename: S W
authors.initials: SW
authors.lastname: Chung
authors.forename: V
authors.initials: V
authors.lastname: Sossi
authors.forename: D
authors.initials: D
authors.lastname: Doudet
authors.forename: D
authors.initials: D
authors.lastname: Green
authors.forename: T J
authors.initials: TJ
authors.lastname: Ruth
authors.forename: R
authors.initials: R
authors.lastname: Parsons
authors.forename: C B
authors.initials: CB
authors.lastname: Verchere
authors.forename: C J
authors.initials: CJ
authors.lastname: Ong
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003433:Crosses, Genetic; D003847:Deoxyglucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D019788:Fluorodeoxyglucose F18; D006580:Genetic Carrier Screening; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D049268:Positron-Emission Tomography
chemical_list: D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D019788:Fluorodeoxyglucose F18; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D005947:Glucose