title: Deletion of Pten in pancreatic ß-cells protects against deficient ß-cell mass and function in mouse models of type 2 diabetes.
abstract: OBJECTIVE
  Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Insulin signaling within the β-cells has been shown to play a critical role in maintaining the essential function of the β-cells. Under basal conditions, enhanced insulin-PI3K signaling via deletion of phosphatase with tensin homology (PTEN), a negative regulator of this pathway, leads to increased β-cell mass and function. In this study, we investigated the effects of prolonged β-cell-specific PTEN deletion in models of type 2 diabetes.
  
  
  METHODS
  Two models of type 2 diabetes were employed: a high-fat diet (HFD) model and a db/db model that harbors a global leptin-signaling defect. A Cre-loxP system driven by the rat insulin promoter (RIP) was employed to obtain mice with β-cell-specific PTEN deletion (RIPcre(+) Pten(fl/fl)).
  
  
  RESULTS
  PTEN expression in islets was upregulated in both models of type 2 diabetes. RIPcre(+) Pten(fl/fl) mice were completely protected against diabetes in both models of type 2 diabetes. The islets of RIPcre(+) Pten(fl/fl) mice already exhibited increased β-cell mass under basal conditions, and there was no further increase under diabetic conditions. Their β-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished β-cell function and attenuated PI3K signaling. These protective effects in β-cells occurred in the absence of compromised response to DNA-damaging stimuli.
  
  
  CONCLUSIONS
  PTEN exerts a critical negative effect on both β-cell mass and function. Thus PTEN inhibition in β-cells can be a novel therapeutic intervention to prevent the decline of β-cell mass and function in type 2 diabetes.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Linyuan
authors.initials: L
authors.lastname: Wang
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Shun
authors.initials: S
authors.lastname: Yan Lu
authors.forename: Kinh-Tung T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Herbert
authors.initials: H
authors.lastname: Gaisano
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods; D005951:Glucose Tolerance Test; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D010179:Pancreas / Q000473:pathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
chemical_list: D001786:Blood Glucose; D007328:Insulin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse