title: PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins.
abstract: OBJECTIVE
  Statins increase the incidence of new onset diabetes. Prolonged statin therapy upregulates PTEN expression. PTEN levels are also elevated in diabetic animals. Activation of protein kinase A by cAMP decreases PTEN expression. We assessed whether prolonged treatment with rosuvastatin (ROS) induces glucose intolerance by upregulating Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) in mice receiving normal (ND) or Western Diet (WD) and whether concomitant treatment with cilostazol (CIL, a phosphodiesterase-3 inhibitor) attenuates the effects.
  
  
  METHODS
  PTEN(loxp/cre) or PTEN(+/-) mice received ND or WD without or with ROS (10 mg/kg/day). Wild-type mice received ND or WD without or with ROS, CIL (10 mg/kg/day), or ROS+CIL for 30 days. Fasting insulin and glucose tolerance test were measured as well as PTEN and P-AKT levels in skeletal muscle.
  
  
  RESULTS
  Serum glucose after intraperitoneal injection of glucose was higher in PTEN(loxp/cre) mice receiving WD or ROS and especially WD+ROS. Levels were lower in PTEN(+/-) mice compared to PTEN(loxp/cre) in each treatment group. CIL decreased glucose levels in mice receiving WD, ROS and their combination. Insulin levels were higher in the WD+ROS group. CIL decreased insulin in mice receiving WD+ROS. WD, ROS and especially their combination increased PTEN and decreased P-AKT levels. CIL attenuated the effect of WD, ROS and their combination.
  
  
  CONCLUSIONS
  Long-term ROS can induce diabetes by upregulating PTEN. CIL attenuates these changes. Partial knockdown of PTEN also ameliorates ROS-induced insulin resistance. Further studies are needed to assess the effects of increasing cAMP levels to prevent the induction of diabetes by statins.
authors.affiliation: The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Yochai
authors.initials: Y
authors.lastname: Birnbaum
authors.forename: Manjyot K
authors.initials: MK
authors.lastname: Nanhwan
authors.forename: Shukuan
authors.initials: S
authors.lastname: Ling
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez-Polo
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajaj
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000235:genetics; D000077407:Cilostazol; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000139:chemically induced*; D066273:Diet, Western; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D058987:Phosphodiesterase 3 Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; D000068718:Rosuvastatin Calcium; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000077407:Cilostazol