title: Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice.
abstract: Signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is crucial for metabolic responses to insulin, and defects in PI3K signaling have been demonstrated in type 2 diabetes. PTEN (MMAC1) is a lipid/protein phosphatase that can negatively regulate the PI3K pathway by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate, but it is unclear whether PTEN is physiologically relevant to insulin signaling in vivo. We employed an antisense oligonucleotide (ASO) strategy in an effort to specifically inhibit the expression of PTEN. Transfection of cells in culture with ASO targeting PTEN reduced PTEN mRNA and protein levels and increased insulin-stimulated Akt phosphorylation in alpha-mouse liver-12 (AML12) cells. Systemic administration of PTEN ASO once a week in mice suppressed PTEN mRNA and protein expression in liver and fat by up to 90 and 75%, respectively, and normalized blood glucose concentrations in db/db and ob/ob mice. Inhibition of PTEN expression also dramatically reduced insulin concentrations in ob/ob mice, improved the performance of db/db mice during insulin tolerance tests, and increased Akt phosphorylation in liver in response to insulin. These results suggest that PTEN plays a significant role in regulating glucose metabolism in vivo by negatively regulating insulin signaling.
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California 92008, USA.
authors.forename: Madeline
authors.initials: M
authors.lastname: Butler
authors.forename: Robert A
authors.initials: RA
authors.lastname: McKay
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Popoff
authors.forename: William A
authors.initials: WA
authors.lastname: Gaarde
authors.forename: Donna
authors.initials: D
authors.lastname: Witchell
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murray
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Dean
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D005947:Glucose; D007328:Insulin; D020319:Oligodeoxyribonucleotides, Antisense; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins