[Pten as target for type 2 diabetes -- Isis]
>>Published online before print February 9, 2004
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0308617100
Medical Sciences
Live-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity
Bangyan Stiles *, Ying Wang *, Andreas Stahl , Sara Bassilian , W. Paul Lee , Yoon-Jung Kim ¶, Robert Sherwin ¶, Sherin Devaskar ||, Ralf Lesche *,**, Mark A. Magnuson , and Hong Wu *
*Departments of Molecular and Medical Pharmacology and Howard Hughes Medical Institute and ||Department of Pediatrics Neonatology and Developmental Biology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Research Institute, Palo Alto Medical Foundation and Stanford School of Medicine, Palo Alto, CA 94301; Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, CA 90502; ¶Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37235
Communicated by Michael G. Rosenfeld, University of California at San Diego, La Jolla, CA, December 23, 2003 (received for review November 5, 2003)
In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes.<<
>>Diabetes. 2002 Apr;51(4):1028-34.
Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice.
Butler M, McKay RA, Popoff IJ, Gaarde WA, Witchell D, Murray SF, Dean NM, Bhanot S, Monia BP.
Isis Pharmaceuticals, Carlsbad, California 92008, USA.
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.<<
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Interesting that Isis is going after the same target that failed for Wyeth. Not sure what that means in terms of Isis' chances here.
Cheers, Tuck |
