RT Journal Article
SR Electronic
T1 Protein–Tyrosine Phosphatase 1B–Deficient Myocytes Show Increased Insulin Sensitivity and Protection Against Tumor Necrosis Factor-α–Induced Insulin Resistance
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 404
OP 413
DO 10.2337/db06-0989
VO 56
IS 2
A1 Nieto-Vazquez, Iria
A1 Fernández-Veledo, Sonia
A1 de Alvaro, Cristina
A1 Rondinone, Cristina M.
A1 Valverde, Angela M.
A1 Lorenzo, Margarita
YR 2007
UL http://diabetes.diabetesjournals.org/content/56/2/404.abstract
AB Protein–tyrosine phosphatase (PTP)1B is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. In this study, we have assessed the role of PTP1B in the insulin sensitivity of skeletal muscle under physiological and insulin-resistant conditions. Immortalized myocytes have been generated from PTP1B-deficient and wild-type neonatal mice. PTP1B−/− myocytes showed enhanced insulin-dependent activation of insulin receptor autophosphorylation and downstream signaling (tyrosine phosphorylation of insulin receptor substrate [IRS]-1 and IRS-2, activation of phosphatidylinositol 3-kinase, and serine phosphorylation of AKT), compared with wild-type cells. Accordingly, PTP1B−/− myocytes displayed higher insulin-dependent stimulation of glucose uptake and GLUT4 translocation to the plasma membrane than wild-type cells. Treatment with tumor necrosis factor-α (TNF-α) induced insulin resistance on glucose uptake, impaired insulin signaling, and increased PTP1B activity in wild-type cells. Conversely, the lack of PTP1B confers protection against insulin resistance by TNF-α in myocyte cell lines and in adult male mice. Wild-type mice treated with TNF-α developed a pronounced hyperglycemia along the glucose tolerance test, accompanied by an impaired insulin signaling and increased PTP1B activity in muscle. However, mice lacking PTP1B maintained a rapid clearance of glucose and insulin sensitivity and displayed normal muscle insulin signaling regardless the presence of TNF-α.