Protein-tyrosine phosphatase 1B-deficient myocytes show increased insulin sensitivity and protection against tumor necrosis factor-alpha-induced insulin resistance.
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-alpha (TNF-alpha) 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-alpha in myocyte cell lines and in adult male mice. Wild-type mice treated with TNF-alpha 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-alpha.
Nieto-Vazquez
Iria
I
Department of Biochemistry, Faculty of Pharmacy, Universidad Complutense, 28040-Madrid, Spain.
Fernández-Veledo
Sonia
S
de Alvaro
Cristina
C
Rondinone
Cristina M
CM
Valverde
Angela M
AM
Lorenzo
Margarita
M
D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D004195:Disease Models, Animal; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051275:Glucose Transporter Type 4; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; D005947:Glucose