Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene

• Published in: Science (American Association for the Advancement of Science) Vol. 283; no. 5407; pp. 1544 - 1548
• Main Authors: Elchebly, M, Payette, P, Michaliszyn, E, Cromlish, W, Collins, S, Loy, A.L, Normandin, D, Cheng, A, Himms-Hagen, J, Chan, C.C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 05.03.1999; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Animals; Biological and medical sciences; blood glucose; Blood Glucose - metabolism; Classical genetics, quantitative genetics, hybrids; Diabetes; Diabetes Mellitus, Type 2 - therapy; Diabetes research; Dietary Fats - administration & dosage; enzyme activity; Female animals; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genes; Genetics of eukaryotes. Biological and molecular evolution; Glucose Tolerance Test; High fat diet; Insulin; Insulin - blood; Insulin - metabolism; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Liver - metabolism; Male; Male animals; metabolic diseases; Mice; Mice, Knockout; modulation; Muscle, Skeletal - metabolism; Muscles; Obesity; Obesity - metabolism; Obesity - therapy; Phosphatases; Phosphoproteins - metabolism; phosphoric monoester hydrolases; Phosphorylation; Phosphotyrosine - metabolism; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Proteins; Receptor, Insulin - metabolism; Receptors; Rodents; Signal Transduction; Vertebrata; Obesity; Pancreatic hormone; Enzyme; Rodentia; Phosphoric monoester hydrolases; Esterases; Insulin; Protein; Protein hormone; Target tissue resistance; Signal transduction; Vertebrata; Mammalia; Sensitivity resistance; Gene; Mouse; Hydrolases; Mutation; Protein-tyrosine-phosphatase
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.283.5407.1544

Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.