Improved Glucose Homeostasis in Mice with Muscle-Specific Deletion of Protein-Tyrosine Phosphatase 1B

Abstract

Obesity and type 2 diabetes are characterized by insulin resistance. Mice lacking the protein-tyrosine phosphatase PTP1B in all tissues are hypersensitive to insulin but also have diminished fat stores. Because adiposity affects insulin sensitivity, the extent to which PTP1B directly regulates glucose homeostasis has been unclear. We report that mice lacking PTP1B only in muscle have body weight and adiposity comparable to those of controls on either chow or a high-fat diet (HFD). Muscle triglycerides and serum adipokines are also affected similarly by HFD in both groups. Nevertheless, muscle-specific PTP1B^−/− mice exhibit increased muscle glucose uptake, improved systemic insulin sensitivity, and enhanced glucose tolerance. These findings correlate with and are most likely caused by increased phosphorylation of the insulin receptor and its downstream signaling components. Thus, muscle PTP1B plays a major role in regulating insulin action and glucose homeostasis, independent of adiposity. In addition, rosiglitazone treatment of HFD-fed control and muscle-specific PTP1B^−/− mice revealed that rosiglitazone acts additively with PTP1B deletion. Therefore, combining PTP1B inhibition with thiazolidinediones should be more effective than either alone for treating insulin-resistant states.

We thank C. Ronald Kahn (Joslin Diabetes Center) for MCK-Cre mice, Young-Bum Kim (BIDMC) for helpful advice on PI3K assays, and Odile Peroni and Thomas Pulinilkunnil (BIDMC) for helpful advice regarding rosiglitazone experiment.

This work was supported by NIH grants DK 60838 and R37 49132 (B.G.N.) and DK 60839 (B.B.K.), by Physiology Core grant DK57521 (B.B.K.), and by a research grant from the American Diabetes Association (B.G.N.). M.D. is the recipient of a postdoctoral fellowship from the American Heart Association. K.K.B. was supported by a postdoctoral fellowship from the Charles A. King Trust (The Medical Foundation) and by a pilot and feasibility grant from the Boston Obesity and Nutrition Research Center (5-P30-DK046200). N.M. is the recipient of a postdoctoral fellowship from the European Association for the Study of Diabetes (EASD) and the American Diabetes Association. Part of this study was performed at the Penn State Mouse Metabolic Phenotyping Center and was supported by grants from the American Diabetes Association (1-04-RA-47 to J.K.K.) and the Pennsylvania Department of Health (Tobacco Settlement Award to J.K.K.).