Protein-tyrosine Phosphatase 1B Deficiency Reduces Insulin Resistance and the Diabetic Phenotype in Mice with Polygenic Insulin Resistance

Bingzhong Xue,Young-Bum Kim,Anna Lee,Elena Toschi,Susan Bonner-Weir,C Ronald Kahn,Benjamin G Neel,Barbara B Kahn

doi:10.1074/jbc.m609680200

Abstract

Mice heterozygous for insulin receptor (IR) and IR substrate (IRS)-1 deficiency provide a model of polygenic type 2 diabetes in which early-onset, genetically programmed insulin resistance leads to diabetes. Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. Mice lacking PTP1B are lean and have increased insulin sensitivity. To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B-/- mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). DHet mice weighed slightly less than wild-type mice and exhibited severe insulin resistance and hyperglycemia, with approximately 35% of DHet males developing diabetes by 9-10 weeks of age. Body weight in DHet mice with PTP1B deficiency was similar to that in DHet mice. However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10-11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3beta, and p70(S6K) was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. In addition, increased phosphoenolpyruvate carboxykinase expression in DHet mouse liver was reversed by PTP1B deficiency. In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes.

Highlights

Insulin plays a dominant role in regulating glucose homeostasis through a highly orchestrated constellation of effects, which include promoting glucose uptake in peripheral tissues such as muscle and fat, suppressing hepatic glucose output, and regulating lipid metabolism
Male and female DHet mice weighed less than their WT littermates, as described previously [30, 31], and had lower fat pad mass even when corrected for lower body weight, i.e. the fat pad/body weight ratio was lower (Table 1)
We investigated the effects of reducing protein-tyrosine phosphatase 1B (PTP1B) expression on insulin sensitivity in a polygenic model of type 2 diabetes with similarities to human diabetes

Summary

Introduction

Insulin plays a dominant role in regulating glucose homeostasis through a highly orchestrated constellation of effects, which include promoting glucose uptake in peripheral tissues such as muscle and fat, suppressing hepatic glucose output, and regulating lipid metabolism. Insulin action is mediated through a complex network of signaling events, which are initiated by the binding of insulin to its cell-surface receptor, the insulin receptor (IR).3 This triggers the intrinsic protein-tyrosine kinase activity of IR, resulting in autophosphorylation of several IR tyrosyl residues and the recruitment and tyrosyl phosphorylation of IR substrate (IRS) proteins. Reduction of PTP1B expression primarily in liver and adipose tissue of ob/ob mice by antisense oligonucleotides has been reported to improve insulin sensitivity, but again, largely in association with decreased adiposity [27,28,29] All of these data strongly support a physiological role for PTP1B in negatively regulating insulin signaling in rodents and humans. The conclusions are tempered by the fact that the accompanying changes in adiposity may play a major role in altering insulin signaling and systemic insulin sensitivity

Methods

Results

Conclusion