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

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 ϳ35% 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 3␤, 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.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. Failure of peripheral tissues to respond to insulin (i.e. insulin resistance) can initially be overcome by a compensatory increase in insulin secretion from pancreatic ␤-cells. When this mechanism fails to compensate sufficiently, frank diabetes and its attendant complications ensue (1-4).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. Subsequently, molecules such as the growth factor receptor-binding protein Grb-2, the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), and the SH2 domaincontaining protein-tyrosine phosphatase Shp2 bind to IRS proteins, leading to the metabolic and growth-promoting effects of insulin (2, 3).The insulin signaling cascade is negatively regulate...

Age- and gender-related changes in glucose homeostasis in glucocorticoid-treated rats

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