Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigma.

Several protein tyrosine phosphatases (PTPs) expressed in insulin sensitive-tissues are proposed to attenuate in- sulin action and could act as key regulators of the insulin receptor (IR) signaling pathway. Among these PTPs, RPTPs is expressed in relatively high levels in insulin-target tissues. We show that RPTPs -/- knockout mice have reduced plasma glucose and insulin concentrations in the fasted state compared with their wild-type siblings. The knockout animals were also more sensitive to exogenous insulin as assayed by insulin-tolerance tests. Despite increased whole-body insulin sensi- tivity, tyrosine phosphorylation of the IR was not increased in muscle of RPTPs -/- animals, as would be expected in insulin- sensitive animals. Instead, the levels of IR tyrosine phosphorylation and PI3-kinase activity were reduced in the muscle of knockout animals stimulated with insulin in vivo. However, insulin-stimulated Akt serine phosphorylation was essentially identical between both groups of mice. Accordingly, muscles isolated from RPTPs -/- mice did not have a significant increase in glucose uptake in response to insulin, suggesting that RPTPs did not play a direct role in this process. Taken together, our results suggest an indirect modulation of the IR signaling pathways by RPTPs. Since low dose injection of growth hormone (GH) normalized the response to exogenous insulin in RPTPs -/- mice, we propose that the insulin hypersensitivity observed in RPTPs -/- mice is secondary to their neuroendocrine dysplasia