期刊
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
卷 84, 期 7, 页码 755-763出版社
CANADIAN SCIENCE PUBLISHING
DOI: 10.1139/Y06-020
关键词
protein tyrosine phosphatase; knockout mice; insulin action; IGF-1/GH; glucose homeostasis
Several protein tyrosine phosphatases (PTPs) expressed in insulin sensitive-tissues are proposed to attenuate insulin action and could act as key regulators of the insulin receptor (IR) signaling pathway. Among these PTPs, RPTP sigma is expressed in relatively high levels in insulin- target tissues. We show that RPTPs sigma(-/-) 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 sensitivity, tyrosine phosphorylation of the IR was not increased in muscle of RPTP sigma(-/-) 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 RPTP sigma(-/-) 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 RPTP sigma(-/-). Since low dose injection of growth hormone (GH) normalized the response to exogenous insulin in RPTP sigma(-/-) mice, we propose that the insulin hypersensitivity observed in RPTP sigma(-/-) mice is secondary to their neuroendocrine dysplasia and GH/IGF-1 deficiency.
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