INSULIN SIGNALING IN MICE EXPRESSING REDUCED LEVELS OF SYP

Syp is a protein tyrosine phosphatase implicated in insulin and growth factor signaling. To evaluate the role of syp in insulin's regulation of plasma glucose, we generated knockout mice, Homozygous knockout mi ce die prior to day 10.5 of embryonic development. Hemizygous mice exp ress half the levels of syp protein compared with their wild type litt ermates but do not display any gross morphological changes. Total body weight (age 2-10 weeks) and plasma insulin and glucose levels both in fasting and glucose-challenged states were comparable in the wild typ e and the hemizygous mice. No differences were observed in insulin-ind uced glucose uptake in soleus muscle and epididymal fat; insulin inhib ition of lipolysis was also similar. We injected insulin into the port al vein of the mice to examine upstream events of the insulin signalin g cascade. Tyrosine phosphorylation of insulin receptor and insulin re ceptor substrate-1 (IRS-1) from hemizygous tissue was similar to that of wild type tissue. Association of the p85 subunit of phosphatidylino sitol 3-kinase to IRS-1 increased an average of a-fold in both groups, We did not observe an increase of IRS-1/syp association after insulin administration, but we did note a significant basal association in bo th wild type and hemizygous tissue, Our results do not support a major role for syp in the acute in, vivo meta belie actions of insulin.