Expression of a dominant-negative mutant human insulin receptor in the muscle of transgenic mice.

摘要: Abstract To examine the in vivo effects of a kinase-deficient mutant human insulin receptor, we used muscle creatine kinase promoter to express putative dominant-negative receptor: Ala1134-->Thr (Moller, D. E., Yokota, A., White, M. F., Pazianos, A. G., and Flier, J. S. (1990) Biol. Chem. 265, 14979-14985) transgenic mice. Two lines were generated, where receptor expression was restricted striated increased by 5-12-fold skeletal muscle. Transgenic gluteal activity reduced approximately 80% after maximal vitro stimulation. Glycogen content this 45% Insulin levels 2-fold higher, glucose concentrations 12% higher transgenics fed ad libitum. mice exhibited sensitivity low dose (0.1 milliunits/g) intravenous insulin. In isolated soleus muscles from transgenics, receptors expressed at lower levels, insulin-stimulated 42%, but 2-deoxyglucose uptake unaffected. These results indicate that (i) overexpression causes level activation, (ii) impairment tyrosine can cause decreased vivo, (iii) kinase-defective mutants may be create novel animal models tissue-specific resistance.