EXPRESSION OF THE GENE ENCODING THE TYROSINE KINASE-DEFICIENT HUMAN INSULIN-RECEPTOR IN TRANSGENIC MICE

Defects in the insulin receptor (IR) in diabetic patients have been gi ven much attention. To address the role of such defects, we generated a transgenic (TG) mouse carrying the cDNA encoding a tyrosine-kinase ( TK)-deficient human IR (hIR), under the control of the native promoter . The TG mouse expressed the transgene (TG) mRNA in the liver, as iden tified in Northern blots. Analyses of various tissues by reverse trans cription-polymerase chain reaction revealed that expressions of the TG mRNA in brain, heart, kidney, lung, stomach, skeletal muscle and adip ose tissue were higher than those seen with the endogenous mouse IR (m IR), but expression in small intestine, colon, spleen, testis and ovar y were approximately half those seen with the endogenous mIR. In the l iver, the expression of the TG was about one tenth that of the endogen ous mIR. In analyses of insulin binding and IR autophosphorylation, us ing a human-specific anti-IR antibody, the TK-deficient hIR was synthe sized in the tissues of the TC mice. Despite the expression of TK-defi cient hIRs in various tissues, including the major insulin-target tiss ues, muscle and adipose tissues, of the TG mice, no glucose intoleranc e was observed as assessed by the intraperitoneal glucose tolerance te st, before and after sucrose feeding for 55 weeks. Our results suggest that a higher expression of the mutated IR, especially in the liver w hich is another major insulin-target tissue, or additional pathogenic factors, environmental or genetic, might be required for glucose intol erance.