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 given 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 identified in Northern blots. Analyses of various tissues by reverse transcription-polymerase chain reaction revealed that expressions of the TG mRNA in brain, heart, kidney, lung, stomach, skeletal muscle and adipose tissue were higher than those seen with the endogenous mouse IR (mIR), but expression in small intestine, colon, spleen, testis and ovary were approximately half those seen with the endogenous mIR. In the liver, the expression of the TG was about one tenth that of the endogenous mIR. In analyses of insulin binding and IR autophosphorylation, using a human-specific anti-IR antibody, the TK-deficient hIR was synthesized in the tissues of the TG mice. Despite the expression of TK-deficient hIRs in various tissues, including the major insulin-target tissues, muscle and adipose tissues, of the TG mice, no glucose intolerance was observed as assessed by the intraperitoneal glucose tolerance test, before and after sucrose feeding for 55 weeks. Our results suggest that a higher expression of the mutated IR, especially in the liver which is another major insulin-target tissue, or additional pathogenic factors, environmental or genetic, might be required for glucose intolerance.
Nishiyama
T
T
Department of Enzyme Genetics, University of Tokushima, Japan.
Shirotani
T
T
Murakami
T
T
Shimada
F
F
Todaka
M
M
Saito
S
S
Hayashi
H
H
Noma
Y
Y
Shima
K
K
Makino
H
H
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D005260:Female; D015870:Gene Expression; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000172:deficiency*; D011972:Receptor, Insulin / Q000235:genetics*; D014018:Tissue Distribution
D007328:Insulin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin