Clarification of signaling pathways mediated by insulin and insulin-like growth factor I receptors in fibroblasts from patients with specific defect in insulin receptor.
Receptor binding and biological action of insulin and insulin-like growth factor I (IGF-I) were studied in fibroblasts from a patient with leprechaunism and a patient with type A syndrome of insulin resistance. Insulin binding was reduced to 18.8 and 27.7% of control value, respectively. In contrast, IGF-I binding was normal in both patients. In competitive binding studies, IGF-I had 0.2% of the ability of insulin to compete with 125I-labeled insulin binding, and insulin had 0.1% of the ability of IGF-I to compete with 125I-labeled IGF-I binding in control subjects and patient fibroblasts. The dose-response curves of insulin stimulation assessed by glucose incorporation and alpha-aminoisobutyric acid uptake showed normal responsiveness, and ED50 was significantly shifted to the right in fibroblasts from both patients. However, normal responsiveness and sensitivity were observed in thymidine incorporation studies. For IGF-I, dose-response curves of glucose incorporation, alpha-aminoisobutyric acid uptake, and thymidine incorporation were all normal in both patients. These results indicate that 1) the defect is specific to the insulin-receptor binding in these patients, 2) insulin and IGF-I activate glucose incorporation and alpha-aminoisobutyric acid uptake mainly through their own specific receptors, but 3) the IGF-I receptor appears to have a more important role in stimulating thymidine incorporation than the insulin receptor in physiological condition or, alternatively, an unknown postreceptor process with cascade signal transmission may overcome the decreased insulin-receptor binding to produce a normal dose-response curve.
Sasaoka
T
T
Third Department of Medicine, Shiga University of Medical Science, Japan.
Kobayashi
M
M
Takata
Y
Y
Ishibashi
O
O
Iwasaki
M
M
Shigeta
Y
Y
Goji
K
K
Hisatomi
A
A
D000621:Aminoisobutyric Acids / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004700:Endocrine System Diseases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D011972:Receptor, Insulin / Q000502:physiology*; D017451:Receptors, Somatomedin; D015398:Signal Transduction
D000621:Aminoisobutyric Acids; D007328:Insulin; D017451:Receptors, Somatomedin; C100049:2-aminoisobutyric acid; D007334:Insulin-Like Growth Factor I; D004247:DNA; D011972:Receptor, Insulin; D005947:Glucose