Regional differences in insulin receptor function in Werner's syndrome

Yamasaki, Hironori; Akazawa, Shoichi; Okuno, Shinichiro; Ikari, Nobuhiko; Yamaguchi, Yoshihiko; Chikuba, Nobuhiro; Yamamoto, H.; Maeda, Yasuo; Tahara, Daigo; Nagataki, Shigenobu

doi:10.1016/0168-8227(92)90013-h

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…The new ELISA which was developed in our laboratory [14] revealed that the number of autophosphorylated insulin receptors was identical to that in normal controls. This may be in agreement with the observations that insulin binding to a variety of tissues were almost normal [13,18,32,33] but may not be consistent with a recent study in which reduced insulin binding was found in fibroblasts from a patient with Werner's syndrome [34].…”

Section: Discussionsupporting

confidence: 83%

Autophosphorylation of Insulin Receptor in a Patient with Werner's Syndrome Associated with Insulin Resistant Diabetes Mellitus.

et al. 1995

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The tissue sensitivity to insulin was evaluated using the hyperinsulinemic euglycemic clamp technique in a 44-year old male with Werner's syndrome associated with diabetes mellitus. In addition, the autophosphorylation of insulin receptors and the number of autophosphorylated insulin receptors were measured in his erythrocytes by a new enzyme-linked immunosorbent assay. He had an increased serum insulin level (30.5 microU/ml) in addition to hyperglycemia (226 mg/dl), suggesting that he had insulin-resistant diabetes mellitus. A clamp study revealed that his insulin-stimulated glucose disposal rate (2.80 mg/kg/min) was comparable to that in noninsulin-dependent diabetes mellitus (4.14 +/- 1.94 (SD) mg/kg/min, n = 23). The number of autophosphorylated insulin receptors per 300 microliters of erythrocytes was also identical to that in normal control subjects. In addition, the autophosphorylation of insulin receptors determined at six different insulin concentrations was within the normal range, even when it was expressed as per 300 microliters of erythrocytes as well as per unit receptor. These results demonstrate that insulin resistance in the patient with Werner's syndrome is caused by a defect that cannot be detected by means employed in this study, and suggest that the defect is present at the steps distal to the autophosphorylation of tyrosine kinase of insulin receptors.

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Section: Discussionsupporting

confidence: 83%

Autophosphorylation of Insulin Receptor in a Patient with Werner's Syndrome Associated with Insulin Resistant Diabetes Mellitus.

et al. 1995

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“…In vitro studies have shown that insulin binding and tyrosine kinase activity are normal using Epstein-Barr virustransformed lymphocytes from patients with WS (7). We have also demonstrated that the number of insulin receptors in abdominal fibroblasts derived from WS patients was not reduced compared with that in control fibroblasts (8). These results indicate that insulin resistance associated with WS arises probably from a postreceptor defect.…”

Section: Discussionsupporting

confidence: 58%

“…These findings are in agreement with hyperinsulinemic euglycemic glucose clamp studies that showed reduced insulin sensitivity in WS patients (6 -9). Although a reduced number of insulin receptors in the fibroblasts was shown in one WS patient (8), no structural changes in the insulin receptor molecule were detected in five WS patients in our laboratory (5). Considered together, it is likely that insulin resistance found in WS patients is due to a deterioration in postreceptor insulin signaling.…”

mentioning

confidence: 95%

Troglitazone Ameliorates Insulin Resistance in Patients with Werner’s Syndrome

Izumino

Sakamaki²,

Ishibashi³

et al. 1997

The Journal of Clinical Endocrinology & Metabolism

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Insulin resistance in Werner's syndrome (WS) is probably due to defective signaling distal to the insulin receptor. To analyze the metabolic effects of troglitazone (TRO) in these patients, we performed frequently sampled iv glucose tolerance tests. Glucose kinetics were analyzed by the minimal model. Five patients with WS (mean age, 41.2 yr; body mass index, 17.0 kg/m 2 ) were treated with TRO (400 mg/day) for 4 weeks. Each subject underwent a 75-g OGTT and frequently sampled iv glucose tolerance tests. Treatment reduced the area under the curve of glucose and insulin in the OGTT by 26% and 43%, respectively. Glucose tolerance, as manifested by the glucose disappearance rate improved significantly (1.36 Ϯ 0.16 to 1.94 Ϯ 0.30%/min; P Ͻ 0.05). Although the first phase insulin secretion was unchanged, insulin sensitivity and glucose effectiveness increased significantly [0.47 Ϯ 0.11 to 1.38 Ϯ 0.37 ϫ 10 Ϫ4 min/pmol⅐L (P Ͻ 0.05) and 1.72 Ϯ 0.17 to 2.52 Ϯ 0.24 ϫ 10 Ϫ2 min Ϫ1 (P Ͻ 0.05), respectively]. However, treatment did not change glucose effectiveness at zero insulin. In patients with WS, TRO ameliorates glucose intolerance mediated by increased insulin sensitivity as well as glucose effectiveness, as assessed by minimal model analysis. TRO may modulate the postreceptor signaling component and be a clinically useful regimen for the treatment of patients with the intracellular insulin signaling

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