Molecular analysis of insulin receptor gene in Werner's syndrome

Uotani, Shigeo; Yamaguchi, Yoshihiko; Yokota, Atsushi; Yamasaki, Hironori; Takino, Hirofumi; Chikuba, Nobuhiro; Goto, Yoshiki; Fujishima, Naoki; Yano, Mototake; Matsumoto, Kazunari; Kawasaki, Eiji; Akazawa, Shoichi; Nagataki, Shigenobu

doi:10.1016/0168-8227(94)90058-2

Cited by 8 publications

(3 citation statements)

References 16 publications

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“…Insulin signaling and gene regulation Molecular analyses of insulin receptor (IR) have been performed in different premature aging syndromes. The results were incongruent showing either differences or normal functionality in patients investigated (Uotani et al, 1994;Fulop et al, 2003). Nucleotide sequencing of intracellular domain of the insulin receptor gene revealed no alteration of amino acids sequence in the patient studied (data not shown).…”

Section: Resultsmentioning

confidence: 90%

Reduced Phosphorylation of Transcription Factor Elk-1 in Cultured Fibroblasts of a Patient with Premature Aging Syndrome and Insulin Resistance

Knebel

Avci²,

Bullmann³

et al. 2005

Exp Clin Endocrinol Diabetes

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The effect of insulin and growth factor mediated signaling to gene regulation was investigated in cultured fibroblasts of a patient with a premature aging syndrome (metageria) and severe insulin resistance. Insulin receptor structure and function as well as major pathways activated by insulin, i.e. phosphatidyl inositol-3 kinase (PI-3 K) cascade or mitogen-activated protein kinase (MAPK) cascades, were functional. Inducibility of the proto-oncogene cfos, a representative endpoint of signaling pathways related to gene expression, by growth factors or insulin was reduced in patient cells. This reduced induction persisted in cfos promoter reporter gene studies indicating that the post receptor defect is localized proximal to the cfos promoter itself. Abundances of the transcription factors Elk-1 and SRF being major players in coupling of MAPKs to cfos promoter activation were not altered. However, basal and inducible phosphorylation of Elk-1 was impaired. In addition, basal and stimulated transcriptional activity mediated by Elk-1 was almost abolished in patient cells. Therefore these results identify a post receptor defect in cFos induction, which appears to be related to a functional alteration of Elk-1. A possible relation of this signal transduction defect to the specific premature aging syndrome remains to be elucidated.

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Section: Resultsmentioning

confidence: 90%

Reduced Phosphorylation of Transcription Factor Elk-1 in Cultured Fibroblasts of a Patient with Premature Aging Syndrome and Insulin Resistance

Knebel

Avci²,

Bullmann³

et al. 2005

Exp Clin Endocrinol Diabetes

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“…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.…”

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confidence: 85%

“…W ERNER'S SYNDROME (WS) is one of the progeria conditions characterized by various phenotypical abnormalities, including gray hair, bird-like face, slender extremities, cataract, and endocrine dysfunction (1)(2)(3)(4)(5). The condition is associated with glucose intolerance in approximately 70% of patients, a complication predominantly resulting from insulin resistance (6).…”

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confidence: 99%

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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Insulin receptors in mouse brain: Reversibility of age-related impairments by a thymic extract

Alimazighi

Piantanelli

2000

AGE

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Recently, we have shown that insulin receptors (InsRs) in the brain undergo impairments with aging. Interestingly, age-related alterations of brain InsRs, are not irreparable as thymus grafts are able to recover them. With the present study we verified the possibility that an aqueous extract from calf thymus (TME) can mimic the restoring action of age-related impairments induced by thymus graft. InsR characteristics were assayed in a group of 25 months old BALB/c-nu mice treated with TME: 2μg/g body weight every third day, for total five subcutaneous injections. The last dose was injected the day before animals were killed. Other two groups of young (4 months) and old (25 months) mice received saline solution with the same schedule. A two-sites model analysis of receptor data confirms the age-dependent decrease of InsR number and kd previously observed in the high affinity population. Furthermore, a statistically significant recovery of number impairment is shown in TME-treated animals. On the contrary, the characteristics of the low affinity receptor subset show no statistically significant differences among the three animal models studied. TME induced recovery of the age-related changes found in brain InsRs, together with previously observed regulatory action of the same thymic extract on the adrenergic system, suggest that thymic gland does not necessarily have to mutually interact with other controlling systems for maintaining or recoving homeostasis of the complex neuroendocrine network during development and aging.

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Molecular analysis of insulin receptor gene in Werner's syndrome

Cited by 8 publications

References 16 publications

Reduced Phosphorylation of Transcription Factor Elk-1 in Cultured Fibroblasts of a Patient with Premature Aging Syndrome and Insulin Resistance

Reduced Phosphorylation of Transcription Factor Elk-1 in Cultured Fibroblasts of a Patient with Premature Aging Syndrome and Insulin Resistance

Troglitazone Ameliorates Insulin Resistance in Patients with Werner’s Syndrome

Insulin receptors in mouse brain: Reversibility of age-related impairments by a thymic extract

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