Mutant insulin receptors in syndromes of insulin resistance

O’Rahilly, Stephen; Moller, David E.

doi:10.1111/j.1365-2265.1992.tb00945.x

Cited by 50 publications

(36 citation statements)

References 101 publications

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“…It will be of interest to see whether the newborn will develop type A insulin resistance in the future. subunit in CHO-R1092Q was also impaired, but was slightly larger than that of CHO-K1, which was consistent with the data in panel B a subunit of the IR which decrease the binding affinity to insulin and/or impair IR processing [1][2][3][4]. In such cases, the intensity of signals from mutated IR to intracellular messenger molecules are diminished due to the defect in ligand-dependent activation of tyrosine kinase in the intact b subunit and/or a decreased amount of IR on the cell surface.…”

Section: Discussionsupporting

confidence: 84%

A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism

et al. 1997

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Section: Discussionsupporting

confidence: 84%

A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism

et al. 1997

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“…However, the diagnosis now encompasses both males and females in teenage or early adult years, who are not obese but have severe insulin resistance and acanthosis nigricans in the absence of insulin receptor autoantibodies (19). Despite the common presenting features, this is undoubtedly a heterogeneous group of patients and at present only about 10% have detectable genetic defects in the insulin receptor (22)(23)(24). It is likely that some will have defects in post-insulin receptor signalling (50).…”

Section: Primary Disorders Of Insulin Actionmentioning

confidence: 99%

IGF-I treatment of insulin resistance

McDonald¹,

Williams²,

Regan³

et al. 2007

eur j endocrinol

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Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue's and Rabson-Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. Paradoxically, subjects with these conditions may present with hypoglycaemia due to mismatch of post-prandial glucose excursion and compensatory hyperinsulinaemia. Ultimately, treatment with insulin and insulin sensitisers will be unsuccessful and subjects may succumb to diabetes or its complications. Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic b-cell may be important in maintaining insulin secretion. Pilot studies confirmed that rhIGF-I could reduce glucose and insulin levels in subjects with type A insulin resistance and those with Rabson-Mendenhall syndrome with sustained beneficial effects on HbA1c. Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue's and type A insulin resistance subjects. Observations that IGF-I treatment can improve C-peptide levels in these subjects may indicate that it might be more valuable as a first line intervention to preserve b-cell function, rather than its current use as a medication of last resort in subjects where all other therapies have failed.European Journal of Endocrinology 157 S51-S56

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“…Natural mutations in the primary sequence of the insulin receptor have been identified in patients with extreme forms of insulin resistance (3,4). Mutations in the extracellular ligand binding domain of the receptor have been shown to result in a decreased affinity of insulin for the receptor (5)(6)(7)(8)(9).…”

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confidence: 99%

Insulin Resistance Is Mediated by a Proteolytic Fragment of the Insulin Receptor

Knutson

Donnelly

Balba

et al. 1995

Journal of Biological Chemistry

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Insulin resistance is a common clinical feature of obesity and non-insulin-dependent diabetes mellitus, and is characterized by elevated serum levels of glucose, insulin, and lipids. The mechanism by which insulin resistance is acquired is unknown. We have previously demonstrated that upon chronic treatment of fibroblasts with insulin, conditions that mimic the hyperinsulinemia associated with insulin resistance, the membrane-associated insulin receptor ␤ subunit is proteolytically cleaved, resulting in the generation of a cytosolic fragment of the ␤ subunit, ␤, and that the generation of ␤ is inhibited by the thiol protease inhibitor E64 (Knutson, V. P. (1991) J. Biol. Chem. 266, 15656 -15662). In this report, we demonstrate that in 3T3-L1 adipocytes: 1) cytosolic ␤ is generated by chronic insulin administration to the cells, and that E64 inhibits the production of ␤; 2) chronic administration of insulin to the adipocytes leads to an insulinresistant state, as measured by lipogenesis and glycogen synthesis, and E64 totally prevents the generation of this insulin-induced cellular insulin resistance; 3) E64 has no effect on the insulin-induced down-regulation of insulin receptor substrate-1, and therefore insulin resistance is not mediated by the down-regulation of insulin receptor substrate-1; 4) under in vitro conditions, partially purified ␤ stoichiometrically inhibits the insulin-induced autophosphorylation of the insulin receptor ␤ subunit; and 5) administration of E64 to obese Zucker fatty rats improves the insulin resistance of the rats compared to saline-treated animals. These data indicate that ␤ is a mediator of insulin resistance, and the mechanism of action of ␤ is the inhibition of the insulin-induced autophosphorylation of the ␤ subunit of the insulin receptor.Insulin resistance is a characteristic clinical feature of a number of disease states, chief among them diabetes mellitus, and is associated with hyperglycemia, hyperinsulinemia, hyperlipidemia, and hypertension (reviewed in Refs. 1 and 2). The potential mechanisms by which cellular insulin resistance is generated are many: a mutation in the gene coding for the insulin receptor protein, resulting in a decreased expression of the protein; a decrease in the binding of insulin; a decrease in the number of insulin receptor molecules expressed on the plasma membrane of the target cell; or a so-called "post-receptor defect" in which there is a decreased interaction between the insulin receptor and downstream effector molecules.Natural mutations in the primary sequence of the insulin receptor have been identified in patients with extreme forms of insulin resistance (3, 4). Mutations in the extracellular ligand binding domain of the receptor have been shown to result in a decreased affinity of insulin for the receptor (5-9). Mutations have also been documented in the intracellular ␤ subunit of the receptor, especially in the ATP binding domain and the autophosphorylation domain of the receptor protein, resulting in a decreased tyrosine kinase activity...

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Mutant insulin receptors in syndromes of insulin resistance

Cited by 50 publications

References 101 publications

A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism

A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism

IGF-I treatment of insulin resistance

Insulin Resistance Is Mediated by a Proteolytic Fragment of the Insulin Receptor

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