Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes.

Boden, Guenther; Fujita‐Yamaguchi, Yoko; Shimoyama, Ryushi; Shelmet, J J; Tappy, Luc; Rezvani, Iraj; Owen, Oliver E.

doi:10.1172/jci113545

Cited by 15 publications

(4 citation statements)

References 29 publications

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“…On the other hand, in TBII-negative patients, the inhibition of TSH-stimulated iodine uptake correlated significantly with that of forskolin-stimulated iodine uptake [22]. These data may suggest that nonbinding inhibitory TSH-receptor antibodies exist, as was found in anti-insulin receptor antibodies in some patients with non-insulin dependent diabetes mellitus [2], and that these antibodies may exert an influence on a post-receptor process.…”

Section: Discussionmentioning

confidence: 68%

Comparison of atrophic and goitrous auto-immune thyroiditis in children: Clinical, laboratory and TSH-receptor antibody studies

et al. 1990

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We studied the clinical features, laboratory and thyroid functions and thyrotropin (TSH)-receptor and thyroid-stimulation antibodies in 21 patients with atrophic auto-immune thyroiditis (AAT) and 48 patients with goitrous auto-immune thyroiditis (GAT) of childhood onset. The clinical features of patient with AAT were cessation of growth and obesity, while asymptomatic enlargement of the thyroid gland was the sole symptom in most patients with GAT. Although the ages at diagnosis were comparable in both groups, the estimated ages at onset were much lower in patients with AAT than in those with GAT. Patients with AAT exhibited more severe hypothyroidism when evaluated by serum thyroxine (T4), tri-iodothyronine (T3), TSH, cholesterol levels and basal metabolic rates. The 24 h 123I-thyroidal uptake was significantly lower in patients with AAT than in those with GAT. None of the 19 patients with AAT possessed TSH-binding inhibitor immunoglobulins (TBII). On the other hand, 3 of the 32 GAT patients tested, possessed weak to potent TBII activities. Three TBII-positive patients with GAT also possessed thyroid-stimulation blocking antibodies. These findings suggest that: 1. Pathogenesis of AAT in children whose onset of hypothyroidism was before puberty is not due to TSH-receptor blocking antibodies, which are often found in patients with AAT of postpubertal onset. 2. AAT in children is considered not to be due to the later stage of GAT. 3. Some patients with GAT possessed TSH-receptor blocking antibodies. The aetiology and pathogenesis of AAT in children have yet to be elucidated.

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Section: Discussionmentioning

confidence: 68%

Comparison of atrophic and goitrous auto-immune thyroiditis in children: Clinical, laboratory and TSH-receptor antibody studies

et al. 1990

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“…First, IGF-1 receptor, insulin and glucagon, all at high concentrations, did not crossreact with the antiserum when diluted 1:3000. IGF-1 receptor did, however, crossreact with the AIRA at dilutions of less than 1:500 (Boden et al 1988). Second, pure placental insulin receptor and solubilized crude human placental membranes both competed with equal potency for binding to the antiserum.…”

Section: Discussionmentioning

confidence: 93%

“…Insulin and IGF-1 receptors are similar in size and structure (LeBon et al 1986;Rechler 1985) and many antiinsulin receptor antibodies have been found to crossreact with IGF-1 receptor (Boden et al 1988;Kasuga, Sasaki, Kahn, Nissley and Rechler 1983;Roth, Maddux, Wong, Styne, Vliet, Humbel and Goldfine 1983). The-antiserum, at the dilution used in this assay, appeared to be specific for the insulin receptor as documented by 2 observations.…”

Section: Discussionmentioning

confidence: 99%

A Radioimmunoassay for Human Insulin Receptor Correlation Between Insulin Binding and Receptor Mass

Boden

Jadali²,

Tappy³

et al. 1991

Horm Metab Res

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We have developed a radioimmunoassay for human insulin receptor. Serum from a patient with Type B severe insulin resistance was used as anti-insulin receptor antiserum. Pure human placental insulin receptor was used as reference preparation and 125I labeled pure insulin receptor as trace. The radioimmunoassay was sensitive (limit of detection less than 17 fmol), reproducible (inter and intra-assay coefficients of variation 12.5% and 1.6% respectively) and specific (no crossreactivity with pure placental IGF-1 receptor, insulin and glucagon). The anti-insulin receptor antibody was, however, able to differentiate between insulin receptor from human placenta and from rat liver. To determine the number of insulin binding sites per receptor, we measured insulin binding (by insulin binding assay) and insulin receptor mass (by radioimmunoassay) in solubilized aliquots from 5 human placentas. The molar ratio of insulin binding to receptor mass was 0.86 +/- 0.12 when binding was determined with monoiodinated 125I-Tyr A 14-insulin. It was 1.94 +/- 0.27 when randomly iodinated 125I-insulin was used. In conclusion, using a sensitive, reproducible and specific radioimmunoassay, we have measured insulin receptor mass independent of insulin binding. Our data are most compatible with binding of one insulin molecule per human placental insulin receptor.

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“…It is likely that heterogeneity of epitopes on the receptor to which distinct subpopulations of these antibodies bind will be shown to account for such differences in clinical outcome in individual patients. Autoantibodies to the insulin receptor are found in a small number of patients with insulinresistant diabetes, and an even smaller number of patients with unexplained hypoglycemia (15), but are not an important cause of insulin resistance in the general population (7,16).…”

Section: Insulin Resistance Due To Autoantibodies To the Insulin Recementioning

confidence: 99%

Lilly Lecture: Syndromes of Insulin Resistance: From Patient to Gene and Back Again

Flier¹

1992

Diabetes

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The syndromes of insulin resistance are a group of clinically diverse disorders, and our understanding of their molecular pathogenesis has advanced in parallel with our understanding of the structure of the insulin receptor and the mechanism of insulin action. The most straightforward progress has related to defining the role of both anti-receptor antibodies and mutations in the insulin receptor gene in causing these disorders. Despite this progress, the cause of severe target cell resistance in patients without defects in the receptor locus remains unknown, and we are limited in our ability to relate specific molecular defects in insulin signalling to in vivo phenotypes, such as those relating to growth and development and function of adipose tissue and muscle. Answers to these questions may ultimately be explained by the existence of multiple species of insulin receptors expressed in different tissues, brought about by alternative splicing and receptor hybrids, and by divergent pathways of insulin signalling with different consequences for specific tissues. The possibility that the insulin receptor and GLUT4 may be candidate genes for inherited insulin resistance in NIDDM has been addressed with the aid of genetic screening techniques such as SSCP. Currently, the loci have not been implicated in studies in most patients. Transgenic methodologies will be powerful tools for pursuit of unanswered questions in the field of insulin resistance in coming years.

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Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes.

Cited by 15 publications

References 29 publications

Comparison of atrophic and goitrous auto-immune thyroiditis in children: Clinical, laboratory and TSH-receptor antibody studies

Comparison of atrophic and goitrous auto-immune thyroiditis in children: Clinical, laboratory and TSH-receptor antibody studies

A Radioimmunoassay for Human Insulin Receptor Correlation Between Insulin Binding and Receptor Mass

Lilly Lecture: Syndromes of Insulin Resistance: From Patient to Gene and Back Again

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