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  • 1
    Electronic Resource
    Electronic Resource
    Individuals with only one allele for a functional insulin receptor have a tendency to hyperinsulinaemia but not to hyperglycaemia (1989)
    Springer
    Diabetologia 32 (1989), S. 740-744 
    Details
    ISSN: 1432-0428
    Keywords: Leprechaunism ; insulin receptor ; insulin resistance ; autophosphorylation ; insulin binding ; glucose tolerance tests
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Recently, we described a leprechaun patient with a genetically transmitted severe insulin resistance due to the absence of functional insulin receptors as inferred from the loss of insulin binding to the patients' fibroblasts and the impaired autophosphorylation of the β-chain of the receptor. This patient was homozygous for the genetic defect which was recently found to be a leucine to proline mutation at position 233 in the α-chain of the insulin receptor. In the present study we have examined insulin receptor functions in relatives of this patient. Some of these individuals are heterozygous for the genetic defect and have only one allele coding for a functional insulin receptor. Insulin binding to cultured fibroblasts from the heterozygous individuals is only 20–40% of control values indicating a Mendelian mode of inheritance of the binding defect. In contrast, insulin stimulated autophosphorylation of the β-chain of the insulin receptor shows normal values, indicating compensation mechanisms operating on this process. The stimulation of the basal level of 2-deoxyglucose uptake by insulin in fibroblasts from the homozygous patient is 1.2 fold whereas the heterozygous and control individuals show stimulation values of approximately 1.65 fold. Basal levels of 2-deoxyglucose uptake are similar in these fibroblasts. Oral glucose tolerance tests on the heterozygous individuals indicate an increased requirement for insulin of the target tissues as concluded from the tendency towards hyperinsulinaemia with no observed hyperglycaemia. The results show that individuals with a genetic lesion in the insulin receptor which leads to decreased insulin binding, have mild abnormalities in their glucose tolerance tests but do not seem to develop hyperglycaemia as seen in Type 2 (non-insulin-dependent) diabetes mellitus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00274534
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  • 2
    Electronic Resource
    Electronic Resource
    An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome (1993)
    Springer
    Diabetologia 36 (1993), S. 1168-1174 
    Details
    ISSN: 1432-0428
    Keywords: Diabetes mellitus ; insulin resistance ; insulin receptor ; Rabson-Mendenhall syndrome ; insertion mutation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have studied the structure and function of the insulin receptor in a patient (PK) with severe insulin resistance and Rabson-Mendenhall syndrome. Insulin binding to cultured fibroblasts from PK was almost not detectable and insulin-induced insulin receptor autophosphorylation and glucose uptake was abolished. The structure of the receptor gene was analysed by sequencing amplified products of the 22 exons with the flanking intron regions directly as well as after subcloning in pUCBM20 plasmids. Two mutant alleles of the insulin receptor gene were detected. One allele contains in-frame 12 additional base pairs in exon 3 coding for the amino acids Leu-His-Leu-Val located between Asp-261 and Leu-262 in the receptor's extracellular domain, being the first report of an insertion mutation of the insulin receptor gene. In the other allele Arg-86 in exon 2 is changed into a stop codon. Therefore, PK is compound heterozygous at the insulin receptor locus. Direct cDNA sequencing indicates that both mutant alleles are expressed in the patient's fibroblasts. Studies of the parents' fibroblasts revealed that PK inherited the insertion mutation from the father and the nonsense mutation from the mother. Insulin binding to fibroblasts of the mother was reduced (63 % of control cells) and hormone binding to the father's cells shows a larger reduction (37 % of control cells), but less severe than the patient's cells (11 % of control). This investigation provides further evidence that the Rabson-Mendenhall syndrome is causally related to mutations in the insulin receptor gene.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401062
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  • 3
    Electronic Resource
    Electronic Resource
    Patients with lipodystrophic diabetes mellitus of the Seip-Berardinelli type, express normal insulin receptors (1993)
    Springer
    Diabetologia 36 (1993), S. 172-174 
    Details
    ISSN: 1432-0428
    Keywords: Lipodystrophic diabetes mellitus ; insulin resistance ; insulin receptor ; IGF-I receptor ; polymorphisms ; Seip-Berardinelli syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Lipodystrophic diabetes mellitus of the Seip-Berardinelli type is a syndrome associated with insulin resistance and recessive inheritance. We have examined whether mutations in the insulin receptor are pathogenetic factors in this syndrome. Fibroblasts from three different patients with Seip-Berardinelli's lipodystrophy were tested for insulin binding, and insulin-stimulated receptor autophosphorylation. In addition, the coding region of both alleles of the insulin receptor gene was sequenced. No abnormalities in the number of high affinity insulin binding sites, and in-sulinstimulated receptor autophosphorylation were detected. The insulin receptor related insulin-like growth factor I receptor also showed no functional changes. DNA sequence analysis of the amplified exons of the insulin receptor gene showed a silent mutation in patient 1 at codon Ser339, changing AGT to AGC. In patient 2 a heterozygous Met for Val substitution at position 985 was detected, which is a rare polymorphism. In patient 3 no mutations, other than described polymorphisms, were observed. These findings demonstrate that the primary genetic lesion in Seip-Berardinelli's lipodystrophy is outside the insulin receptor gene and that an involvement of the insulin-like growth factor I receptor is also unlikely.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400701
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    Paper (German National Licenses)
    Fulltext
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