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  • 1
    ISSN: 1432-0428
    Keywords: Keywords Insulin resistance syndrome ; mutation ; genotype ; phenotype ; tyrosine kinase.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We report a homozygous missense mutation at position 1092 (substitution of glutamine for arginine) in the tyrosine kinase domain of the insulin receptor in a patient with leprechaunism associated with severe insulin resistance and intrauterine growth retardation. Site-directed mutagenesis as well as analyses of the patient's lymphocytes revealed that this mutation causes a marked decrease in tyrosine kinase activity of the insulin receptor without any defect in insulin binding, which causes severe defects in insulin-stimulated glucose transport, glycogen synthesis and DNA synthesis. Thus, this is the first homozygous mutation resulting in a selective-kinase defect of the insulin receptor. Interestingly, the parents who are cousins and are heterozygous for the mutation have type A insulin resistance syndrome. This correlation between genotype and phenotype in a single pedigree suggests that the severity of the mutation will determine the phenotype. Based upon this assumption, we have been successful in prenatal diagnosis of the fifth child. Furthermore, we have demonstrated the effectiveness of clinical administration of insulin-like growth factor-I (IGF-I) in this patient and in vitro analysis of the patient's skin fibroblasts, suggesting that IGF-I can compensate for insulin action via the IGF-I receptor in a patient almost lacking functional insulin receptors. [Diabetologia (1997) 40: 412–420]
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Keywordsβ3-adrenergic receptor ; body mass index ; visceral obesity ; triglyceride ; lipolysis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The Trp64Arg mutation of the β3-adrenergic receptor (β3AR) is prevalent in several ethnic groups and is associated with weight gain, and some features of syndrome X such as insulin resistance and dyslipidaemia. Nevertheless, it is not known at present whether this mutation is associated with visceral obesity, which is an important risk factor for the development of hypertension, dyslipidaemia, insulin resistance, non-insulin-dependent diabetes mellitus, and atherosclerosis. To investigate whether this mutation may contribute to visceral obesity, we studied the relationships between β3AR genotypes and clinical phenotypes. The Trp64Arg allele of β3AR was examined in 278 Japanese men with respect to variables relating to visceral obesity assessed by computerised tomography. To detect the Trp64Arg mutation, polymerase chain reaction-restriction fragment length polymorphism analysis using Bst NI digestion was performed. This mutation was more frequently observed in subjects with higher body mass index (BMI) (p = 0.02). Moreover, in 120 subjects with a moderate degree of obesity (22 M BMI 〈 26.4 kg/m2), the mutation (homozygotes and heterozygotes) was associated with visceral obesity (higher ratio of visceral to subcutaneous fat area; V/S) (p = 0.03). Furthermore, the Trp64Arg allele was more frequent in subjects with lower serum triglyceride levels (p = 0.02) and the Trp64Arg homozygotes, but not heterozygotes, exhibited lower triglyceride levels. Thus, this mutation appears to be associated with visceral obesity but with lower serum triglyceride. It is suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue. [Diabetologia (1997) 40: 469–472]
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Hyperinsulinaemia ; tyrosine kinase activity ; Type 2 (non-insulin-dependent) diabetes mellitus ; obesity ; screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We analyzed single-stranded conformational poly morphisms to screen for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Using this new technique, we demonstrated the existence of mutations in the insulin receptor gene which we had identified previously. In addition, a new mutation was found in exon 20 of the insulin receptor gene in a patient with moderate insulin resistance associated with morbid obesity, acanthosis nigricans, and polycystic ovary syndrome. The patient was heterozygous for a mutation substituting Leu (CTG) for Pro (CCG) at codon 1178. Pro1178 is a part of a characteristic sequence motif (D1150 F1151 G1152-A1177 P1178 E1179) common to many protein kinases. Analysis of single-stranded conformational polymorphisms was also used to estimate the frequency of a polymorphism at codon 1058. The two codons CAC (1058 His) and CAT (1058 His) both had a prevalence of 50% in 30 Japanese subjects. These data demonstrate that analysis of single-stranded conformational polymorphisms is a simple and sensitive screening method for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Identification of a mutation in the insulin receptor gene in a patient with a moderate degree of insulin resistance associated with morbid obesity suggests that insulin receptor mutations may exist in patients with Type 2 (non-insulin-dependent) diabetes mellitus associated with a moderate degree of insulin resistance.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Key words Mitochondrial DNA mutation ; insulin-dependent diabetes mellitus ; non-insulin-dependent diabetes mellitus ; gestational diabetes mellitus.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mitochondrial DNA is exclusively maternally inherited. We recently found the prevalence of diabetic patients with an A to G transition at position 3243 of leucine tRNA (3243 base pair (bp) mutation) to be nearly 1 % in randomly selected Japanese subjects. Here, we report the higher prevalence of diabetic patients with the 3243 bp mutation in a specific Japanese population of women attending a diabetic pregnancy clinic. Of 102 patients with non-insulin-dependent diabetes mellitus 6 (5.9 %) were positive for the mutation, 1 (8.3 %) of 12 patients with gestational diabetes and 2 (5.9 %) out of 34 borderline diabetic patients. In contrast, none of 64 patients (0 %) with insulin-dependent diabetes mellitus had the 3243 bp mutation. Moreover, there was a difference in the prevalence of spontaneous abortions between patients with and without this mutation (27.3 vs 12.4 %). Among nine probands with the mutation, four had a history of one spontaneous abortion (p = 0.0518) and two had a history of two abortions (p = 0.0479). Two probands had a spontaneous abortion even while under strict diabetic metabolic control. The 3243 bp mutation thus may cause spontaneous abortion during pregnancy. [Diabetologia (1995) 38: 809–815]
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 39 (1996), S. 375-382 
    ISSN: 1432-0428
    Keywords: Genetics ; maternally inherited diabetes and deafness ; NIDDM ; IDDM ; mitochondria ; MELAS syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Diabetes mellitus is a common disease with many forms of clinical expression. In addition, the development of diabetic complications is not only dependent on glycaemic control but also on individual factors which may be related to genetic heterogeneity. At present, multiple genetic factors are being recognized as contributing to the development of diabetes or possibly modulating its clinical expression. The purpose of this review is to give an overview of our current knowledge on a subtype of diabetes which is apparently caused by a single mutation in the mitochondrial DNA.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 39 (1996), S. 375-382 
    ISSN: 1432-0428
    Keywords: Keywords Genetics ; maternally inherited diabetes and deafness ; NIDDM ; IDDM ; mitochondria ; MELAS syndrome.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Diabetes mellitus is a common disease with many forms of clinical expression. In addition, the development of diabetic complications is not only dependent on glycaemic control but also on individual factors which may be related to genetic heterogeneity. At present, multiple genetic factors are being recognized as contributing to the development of diabetes or possibly modulating its clinical expression. The purpose of this review is to give an overview of our current knowledge on a subtype of diabetes which is apparently caused by a single mutation in the mitochondrial DNA. [Diabetologia (1996) 39: 375–382]
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0428
    Keywords: Keywords ATP-sensitive K-current ; glucokinase ; beta cell ; insulin secretion ; MODY.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary One type of maturity-onset diabetes of the young (MODY2) is caused by mutations in the glucokinase gene, a key glycolytic enzyme in the beta cell and liver. Glucose fails to stimulate insulin secretion in mice in which the glucokinase gene has been selectively knocked out in the beta cell. We tested the hypothesis that this effect results from defective metabolic regulation of beta cell ATP-sensitive potassium (KATP) channels. Glucose had little effect on KATP currents in homozygous (-/-) mice but inhibited KATP currents in wild-type (+/+) and heterozygous ( + /-) mice with EC50 of 3.2 mM and 5.5 mM, respectively, in newborn animals, and of 4.7 mM and 9.9 mM, respectively, in 1.5-year-old mice. Glucose (20 mmol/l) did not affect the resting membrane potential of -/- beta cells but depolarised wild-type and + /- beta cells and induced electrical activity. In contrast, 20 mmol/l ketoisocaproic acid or 0.5 mmol/l tolbutamide depolarised all three types of beta-cell. These results support the idea that defective glycolytic metabolism, produced by a loss (-/- mice) or reduction ( + /- mice) of glucokinase activity, leads to defective KATP channel regulation and thereby to the selective loss, or reduction, of glucose-induced insulin secretion. [Diabetologia (1998) 41: 654–659]
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Biochemical and Biophysical Research Communications 127 (1985), S. 493-500 
    ISSN: 0006-291X
    Keywords: [abr] Hepes; 4(2-hydroxyethyl)-1-piperazine ethanesulfonic acid ; [abr] NaDodSO"4; sodium dodecyl sulfate
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0006-291X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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