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  • 1
    Electronic Resource
    Electronic Resource
    Non-linkage of the islet amyloid polypeptide gene with Type 2 (non-insulin-dependent) diabetes mellitus (1991)
    Springer
    Diabetologia 34 (1991), S. 103-108 
    Details
    ISSN: 1432-0428
    Keywords: Linkage ; islet amyloid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Type 2 (non-insulin-dependent) diabetes is associated with the deposition of islet amyloid. The major formative peptide, islet amyloid polypeptide, has recently been characterised and an abnormality of the structure or expression of this gene is a possible candidate for the inherited component of Type 2 diabetes. A restriction fragment length polymorphism of the gene has been identified with Pvu II. To study the relationship between the islet amyloid polypeptide gene and Type 2 diabetes, two distinct genetic approaches have been undertaken. Firstly, non-linkage has been demonstrated in four pedigrees, with four normoglycaemic first degree relatives having an allele associated with diabetes in other family members, and one affected relative not having the putatively associated allele. The LOD score taking age-related penetrance into account was −1.68, making linkage unlikely (p=0.02). Secondly, in a population-based restriction fragment length polymorphism survey, no linkage disequilibrium of the alleles was found between a population of unrelated Caucasian subjects with Type 2 diabetes and a normal population. A mutation in or near the islet amyloid polypeptide gene is thus unlikely to be a common cause of Type 2 diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00500380
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  • 2
    Electronic Resource
    Electronic Resource
    Analysis of the HepG2/erythrocyte glucose transporter locus in a family with Type 2 (non-insulin-dependent) diabetes and obesity (1989)
    Springer
    Diabetologia 32 (1989), S. 266-269 
    Details
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes ; genetics ; linkage ; glucose transporter
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A recent report has shown an association between a specific Xba1 restriction fragment of the human HepG2-Erythrocyte glucose transporter gene and Type 2 (non-insulin dependent) diabetes. To further examine the significance of this finding we have studied Type 2 diabetic pedigrees for linkage between the Xba1 alleles of this glucose transporter gene and diabetes. One large pedigree, in which the diabetic phenotype was associated with obesity and insulin resistance, was informative. In this family the disease did not co-segregate with the glucose transporter locus. Formal linkage analysis was performed assuming autosomal dominant inheritance with age-dependent penetrance. At putative gene frequencies of 0.01 and 0.001 the logarithin of the odds for linkage versus non-linkage at a recombination fraction of 0.001 was −1.84 and −3.32 respectively (a value of 〈-2 indicates definite non-linkage). Genetic variations in the HepG2-Erythrocyte glucose transporter gene are unlikely to be responsible for the development of diabetes in this pedigree.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00285296
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  • 3
    Electronic Resource
    Electronic Resource
    Natural variants of human p85α phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity (2000)
    Springer
    Diabetologia 43 (2000), S. 321-331 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Keywords Genetics, insulin signalling, phosphatidylinositol 3-kinase.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Phosphoinositide 3-kinase (PI 3K) plays a central part in the mediation of insulin-stimulated glucose disposal. No genetic studies of this enzyme in human syndromes of severe insulin resistance have been previously reported.¶Methods. Phosphoinositide 3-kinase p85α regulatory subunit cDNA was examined in 20 subjects with syndromes of severe insulin resistance by single strand conformational polymorphism and restriction fragment length polymorphism analyses. Insulin-stimulated phosphoinositide 3-kinase activity and recruitment into phosphotyrosine complexes of variants of p85α were studied in transiently transfected HEK293 cells. Phosphopeptide binding characteristics of wild-type and mutant p85α-GST fusion proteins were examined by surface plasmon resonance.¶Results. The common p85α variant, Met326I1e, was identified in 9 of the 20 subjects. Functional studies of the Met326Ile variant showed it to have equivalent insulin-stimulated lipid kinase activity and phosphotyrosine recruitment as wild-type p85α. A novel heterozygous mutation, Arg409Gln, was detected in one subject. Within the proband's family, carriers of the mutation had a higher median fasting plasma insulin (218 pmol/l) compared with wild-type relatives (72 mol/l) (n = 8 subjects, p = 0.06). The Arg409Gln p85α subunit was associated with lower insulin-stimulated phosphoinositide 3-kinase activity compared with wild-type (mean reduction 15 %, p 〈 0.05, n = 5). The recruitment of Arg409Gln p85α into phosphotyrosine complexes was not significantly impaired. GST fusion proteins of wild-type and mutant p85α showed identical binding to phosphopeptides in surface plasmon resonance studies.¶Conclusion/interpretation. Mutations in p85α are uncommon in subjects with syndromes of severe insulin resistance. The Met326Ile p85α variant appears to have no functional effect on the insulin-stimulated phosphoinositide 3-kinase activity. The impaired phosphoinositide 3-kinase activity of the Arg409Gln mutant suggests that it could contribute to the insulin resistance seen in this family. [Diabetologia (2000) 43: 321–331]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050050
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  • 4
    Electronic Resource
    Electronic Resource
    Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a welsh type 2 (non-insulin-dependent) diabetic population (1992)
    Springer
    Diabetologia 35 (1992), S. 486-489 
    Details
    ISSN: 1432-0428
    Keywords: Genetics ; Type 2 (non-insulin-dependent) ; diabetes mellitus ; insulin receptor ; glucose transporters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have recently examined the exons encoding the insulin receptor tyrosine kinase domain and GLUT 4 in 30 subjects with Type 2 (non-insulin-dependent) diabetes mellitus using a molecular scanning approach. The variant sequences Val-Met985 and Lys-Glu1068 of the insulin receptor and Val-Ile383 of GLUT 4 were each separately found in three different diabetic subjects. In a study of a Welsh population, the GLUT 4383 variant was found in three of 160 diabetic and none of the 80 control subjects. In this study, the same group of Welsh Type 2 diabetic and control subjects was analysed using allele-specific oligonucleotide hybridisation, single nucleotide primer extension and allele-specific restriction digestion to ascertain the frequency of the two insulin receptor mutations. The Val-Met985 mutation was found in none of the 160 Welsh Caucasian Type 2 diabetic subjects and two of 80 control subjects. The Lys-Glu1068 mutation removes a Sty 1 site and digestion of amplified exon 18 with Sty 1 confirmed the presence of this mutation in the heterozygous state in the original subject. None of the Welsh diabetic or control subjects had the Glu1068 mutation. The discovery of a very common silent polymorphism at codon 130 of GLUT 4 allowed examination of the association of this locus with Type 2 diabetes using allele-specific oligonucleotide hybridisation in a subset of the Welsh subjects. The genotypic frequencies (homozygous wild-type and heterzygous polymorphic (poly) sequences) were not significantly different between diabetic and control subjects (Type 2 diabetic subjects: wild-type/wild-type 40%, wild-type/poly 46%, poly/poly 14%; Control subjects: wild-type/wild-type 37%0, wild-type/poly 45 %, poly/poly 18 %;p 〉 0.05). In conclusion, in a British Caucasian population the examined insulin receptor tyrosine kinase domain mutations are uncommon. Also the GLUT 4 locus does not appear to be strongly associated with Type 2 diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02342449
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  • 5
    Electronic Resource
    Electronic Resource
    Mitochondrial DNA, diabetes and pancreatic pathology in Kearns–Sayre syndrome (1995)
    Springer
    Diabetologia 38 (1995), S. 868-871 
    Details
    ISSN: 1432-0428
    Keywords: Key words Mitochondrial DNA ; pancreatic islets ; diabetes ; Kearns ; Sayre syndrome.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mitochondrial DNA (mtDNA) mutations are associated with diabetes mellitus but their role in the onset of hyperglycaemia is unclear. A patient presented with diabetes requiring insulin therapy at the age of 7 years, followed by diagnosis of Kearns–Sayre syndrome (KSS). Beta-cell function was absent at age 19 years as shown by lack of glucose-stimulated C-peptide secretion. Following development of a cardiac conduction defect the patient died aged 21 years. Analysis of mtDNA in blood and several tissues revealed related re-arranged deletions, duplications and deletion dimers in addition to normal mtDNA with the highest levels of duplications in kidney and blood. Pancreatic tissue from the KSS patient was compared with tissue from an insulin-dependent diabetic patient with a similar clinical history of diabetes. Islets in KSS were small, regular in shape and contained predominantly glucagon-containing cells with no evidence of beta cells. In comparison, a small number of beta cells were present in some of the larger more irregularly-shaped islets from the insulin-dependent diabetic patient. These data together suggest that in KSS the loss of beta cells at the onset of diabetes is less disruptive to islet architecture: a small proportion of beta cells or their gradual destruction over a long period would allow retention of islet shape. Abnormal function of the re-arranged mtDNA could affect both development and function of pancreatic islet cells since glucose-stimulated insulin secretion is energy dependent. [Diabetologia (1995) 38: 868–871].
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050366
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  • 6
    Electronic Resource
    Electronic Resource
    Multipoint linkage analysis of the short arm of chromosome 11 in non-insulin dependent diabetes including maturity onset diabetes of youth (1992)
    Springer
    Human genetics 〈Berlin〉 89 (1992), S. 207-212 
    Details
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Members of three families with maturity onset diabetes of youth (MODY) and seven with “common” type 2 diabetes were typed for six DNA markers (H-RAS, INS, HBBC, PTH, CALC1, CAT) on the short arm of chromosome 11. Using conventional pairwise linkage analysis, close linkage in the MODY families was excluded for all six markers. By multipoint analysis and a genetic map of the short arm of chromosome 11, MODY was excluded from a region of at least 35 and up to 60 centiMorgans (cM) on the short arm of chromosome 11. Multipoint analysis in the type 2 families also excludes linkage to the INS, H-RAS region of at least 3 and up to 30 cM. This study using multipoint linkage analysis in non-insulin dependent diabetes provides strong evidence against a role for mutations in or around the insulin gene in the causation of MODY or type 2 diabetes in the families studied.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217125
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  • 7
    Electronic Resource
    Electronic Resource
    Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension (1999)
    [s.l.] : Macmillian Magazines Ltd.
    Nature 402 (1999), S. 880-883 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Thiazolidinediones are a new class of antidiabetic agent that improve insulin sensitivity and reduce plasma glucose and blood pressure in subjects with type 2 diabetes. Although these agents can bind and activate an orphan nuclear receptor, peroxisome proliferator-activated receptor gamma ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/47254
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  • 8
    Electronic Resource
    Electronic Resource
    Haemolysis affects insulin but not C-peptide immunoassay (1987)
    Springer
    Diabetologia 30 (1987), S. 394-396 
    Details
    ISSN: 1432-0428
    Keywords: Insulin ; C-peptide ; radio-immunoassay ; haemolysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Venous blood was taken at the end of a glucose infusion test in 19 individuals and divided into four aliquots, 3 of which were variably haemolysed by repeated passage through a 23-gauge needle to simulate traumatic venepuncture. Plasma insulin (measured by both a charcoal separation and a double-antibody method), C-peptide, and haemoglobin were measured in each aliquot, and haemolysis was also assessed visibly. A significant loss of immuno-assayable plasma insulin was found in samples with only a trace of visible haemolysis, with up to 90% lost in severely haemolysed samples. Plasma C-peptide was unaffected by haemolysis. This represents an additional advantage for the use of plasma C-peptide in assessing insulin secretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00292540
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  • 9
    Electronic Resource
    Electronic Resource
    Linkage analysis of the human insulin receptor gene in Type 2 (non-insulin-dependent) diabetic families and a family with maturity onset diabetes of the young (1988)
    Springer
    Diabetologia 31 (1988), S. 792-797 
    Details
    ISSN: 1432-0428
    Keywords: Genetics ; Type 2 (non-insulin-dependent) diabetes ; insulin receptor ; linkage analysis ; maturity onset diabetes of the young
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The possibility of linkage between the human insulin receptor gene locus and diabetes was examined in three Type 2 (non-insulin-dependent) diabetic families and one family with maturity onset diabetes of the young. Insulin receptor gene haplotypes were established using BglII, Rsal and Sstl restriction enzyme digests of genomic DNA from all available family members. The digested DNA was subjected to agarose gel electrophoresis, Southern blotted, and hybridised to 32P-labelled human insulin receptor gene cDNA. In the pedigree with maturity onset diabetes of the young, formal linkage analysis allowed exclusion of close linkage between the insulin receptor locus and diabetes (logarithm of the odds for linkage versus non-linkage was −5.35 at recombination fraction of 0.01). This confirms the absence of linkage between insulin receptor and diabetes which has been reported in two similar pedigrees. In the three Type 2 diabetic families there were a minimum of 4 recombinants between the insulin receptor locus and diabetes, which makes a direct role for insulin receptor defects unlikely. The importance of using realistic estimates of penetrance when performing linkage analysis in a disease with a late age of onset is emphasised. In contrast to the one previous linkage analysis study of the insulin receptor gene, no specific association of diabetes with the rare Sstl Sl(-) allele was observed in either the maturity onset diabetes of the young or the Type 2 diabetic families.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00277479
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  • 10
    Electronic Resource
    Electronic Resource
    Type 2 (non-insulin-dependent) diabetes mellitus new genetics for old nightmares (1988)
    Springer
    Diabetologia 31 (1988), S. 407-414 
    Details
    ISSN: 1432-0428
    Keywords: Genetics ; Type 2 (non-insulin-dependent) diabetes ; linkage analysis ; restriction fragment length polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the last five years, genetic markers for a large number of diseases have been localised using linkage analysis of DNA polymorphisms in affected families. The site of the genetic defect or defects leading to Type 2 (non-insulin-dependent) diabetes mellitus, a common illness with a major genetic component, remains unknown. This is due, at least in part, to the lack of large well-defined Type 2 diabetic pedigrees suitable for linkage analysis. There are several features of the disease which make large pedigrees difficult to find. The late age of onset of most probands means that informative older generations are often dead, while there is difficulty in detecting disease in younger generations. The diagnostic criteria for diabetes are, as yet, dependent on an arbitrary cut-off along a continuum of plasma glucose. The high prevalence of the disease may also produce problems as, in any given family, diabetogenic genes may be contributed by more than one parent. Varieties of the disease with a well-defined inheritance, such as maturity onset diabetes of youth, are more suitable for linkage analysis but might be due to defects at a different gene locus. Despite these difficulties, once large well-defined pedigrees have been found, linkage analysis using both candidate genes and random highly polymorphic markers is the strategy most likely to find genetic markers for the disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271584
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