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  • 1
    Electronic Resource
    Electronic Resource
    Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4α in Caucasians with maturity onset NIDDM (1997)
    Springer
    Diabetologia 40 (1997), S. 980-983 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Hepatocyte nuclear factor-4α ; non-insulin-dependent diabetes mellitus ; insulin response ; mutations ; transcription factors.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mutations in the hepatocyte nuclear factor-4α (HNF-4α) gene cause the type 1 form of maturity onset diabetes of the young (MODY1). To address the question of whether genetic variability of HNF-4α is associated with late onset non-insulin-dependent diabetes mellitus (NIDDM) we have sequenced the coding region and intron/exon boundaries of the gene in 36 randomly recruited Danish NIDDM patients. Two nucleotide substitutions that changed the sequence of HNF-4α were identified: Thr/Ile130, which has been reported previously and a novel Val/Met255. The Val/Met 255 mutation was found in 4 of 477 Danish NIDDM patients and in none of 217 glucose tolerant control subjects; thus it cannot be excluded that this mutation may have an impact on NIDDM susceptibility. Among 509 NIDDM patients the allelic frequency of the Thr/Ile130 variant was 4.7 % (95 % confidence interval: 3.4–6.0 %) compared to 1.9 % (0.7–3.1 %) among 239 control subjects (p = 0.008). However, in a population sample of 942 Swedish men with an average age of 70 years the allelic frequency of the variant was similar in 246 men with either impaired glucose tolerance (5.6 % [2.6–8.6 %]) or NIDDM (5.4 % [2.7–8.1 %]) as compared to 666 glucose tolerant men (5.1 % [3.9–6.3 %]). Also in a population sample of 369 young healthy Danes the prevalence of the codon 130 variant (4.7 % [3.2–6.2 %]) was similar to what was found in Swedish Caucasians. Thus, the allelic frequency of the Thr/Ile130 variant among the control subjects in the Danish case-control study deviates from the prevalence in the two other studies which is why we consider the significant association between the codon 130 variant and NIDDM an incidental finding. In glucose tolerant subjects the codon 130 variant in its heterozygous form had no major effect on glucose-induced insulin and C-peptide release although a tendency to a lower insulin secretion during an oral glucose tolerance test was seen in middle-aged subjects. In conclusion, variability in the coding region of the HNF-4α gene is not a common cause of NIDDM among whites of Danish ancestry. However, a Val/Met255 mutation was found exclusively in NIDDM patients (0.8 % of cases) and functional as well as family segregation studies are needed to determine whether this HNF-4α variant is a NIDDM causing mutation. [Diabetologia (1997) 40: 980–983]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050778
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  • 2
    Electronic Resource
    Electronic Resource
    Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity (1999)
    Springer
    Diabetologia 42 (1999), S. 1244-1249 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin receptor substrate-2 ; mutations ; Type II diabetes ; insulin secretion ; insulin sensitivity.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The aim of this study was to screen part of the putative promoter sequence in addition to 14 potential phosphotyrosine residues of human IRS-2 for genetic variability which might cause changes in protein expression or function. Furthermore, the potential impact on insulin secretion and sensitivity of a previously identified IRS-2 variant (Gly1057Asp) was analysed Methods. The screenings were carried out by the SSCP-heteroduplex technique on DNA from Type II (non-insulin-dependent) diabetic patients. The impact of the Gly1057Asp variant was analysed in four glucose-tolerant Scandinavian study groups. Results. The results showed no nucleotide substitutions in the promoter sequence, however, a novel heterozygous amino acid variant was identified (Leu647Val). In an association study, the new variant was found in 3 of 413 diabetic patients and in none of 280 glucose tolerant subjects. The variant did not affect the binding of IRS-2 to the insulin receptor or p85α of phosphatidylinositol 3-kinase when measured in the yeast two-hybrid system. Examination of the common Gly1057Asp variant in 363 young healthy subjects and in 228 glucose tolerant offspring of one diabetic parent showed no differences in insulin secretion or insulin sensivity after an intravenous glucose tolerance test. Glucose tolerant middle-aged subjects homozygous for the polymorphism (n = 31), however, had on average a 25 % decrease in fasting serum insulin concentrations (p = 0.009) and 28 % (p = 0.01) and 34 % (p = 0.003) reductions in serum insulin concentrations at 30 and 60 min, respectively, during an OGTT compared with wildtype carriers (n = 107). In a cohort of 639 elderly Swedish men the amino acid variant did not have any detectable impact on insulin secretion after an OGTT. Conclusion/interpretation. No genetic variability was found in the IRS-2 promoter. A rare IRS-2 variant at codon 647 has been identified in Type II diabetic patients. The prevalent codon 1057 polymorphism had no consistent effect on insulin secretion or insulin sensitivity. [Diabetologia (1999) 42: 1244–1249]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051299
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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