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  • 1
    Digitale Medien
    Digitale Medien
    Variant sequences of the Hexokinase II gene in familial NIDDM (1996)
    Springer
    Diabetologia 39 (1996), S. 322-328 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Hexokinase II ; candidate gene analysis ; insulin resistance ; familial non-insulin-dependent diabetes mellitus
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Hexokinase II (HKII) plays a central role in the intracellular metabolism of glucose in skeletal muscle, catalysing the phosphorylation of glucose to glucose 6-phosphate. It is therefore considered to be a potentially important candidate gene in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to screen the HKII gene for mutations in NIDDM subjects from insulin-resistant families. Insulin sensitivity was assessed in unaffected first degree relatives from families with two or more living NIDDM subjects, and 15 families were identified as being insulin resistant. In 15 NIDDM subjects (one from each family) and 4 normoglycaemic control subjects, all 18 exons of the HKII gene were amplified by the polymerase chain reaction, and the products screened for mutations using a combination of single-stranded conformational polymorphism analysis and direct sequencing. Six sequence variations were detected in the NIDDM subjects; four silent polymorphisms [GAT vs GAC at codon 251 in exon 7, AAT vs AAC at codon 692 in exon 15, CCG vs CCC at codon 736 in exon 15, and CTG vs CTA at codon 766 in exon 16]; a single base change [T→C], 22 base pairs distal to the exon-intron junction of exon 17 in the 5′-splice donor; and a single amino acid substitution [Gln142→His] in exon 4, which was identified in 6 of the 15 NIDDM subjects. The frequency of the mutated codon 142 allele however, was comparable between NIDDM subjects with familial NIDDM (n=56) and normoglycaemic control subjects (n=48) (18.8% and 14.6% for NIDDM subjects and control subjects respectively; χ2=0.6, p〉0.25). In addition, measures of insulin sensitivity were comparable in normal glucose tolerant subjects with (n=20) and without (n=40) the codon 142 polymorphism. In conclusion: (1) mutations in the coding regions of the HKII gene are unlikely to be major determinants in the development of insulin resistance and familial NIDDM; although (2) the influence of the codon 142 mutation in combination with other abnormalities of the insulin-signalling pathway on insulin action remain to be addressed.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00418348
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  • 2
    Digitale Medien
    Digitale Medien
    Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance (1998)
    Springer
    Diabetologia 41 (1998), S. 430-434 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Keywords Tumour necrosis factor-alpha ; insulin resistance ; polymorphism ; gene promoter ; relatives ; family.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNFα) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNFα promoter region (positions –238 and –-308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The –238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the –238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 ± 2.1 [means ± SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 ± 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased KITT (3.8, 3.0 ± 1.0 %/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the –308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals. [Diabetologia (1998) 41: 430–434]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s001250050926
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  • 3
    Digitale Medien
    Digitale Medien
    Twenty-four-hour insulin secretion rates, circulating concentrations of fuel substrates and gut incretin hormones in healthy offspring of Type II (non-insulin-dependent) diabetic parents: evidence of several aberrations (1999)
    Springer
    Diabetologia 42 (1999), S. 1314-1323 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Keywords Prediabetes ; physiological approach ; 24-h profile ; glucose ; insulin ; insulin secretion ; proinsulin ; non-esterified fatty acids ; gut incretin hormones ; intermediary metabolites.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Aims/hypothesis. Insulin resistance is a common feature in relatives of patients with Type II (non-insulin-dependent) diabetes mellitus and abnormalities in beta-cell function can also exist. Insight into non-fasting carbohydrate metabolism in these potentially prediabetic subjects relies almost exclusively on studies in which glucose is infused or ingested or both. We aimed to characterize insulin secretion and aspects of hormonal and metabolic patterns in relatives using a physiological approach. Methods. We examined profiles of insulin, C peptide, proinsulin, gut incretin hormones and fuel substrates in 26 glucose tolerant but insulin resistant (clamp) relatives and 17 control subjects during a 24-hour period including three meals. Results. During the day plasma glucose was slightly raised in relatives (p 〈 0.05). Overall insulin secretion calculated on the basis of C peptide kinetics were increased in relatives (p 〈 0.0005) whereas incremental insulin secretion after all three meals were similar. Peak incremental insulin secretion tended, however, to be reduced in relatives (p 〈 0.10). Despite considerably increased insulin concentrations in relatives (70 %, p 〈 0.001), serum NEFA did not differ. Postprandial proinsulin concentrations (p 〈 0.05), but not proinsulin:insulin ratios, were increased in relatives. After meals concentrations of glucose-dependent-insulinotropic polypeptide (p 〈 0.05) were increased in relatives. Glucagon-like peptide-1 concentrations were similar. Conclusion/interpretation. Several hormonal and metabolic aberrations are present in healthy relatives of Type II diabetic patients during conditions that simulate daily living. Increased concentrations of glucose-dependent-insulinotropic polypeptide could indicate a beta-cell receptor defect for glucose-dependent-insulinotropic polypeptide in the prediabetic stage of Type II diabetes. Incremental insulin secretion after mixed meals appear normal in relatives, although a trend towards diminished peak values possibly signifies early beta-cell dysfunction. [Diabetologia (1999) 42: 1314–1323]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s001250051444
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  • 4
    Digitale Medien
    Digitale Medien
    Variant sequences of the Hexokinase II gene in familial NIDDM (1996)
    Springer
    Diabetologia 39 (1996), S. 322-328 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Keywords Hexokinase II ; candidate gene analysis ; insulin resistance ; familial non-insulin-dependent diabetes mellitus.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Hexokinase II (HKII) plays a central role in the intracellular metabolism of glucose in skeletal muscle, catalysing the phosphorylation of glucose to glucose 6-phosphate. It is therefore considered to be a potentially important candidate gene in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to screen the HKII gene for mutations in NIDDM subjects from insulin-resistant families. Insulin sensitivity was assessed in unaffected first degree relatives from families with two or more living NIDDM subjects, and 15 families were identified as being insulin resistant. In 15 NIDDM subjects (one from each family) and 4 normoglycaemic control subjects, all 18 exons of the HKII gene were amplified by the polymerase chain reaction, and the products screened for mutations using a combination of single-stranded conformational polymorphism analysis and direct sequencing. Six sequence variations were detected in the NIDDM subjects; four silent polymorphisms [GAT vs GAC at codon 251 in exon 7, AAT vs AAC at codon 692 in exon 15, CCG vs CCC at codon 736 in exon 15, and CTG vs CTA at codon 766 in exon 16]; a single base change [T→C], 22 base pairs distal to the exon-intron junction of exon 17 in the 5 ′-splice donor; and a single amino acid substitution [Gln142→His] in exon 4, which was identified in 6 of the 15 NIDDM subjects. The frequency of the mutated codon 142 allele however, was comparable between NIDDM subjects with familial NIDDM (n = 56) and normoglycaemic control subjects (n = 48) (18.8 % and 14.6 % for NIDDM subjects and control subjects respectively; χ 2 = 0.6, p 〉 0.25). In addition, measures of insulin sensitivity were comparable in normal glucose tolerant subjects with (n = 20) and without (n = 40) the codon 142 polymorphism. In conclusion: (1) mutations in the coding regions of the HKII gene are unlikely to be major determinants in the development of insulin resistance and familial NIDDM; although (2) the influence of the codon 142 mutation in combination with other abnormalities of the insulin-signalling pathway on insulin action remain to be addressed. [Diabetologia (1996) 39: 322–328]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00418348
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  • 5
    Digitale Medien
    Digitale Medien
    Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families (1997)
    Springer
    Diabetologia 40 (1997), S. 1185-1190 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Keywords C-peptide ; proinsulin ; insulin ; insulin secretion ; insulin resistance ; insulin clearance ; families ; adiposity ; glucose intolerance.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Non-diabetic first degree relatives of non-insulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p 〈 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3 %, p 〈 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pair-matched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and C-peptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion. [Diabetologie (1997) 40: 1185–1190]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s001250050805
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  • 6
    Digitale Medien
    Digitale Medien
    Childhood size is more strongly related than size at birth to glucose and insulin levels in 10–11-year-old children (1997)
    Springer
    Diabetologia 40 (1997), S. 319-326 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Keywords Birth weight ; ponderal index ; glucose ; insulin ; children.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In adults low birthweight and thinness at birth are associated with increased risk of glucose intolerance and non-insulin-dependent diabetes mellitus. We have examined the relations between size at birth (birthweight, thinness at birth) and levels of plasma glucose and serum insulin in children, and compared them with the effects of childhood size. We performed a school-based survey of 10–11-year-old British children (response rate 64 %) with measurements made after an overnight fast. One group of children (n = 591) was studied fasting while the other (n = 547) was studied 30 min after a standard oral glucose load (1.75 g/kg). Serum insulin was measured by a highly specific ELISA method. Birthweight was assessed by maternal recall and thinness at birth using birth records. Neither fasting nor post-load glucose levels showed any consistent relationship with birthweight or ponderal index at birth. After adjustment for childhood height and ponderal index, both fasting and post-load insulin levels fell with increasing birthweight. For each kg increase in birthweight, fasting insulin fell by 16.9 % (95 % confidence limits 7.1–25.8 %, p = 0.001) and post-load insulin by 11.6 % (95 % confidence limits 3.5–19.1 %, p = 0.007). However, the proportional change in insulin level for a 1 SD increase in childhood ponderal index was much greater than that for birthweight (27.2 % and − 8.8 %, respectively, for fasting insulin). We conclude that low birthweight is not related to glucose intolerance at 10–11 years, but may be related to the early development of insulin resistance. However, in contemporary children obesity is a stronger determinant of insulin level and insulin resistance than size at birth. [Diabetologia (1997) 40: 319–326]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s001250050681
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