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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
    Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance (1995)
    Springer
    Diabetologia 38 (1995), S. 699-704 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Key words Impaired glucose tolerance ; insulin sensitivity ; hepatic glucose output ; insulin secretion ; labelled infusion technique.
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Recent evidence suggests that the postprandial hyperglycaemia in impaired glucose tolerance is primarily due to impaired suppression of basal hepatic glucose output. This in turn appears to be secondary to decreased first phase insulin secretion, although decreased hepatic insulin sensitivity, which is a feature of non-insulin-dependent diabetes mellitus, might also play a role. Eight mildly overweight subjects with impaired glucose tolerance and eight closely matched control subjects with normal glucose tolerance underwent an intravenous glucose tolerance test to assess first phase insulin secretion. Insulin sensitivity was examined by a 150-min hyperinsulinaemic-euglycaemic clamp. Somatostatin was infused from 150 min to suppress endogenous insulin secretion, and glucagon and insulin were replaced by constant infusion. Glucose with added dideuterated glucose (labelled infusion technique) was infused to maintain euglycaemia. First phase insulin secretion (Δ 0–10 min insulin area 7 Δ 0–10 min glucose area) was significantly decreased in the subjects with impaired glucose tolerance (median [range]: 1.2 [0.2–19.4] vs 9.1 [2.6–14.5] mU · mmol−1; p 〈 0.01). During the clamp, circulating insulin (93 ± 8 [mean ± SEM] and 81 ± 10 mU · l−1) and glucagon (54 ± 4 and 44 ± 6 ng · l−1) levels were comparable. Total glucose disposal was decreased in subjects with impaired glucose tolerance (2.78 ± 0.27 vs 4.47 ± 0.53 mg · kg−1· min−1; p 〈 0.02), and was primarily due to decreased non-oxidative glucose disposal. However, hepatic glucose output rates were comparable during the clamp (0.38 ± 0.10 and 0.30 ± 0.18 mg · kg−1· min−1). Therefore, the main defects in subjects with impaired glucose tolerance are decreased first phase insulin secretion and peripheral non-oxidative glucose disposal, but hepatic glucose output shows normal responsiveness to insulin. [Diabetologia (1995) 38: 699–704]
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00401842
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 3
    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
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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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
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Artikel (Nationallizenzen)
    Volltext
  • 5
    Digitale Medien
    Digitale Medien
    Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance (1995)
    Springer
    Diabetologia 38 (1995), S. 699-704 
    Details
    ISSN: 1432-0428
    Schlagwort(e): Impaired glucose tolerance ; insulin sensitivity ; hepatic glucose output ; insulin secretion ; labelled infusion technique
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Recent evidence suggests that the post-prandial hyperglycaemia in impaired glucose tolerance is primarily due to impaired suppression of basal hepatic glucose output. This in turn appears to be secondary to decreased first phase insulin secretion, although decreased hepatic insulin sensitivity, which is a feature of non-insulin-dependent diabetes mellitus, might also play a role. Eight mildly overweight subjects with impaired glucose tolerance and eight closely matched control subjects with normal glucose tolerance underwent an intravenous glucose tolerance test to assess first phase insulin secretion. Insulin sensitivity was examined by a 150-min hyperinsulinaemic-euglycaemic clamp. Somatostatin was infused from 150 min to suppress endogenous insulin secretion, and glucagon and insulin were replaced by constant infusion. Glucose with added dideuterated glucose (labelled infusion technique) was infused to maintain euglycaemia. First phase insulin secretion (Δ 0–10 min insulin area ÷Δ 0–10 min glucose area) was significantly decreased in the subjects with impaired glucose tolerance (median [range]: 1.2 [0.2–19.4] vs 9.1 [2.6–14.5] mU·mmol−1; p〈0.01). During the clamp, circulating insulin (93±8 [mean±SEM] and 81±10 mU·l−1) and glucagon (54±4 and 44±6 ng·l−1) levels were comparable. Total glucose disposal was decreased in subjects with impaired glucose tolerance (2.78±0.27 vs 4.47±0.53 mg·kg−1·min−1; p〈0.02), and was primarily due to decreased non-oxidative glucose disposal. However, hepatic glucose output rates were comparable during the clamp (0.38±0.10 and 0.30±0.18 mg·kg−1·min−1). Therefore, the main defects in subjects with impaired glucose tolerance are decreased first phase insulin secretion and peripheral non-oxidative glucose disposal, but hepatic glucose output shows normal responsiveness to insulin.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00401842
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Artikel (Nationallizenzen)
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  • 6
    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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