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  • 1
    Electronic Resource
    Electronic Resource
    Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase (1995)
    Springer
    Diabetologia 38 (1995), S. 1055-1060 
    Details
    ISSN: 1432-0428
    Keywords: Key words Maturity-onset diabetes of the young ; glucokinase ; adenosine deaminase ; pituitary adenylate cyclase-activation polypeptide receptor ; hexokinase II ; glucagon-like peptide-1 receptor ; polymerase chain reaction ; linkage analysis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterised by an early age of onset and an autosomal dominant mode of inheritance. Only a proportion of cases are due to mutations in the glucokinase gene. We have studied five Caucasian MODY families, including the first MODY family to be described, with five candidate genes implicated in regulation of insulin secretion. The affected subjects showed more marked hyperglycaemia than that found in subjects with glucokinase mutations. We assessed polymorphic markers close to the genes for glucokinase, hexokinase II, adenosine deaminase, pituitary adenylate cyclase-activating polypeptide receptor, and glucagon-like peptide-1 receptor. Linkage analysis with diabetes gave cumulative log of the odds (LOD) scores of less than –3, implying that mutations in these genes are unlikely to provide a major genetic contribution to this form of MODY. [Diabetologia (1995) 38: 1055–1060]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00402175
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  • 2
    Electronic Resource
    Electronic Resource
    Maternal diabetes alters birth weight in glucokinase-deficient (MODY2) kindred but has no influence on adult weight, height, insulin secretion or insulin sensitivity (2000)
    Springer
    Diabetologia 43 (2000), S. 1060-1063 
    Details
    ISSN: 1432-0428
    Keywords: Keywords MODY ; glucokinase mutations ; low birth weight ; macrosomia ; gestational diabetes ; insulin secretion defect.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Altered fetal insulin secretion caused by fetal or maternal glucokinase mutations influence birth weight. Here, we attempt to answer two additional questions: firstly, whether this variation in birth weight (from low birth weight to macrosomia) has an effect on adult height or weight. Secondly, whether maternal hyperglycaemia during fetal life has an effect on metabolic phenotypes of the adult offspring. Methods. We studied 447 family members from 37 MODY2 kindred, divided into four groups according to the presence or absence of a glucokinase mutation in the subject (S + or S–, respectively) and his/her mother (M + or M–). Birth weight data were obtained from a questionnaire sent to the mothers. Results. Birth weight was reduced in the presence of a fetal mutation (M–S + ) and increased in the presence of a maternal mutation (M + S–). These effects are additive as similar birth weights were observed in M + S + and M–S– offspring. Adult height, weight or body mass index (weight/height2) were, however, similar in the four groups of subjects. Non-diabetic adult offspring, regardless of the glycaemic status of the mothers (M + S– or M–S–), had similar insulin secretion, insulin sensitivity, blood pressures and lipid profiles. These variables as well as the severity of hyperglycaemia were similar in adult M + S + and M–S + MODY2 subjects. Conclusion/Interpretation. Maternal environment and fetal genotypes could alter growth in utero by changing fetal insulin secretion but these effects do not result in a persistent programming in latter life. [Diabetologia (2000) 43: 1060–1063]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051490
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  • 3
    Electronic Resource
    Electronic Resource
    Non-linkage of the glucagon-like peptide 1 receptor gene with maturity onset diabetes of the young (1994)
    Springer
    Diabetologia 37 (1994), S. 721-724 
    Details
    ISSN: 1432-0428
    Keywords: Glucagon-like peptide-1 receptor ; non-insulin-dependent diabetes mellitus ; maturity onset diabetes of the young ; polymerase chain reaction ; linkage analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glucagon-like peptide-1 (GLP-1) is a hormone derived from the preproglucagon molecule that is secreted by intestinal L cells and stimulates insulin secretion from betacells. The GLP-1 receptor is a candidate gene for diabetes mellitus, as mutations may induce the impaired insulin response that is a characteristic feature of NIDDM. To study the relationship between the GLP-1 receptor gene and NIDDM, linkage of a microsatellite polymorphism flanking the GLP-1 receptor gene with diabetes was investigated in three Caucasian families with MODY and in the nuclear families of 12 NIDDM probands. A cumulative LOD score −8.50 excludes linkage in these MODY pedigrees. A LOD score of −1.24 in the NIDDM nuclear pedigrees makes linkage improbable. Mutations in or near the GLP-1 receptor gene are unlikely to be the major cause of the inherited predisposition to NIDDM in Caucasian pedigrees, but we cannot exclude a role for this locus in a polygenic model or a major role in some pedigrees.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00417698
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  • 4
    Electronic Resource
    Electronic Resource
    Prevalence of diabetes mellitus and impaired glucose tolerance in parents of women with gestational diabetes (1995)
    Springer
    Diabetologia 38 (1995), S. 693-698 
    Details
    ISSN: 1432-0428
    Keywords: Inheritance diabetes ; beta cell function ; gestational diabetes ; non-insulin-dependent diabetes ; impaired glucose tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Nuclear families of non-insulin-dependent diabetic (NIDDM) patients are uncommon, as usually one or both parents have died. In order to aid identification of complete nuclear families, we have ascertained the disease process at a younger age by studying subjects with previous gestational diabetes. One hundred women who had had gestational diabetes, age (±SD) 38 (6) years, were screened by fasting plasma glucose (fpg). Sixty-one were found to have either fasting hyperglycaemia (5.5≤fpg〈7.8 mmol/l) or diabetes. Of these women 35 had both parents alive and the parents of 14 of these women agreed to the assessment of their metabolism by a continuous infusion of glucose with model assessment (CIGMA). Seven probands had impaired glucose tolerance (IGT) and seven were diabetic. They were age 35 (4) years and had body mass index (BMI) 26 (5) kg/m2. The parents were aged 62 (6) years and had BMI 29 (6) kg/m2 and their affection status was defined as presence of glucose intolerance (fpg or post-infusion achieved plasma glucose level 〉2 SD of an age and obesity matched population). In the 14 families, five probands (36%) had neither parent affected, six (43%) had one parent affected and three (21%) had both parents affected. Only three probands had a parent with diabetes as defined by World Health Organisation criteria. We concludes that the study of women who have had gestational diabetes allows detection of probands with diabetes or impaired glucose tolerance, who have both parents available for study. A substantial proportion had neither parent affected with impaired glucose tolerance or diabetes, similar to the nuclear families of NIDDM patients. The results are in accord with studies of nuclear families of NIDDM patients in suggesting polygenic inheritance or environmental influences rather than autosomal dominant inheritance with high penetrance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401841
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  • 5
    Electronic Resource
    Electronic Resource
    Prevalence of diabetes mellitus and impaired glucose tolerance in parents of women with gestational diabetes (1995)
    Springer
    Diabetologia 38 (1995), S. 693-698 
    Details
    ISSN: 1432-0428
    Keywords: Key words Inheritance diabetes ; beta cell function ; gestational diabetes ; non-insulin-dependent diabetes ; impaired glucose tolerance.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Nuclear families of non-insulin-dependent diabetic (NIDDM) patients are uncommon, as usually one or both parents have died. In order to aid identification of complete nuclear families, we have ascertained the disease process at a younger age by studying subjects with previous gestational diabetes. One hundred women who had had gestational diabetes, age (± SD) 38 (6) years, were screened by fasting plasma glucose (fpg). Sixty-one were found to have either fasting hyperglycaemia (5.5 ≤ fpg 〈 7.8 mmol/l) or diabetes. Of these women 35 had both parents alive and the parents of 14 of these women agreed to the assessment of their metabolism by a continuous infusion of glucose with model assessment (CIGMA). Seven probands had impaired glucose tolerance (IGT) and seven were diabetic. They were age 35 (4) years and had body mass index (BMI) 26 (5) kg/m2. The parents were aged 62 (6) years and had BMI 29 (6) kg/m2 and their affection status was defined as presence of glucose intolerance (fpg or post-infusion achieved plasma glucose level 〉 2 SD of an age and obesity matched population). In the 14 families, five probands (36 %) had neither parent affected, six (43 %) had one parent affected and three (21 %) had both parents affected. Only three probands had a parent with diabetes as defined by World Health Organisation criteria. We concludes that the study of women who have had gestational diabetes allows detection of probands with diabetes or impaired glucose tolerance, who have both parents available for study. A substantial proportion had neither parent affected with impaired glucose tolerance or diabetes, similar to the nuclear families of NIDDM patients. The results are in accord with studies of nuclear families of NIDDM patients in suggesting polygenic inheritance or environmental influences rather than autosomal dominant inheritance with high penetrance. [Diabetologia (1995) 38: 693–698]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401841
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  • 6
    Electronic Resource
    Electronic Resource
    A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young (1997)
    Springer
    Diabetologia 40 (1997), S. 859-862 
    Details
    ISSN: 1432-0428
    Keywords: Keywords MODY ; MODY1 ; HNF-4α ; mutation analysis ; sequencing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised by an early age of onset (〈 25 years) and an autosomal dominant mode of inheritance. MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4α) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1α) [MODY3]. A nonsense mutation in the HNF-4α gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at θ = 0) for mutations in the coding region of the HNF-4α gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4α gene. [Diabetologia (1997) 40: 859–862]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050760
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  • 7
    Electronic Resource
    Electronic Resource
    Evidence that single nucleotide polymorphism in the uncoupling protein 3 (UCP3) gene influences fat distribution in women of European and Asian origin (2000)
    Springer
    Diabetologia 43 (2000), S. 1558-1564 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Uncoupling protein-3 ; Europeans ; South Indians ; family association ; fat distribution ; body mass index ; Type II diabetes.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (–55 c→t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations. Methods. The –55 c→t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes. Results. In South Indian and European parent-offspring trios there was no preferential transmission of either allele at the –55 c→t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers p = 0.036, daughters p = 0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the population-based survey (p = 0.039). Conclusion/interpretation. The consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females. [Diabetologia (2000) 43: 1558–1564]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051569
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  • 8
    Electronic Resource
    Electronic Resource
    High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population (1996)
    Springer
    Diabetologia 39 (1996), S. 1325-1328 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Non-insulin-dependent diabetes mellitus ; gestational diabetes ; glucokinase ; single-stranded conformational polymorphism analysis ; founder effect.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5–10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299→ Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/GCK2) haplotype, suggesting that the observed high prevalence of the Gly299→ Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs. [Diabetologia (1996) 39: 1325–1328]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050577
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  • 9
    Electronic Resource
    Electronic Resource
    A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria (2000)
    Springer
    Diabetologia 43 (2000), S. 250-253 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Glucokinase, gestational diabetes, maturity-onset diabetes of the young, mutation analysis, phenotype selection.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Patients with glucokinase mutations are characterised by mild, persistent fasting hyperglycaemia, a small increment in glucose in response to an oral load and a dominant family history. These patients frequently present with gestational diabetes and often require insulin treatment during pregnancy. We assessed whether the selection of gestational diabetic subjects by clinical criteria would result in a high detection rate of glucokinase mutations.¶Methods. Caucasian gestational diabetic subjects from the United Kingdom who had fasting hyperglycaemia in pregnancy but did not meet the diagnostic criteria for maturity-onset diabetes of the young (MODY) were selected for direct sequencing of the glucokinase gene if they fulfilled the following four criteria; (1) persisting fasting hyperglycaemia outside pregnancy (5.5–8 mmol/l) (2) a small increment ( 〈 4.6 mmol/l) during a 2-h oral glucose tolerance test (3) insulin treatment during at least one pregnancy but subsequently controlled on diet and (4) a history of Type II (non-insulin-dependent) diabetes mellitus, gestational diabetes or fasting hyperglycaemia ( 〉 5.5 mmol/l) in a first-degree relative.¶Results. Of the 15 subjects 12 (80 %) with all these clinical criteria had glucokinase gene mutations. These included four previously unreported mutations (N180K, R191W, Y215X and L288–1G → A).¶Conclusion/interpretation. Phenotypic selection of subjects with gestational diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene as previous studies have suggested a prevalence of 2.5 % (range 0–6 %). Our study in gestational diabetes to successfully used clinical criteria to assist in the definition of a genetic subgroup. [Diabetologia (2000) 43: 250–253]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050038
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  • 10
    Electronic Resource
    Electronic Resource
    Segregation analysis of NIDDM in Caucasian families (1994)
    Springer
    Diabetologia 37 (1994), S. 1231-1240 
    Details
    ISSN: 1432-0428
    Keywords: Key words Non-insulin-dependent diabetes mellitus ; genetic epidemiology ; genetic linkage.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypotheses, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4 %. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity. [Diabetologia (1994) 37: 1231–1240]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00399797
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