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  • 1
    Electronic Resource
    Electronic Resource
    Long-term risk of IDDM in first-degree relatives of patients with IDDM (1994)
    Springer
    Diabetologia 37 (1994), S. 321-327 
    Details
    ISSN: 1432-0428
    Keywords: IDDM ; first-degree relatives ; familial aggregation ; recurrence risk ; life-table analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Due to a short observation period previous studies may have underestimated prevalence and recurrence risk of IDDM in relatives of IDDM patients. To obtain a more exact life-time risk estimate we identified 310 probands, representative of Danish IDDM patients, characterized by current age more than 50 years, age at onset 40 years or less and diabetes duration of more than 30 years. Family data were obtained from 291 probands. Mean “observation” times (age) (± SD) for siblings (n = 553) and offspring (n=359) were 59.4 ± 16.1 years and 33.8 ± 8.8 years, respectively. Of the probands 73 (25.1%) had at least one first-degree relative with IDDM. Seventeen percent had at least one affected sibling. An increase from 10.4% to 22.4% of having first-degree relatives with IDDM among probands with age at onset below 20 years was observed during the period from proband at age 21 years up to 1 September 1992. Among affected siblings 48% of the second cases were affected more than 10 years after the first affected sibling. Using the life-table method cumulative recurrence risks from time of birth were calculated for siblings up to age 30 years of 6.4% and up to age 60 years of 9.6%. For offspring the risk up to age 34 years was 6.3%. In addition, we present a life-table method evaluating the cumulative recurrence risk from time of onset in the proband, as this is the most relevant when giving genetic counselling. In conclusion, the long-term risks of IDDM in siblings and offspring are high compared to that shown in previous reports.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00398061
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  • 2
    Electronic Resource
    Electronic Resource
    Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats (1993)
    Springer
    Diabetologia 36 (1993), S. 759-766 
    Details
    ISSN: 1432-0428
    Keywords: Cytokine ; interleukin-1 receptor antagonist ; insulin-dependent diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The monokines interleukin-1α and -β have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1β, and on interleukin-1β induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1β on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100–1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1βon rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1β-induced inhibition of insulin release after 24 h. In contrast, interleukin-1β-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1β stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1β effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1β effects on isolated mouse islets. A 10–100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1β-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1β-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1β effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401148
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  • 3
    Electronic Resource
    Electronic Resource
    A nationwide population-based study of the familial aggregation of Type 1 (insulin-dependent) diabetes mellitus in Denmark (1993)
    Springer
    Diabetologia 36 (1993), S. 870-875 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; nationwide population-based ; familial prevalence ; sporadic cases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The objective of the present study was to assess the prevalence of familial aggregation of Type 1 (insulin-dependent) diabetes mellitus among Danish families with a diabetic child aged 20 years or less and to compare epidemiological data for familial and sporadic cases. We attempted to identify all patients with Type 1 diabetes aged 0–19 years in Denmark treated at paediatric departments or at departments of internal medicine. This comprises more than 98% of all patients with Type 1 diabetes in this age group. Patients were identified through the local diabetic out-patient registry and asked to complete a questionnaire regarding data on diabetes onset and family history. Of 1574 probands 1419 agreed to participate (90.2%). Additional cases of Type 1 diabetes were found in 171 families (12.8%). Of these 115 were parent-offspring affected families, and in 56 families at least two siblings had Type 1 diabetes and healthy parents. Significant correlation in age at onset of Type 1 diabetes in concordant siblings was observed (r=0.5, p=0.0004). Significantly more probands had an affected father with Type 1 diabetes than a mother affected (p〈0.0001). Heterogeneity in epidemiological characteristics was observed between familial and sporadic cases, i.e. familial index cases were younger at onset of the disease, their parents were younger at birth of the index case, and there was no difference in gender of familial cases in contrast to sporadic cases where significantly more males were found. Over a 4-year period (1986–1989) an increasing trend in incidence was observed. However, an increase in incidence compared to previous Danish data from the 1970s and 1980 s could not be demonstrated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400364
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  • 4
    Electronic Resource
    Electronic Resource
    On the pathogenesis of IDDM (1994)
    Springer
    Diabetologia 37 (1994), S. S82 
    Details
    ISSN: 1432-0428
    Keywords: Insulin-dependent diabetes mellitus ; free radicals ; cytokines ; beta-cell destruction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2 − and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400830
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  • 5
    Electronic Resource
    Electronic Resource
    Complete molecular scanning of the human Fas gene: mutational analysis and linkage studies in families with Type I diabetes mellitus (2000)
    Springer
    Diabetologia 43 (2000), S. 800-808 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Genetics, candidate gene, apoptosis, tolerance, microsatellite, ALPS, c-Myb, SP-1, NF-kB.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The human Fas gene (FAS) on chromosome 10q24.1 encoding a cell surface receptor involved in apoptosis was evaluated as a candidate susceptibility gene for Type I (insulin-dependent) diabetes mellitus. Apoptosis mediated by Fas is important in maintaining peripheral self-tolerance and in down-regulating the immune response and could have a role in immune-mediated beta-cell destruction.¶Methods. We did a molecular scan of the entire human FAS (promoter, exons 1–9 including exon-intron boundaries and the 3 ′UTR) using single strand conformational polymorphism-heteroduplex analysis.¶Results. We identified 15 mutations, of which 11 are new. Of these a g-1194A→T and a g-295Ains give rise to alterations of transcription-factor-binding consensus sequences for c-Myb, SP-1 and NF-kB, respectively. A total of 1068 people from a Danish family collection comprising 138 Type I diabetic sib-pair families (289 affected and 121 unaffected offspring) and 103 Type I diabetic parent-offspring multiplex families (103 affected and 112 unaffected offspring) were typed for the three most frequent polymorphisms with high heterozygosity indices and for a FAS microsatellite. Haplotypes were established and data analysed using the extended transmission disequilibrium test, ETDT.¶Conclusion/interpretation. We found no overall evidence for linkage of the FAS polymorphisms to Type I diabetes. We conclude that it is unlikely that the Fas gene does contribute to genetic susceptibility for Type I diabetes. [Diabetologia (2000) 43: 800–808]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051378
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  • 6
    Electronic Resource
    Electronic Resource
    Long-term risk of IDDM in first-degree relatives of patients with IDDM (1994)
    Springer
    Diabetologia 37 (1994), S. 321-327 
    Details
    ISSN: 1432-0428
    Keywords: Key words IDDM, first-degree relatives, familial aggregation, recurrence risk, life-table analysis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Due to a short observation period previous studies may have underestimated prevalence and recurrence risk of IDDM in relatives of IDDM patients. To obtain a more exact life-time risk estimate we identified 310 probands, representative of Danish IDDM patients, characterized by current age more than 50 years, age at onset 40 years or less and diabetes duration of more than 30 years. Family data were obtained from 291 probands. Mean “observation” times (age) (± SD) for siblings (n =553) and offspring (n =359) were 59.4±16.1 years and 33.8±8.8 years, respectively. Of the probands 73 (25.1 %) had at least one first-degree relative with IDDM. Seventeen percent had at least one affected sibling. An increase from 10.4 % to 22.4 % of having first-degree relatives with IDDM among probands with age at onset below 20 years was observed during the period from proband at age 21 years up to 1 September 1992. Among affected siblings 48 % of the second cases were affected more than 10 years after the first affected sibling. Using the life-table method cumulative recurrence risks from time of birth were calculated for siblings up to age 30 years of 6.4 % and up to age 60 years of 9.6 %. For offspring the risk up to age 34 years was 6.3 %. In addition, we present a life-table method evaluating the cumulative recurrence risk from time of onset in the proband, as this is the most relevant when giving genetic counselling. In conclusion, the long-term risks of IDDM in siblings and offspring are high compared to that shown in previous reports. [Diabetologia (1994) 37: 321–327]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00398061
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  • 7
    Electronic Resource
    Electronic Resource
    Predictors of IDDM recurrence risk in offspring of Danish IDDM patients (1998)
    Springer
    Diabetologia 41 (1998), S. 666-673 
    Details
    ISSN: 1432-0428
    Keywords: Keywords IDDM ; epidemiology ; offspring ; recurrence risk ; sex difference ; prediction ; cumulative risk ; Cox proportional hazards model.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It has previously been observed that offspring of mothers with insulin-dependent diabetes mellitus (IDDM) have a lower risk of IDDM than offspring of IDDM affected fathers. To assess the offspring IDDM recurrence risk in a Danish population-based study and to investigate parental and offspring-related biological variables that might influence this risk, we identified 2726 IDDM probands and their 2826 offspring from a background population of 1.725 million people (33 % of the Danish population). Current age of probands was 20–65 years and their age at IDDM onset was 30 years or less. Sixty-nine offspring (2.4 %) were affected with IDDM. The sex difference in the parental-offspring IDDM transmission rate was confirmed. The cumulative IDDM risk up to age 30 years was found to be significantly decreased in maternal offspring compared to paternal offspring (2.3 ± 0.6 and 5.7 ± 0.9 %, RR = 2.40, 95 % CI 1.30–4.47; p = 0.004) only if parents were diagnosed with IDDM before birth of the offspring. However, due to the low number of diabetic offspring of probands diagnosed with IDDM after offspring birth, this observation needs to be confirmed in a larger population. In a subpopulation of the 2380 offspring, whose parents were all diagnosed with IDDM before offspring birth, the recurrence risk was significantly increased in offspring of male probands diagnosed up to age 17 years compared to offspring of fathers diagnosed at older ages (8.5 ± 1.8 and 3.6 ± 1.0 %; RR = 2.27, 95 % CI 1.21–4.25; p = 0.006). No such relation was found in maternal offspring. Using the Cox proportional hazards model on this offspring subpopulation we found that paternal age at IDDM onset was the only statistically significant predictor of IDDM recurrence risk. Our findings may be important for counselling families in which one parent has IDDM. [Diabetologia (1998) 41: 666–673]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050966
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  • 8
    Electronic Resource
    Electronic Resource
    Mutations in the hepatocyte nuclear factor-1α gene in Caucasian families originally classified as having Type I diabetes (1998)
    Springer
    Diabetologia 41 (1998), S. 1528-1531 
    Details
    ISSN: 1432-0428
    Keywords: Keywords HNF-1α ; Mutations ; IDDM ; MODY3 ; Misclassification ; non-DR3 and non-DR4 genotypes.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mutations in the hepatocyte nuclear factor-1α (HNF-1α) gene are the cause of maturity-onset diabetes of the young type 3 (MODY3), which is characterised by a severe impairment of insulin secretion and an early onset of the disease. Also at onset of diabetes some MODY patients show similar clinical symptoms and signs as patients with Type I (insulin-dependent) diabetes mellitus. The objective of this study was to estimate the prevalence of MODY3 patients misclassified as Type I diabetic patients. From a large population-based sample of unrelated Danish Caucasian Type I diabetic patients with an affected first degree relative, 39 patients (6.7 %) who did not carry any high-risk HLA-haplotypes, i. e. DR3 or DR4 or both were examined by single-strand conformational polymorphism scanning and direct sequencing of the coding region and the minimal promoter of the HNF-1α gene. Four of the 39 Type I diabetic patients (10 %) were identified as carrying mutations in the HNF-1α gene. One patient carried a missense mutation (Glu48Lys) in exon 1, two patients carried a missense mutation (Cys241Gly) in exon 4 and one patient carried a frameshift mutation (Pro291fsdelA) in exon 4. The mutations were all identified in heterozygous form, segregated with diabetes, and were not identified in 84 unrelated, healthy subjects. Furthermore, family history in three of the four families showed diabetes in four consecutive generations, suggestive of an autosomal dominant inheritance. In conclusion, about 10 % of Danish diabetic patients without a high-risk HLA-haplotype, originally classified as having Type I diabetes could have diabetes caused by mutations in the HNF-1α gene. Clinical awareness of family history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY3 patients. [Diabetologia (1998) 41: 1528–1531]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051101
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  • 9
    Electronic Resource
    Electronic Resource
    A Tumour Necrosis Factor Beta Gene Polymorphism in Relation to Monokine Secretion and Insulin-Dependent Diabetes Mellitus (1991)
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 33 (1991), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: HLA-class III region genes may be associated with susceptibility to insulin-dependent diabetes mellitus (IDDM). In this study an Ncol polymorphism of the tumour necrosis factor beta (TNF-β) gene, which is positioned next lo the tumour necrosis factor alpha (TNF-α) gene in the HLA class 111 region, was detected by restriction fragment length polymorphism (RFLP). This polymorphism has previously been reported lo be located in the TNF-α gene. Caucasian HLA-DR3.4 heterozygous IDDM patients (n=-26) and DR-matched healthy controls (n=19). as well as randomly selected IDDM patients (n = 27) and controls (n = 25) were studied. In addition four multiplex families (49 individuals) and eight HLA-non-identical sibpairs concordant for IDDM were analysed.The TNF-β gene RFLP analysis showed fragments of 5.5 kb and 10.5 kb, which behaved as alleles. In all groups there was a haplotype assignment of the TNF-β 5.5-kb allele to BS, DR3 haplotypes, and of the TNF-β 10.5-kb allele to B15.DR4-positive haplotypes. The allelic and genotypic frequencies differed between DR3.4 IDDM patients and DR3,4 controls, and the DR3.4 control group differed significantly from the randomly selected control group (P 〈 0.0079), In HLA-DR3,4-atid DQw8-positive persons, the DR3 haplotypes carried the 10.5-kb allele ihrcL- times more frequently in IDDM patients than in controls, suggesting that the 10.5-kb allele when present on DR3 haplotyes may contribute lo susceplibility to IDDM in DR3.4 heterozygous individuals, A contributory role of the Hl.5-kballele in genetic IDDM susceptibility was supported by the sibpair analysis, in which all were TNF-/1 identical. Five were 10,5 kb homozygous. and the remaining three pairs were 5.5.10,5 kb heterozygous.Twenty-five healthy and eight newly diagnosed IDDM patients were randomly selected to study the Escherichia coli lipopolysaccharides (LPS)-purified protein derivate (tuberculin) (PPD)-, and phytohaemagglutinin (PHA)-stimulated monocyte (Mo) secretions of interleukin 1 bela (IL-1/J)and TNb-α in relation lo the Ncol TNF-/f gene polymorphism. The LPS- and PHA stimulated Mo IL-l/f and TNF-a: secretions were significantly lower for the TNF-β 5.5.10,5 kb heterozygous individuals than for TNF-β 10.5 kb homozygous individuals. Furthermore, the Mo IL-1β and TNF-a secretions of IDDM patients were significantly higher than the Mo secretions of TNF-β genolype-matched healthy controls.This study suggests an association between the 10.5 kb TNF-β allele and IDDM, and demonstrates an association between monokine responses and TNF-β genotypes. These observations may have implications for understanding the pathogenesis of HLA-associated autoimmune diseases including IDDM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3083.1991.tb02490.x
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  • 10
    Electronic Resource
    Electronic Resource
    Monocyte Function in IDDM Patients and Healthy Individuals (1990)
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 32 (1990), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Interleukin 1β(IL-1β) and tumour necrosis factor alpha (TNF-α) may be pathogenetically important in insulin-dependent diabetes mellitus (IDDM), which is associated with genes of the HLA region. Since a regulatory role of HLA region genes on monokine production may exist, we looked for an association between the monokine and prostaglandin E2 (PGE2) responses of monocytes (Mo) from 20 healthy males (18–50 years) with HLA-DR types relevant for IDDM susceptibility and resistance (DR 1,2, DR 1,3, DR 1,4, DR 3,4). Monokine assays were established and evaluated and the secretions of IL-1β, TNF-α, and PGE2 measured in Mo cultures (2 h, 6 h, 20 h) prepared by endotoxin-free techniques and stimulated by low-dose E. coli lipopolysaccharides (LPS). There were no significant associations between Mo responses and HLA-DR phenotype. Likewise, Mo from DR2 (n=5) and DR4 (n= 5) homozygous healthy males demonstrated no significant differences in monokine and PGE2 responses of Mo.In the HLA class III region a diallelic TNF-β gene Ncol polymorphism consisting of alleles of 5.5 kb and 10.5 kb was recently described and associated with susceptibility to autoimmune diseases including IDDM. We report that IL-1β and TNF-α responses of Mo from TNF-β 10.5 kb homozygous healthy individuals were significantly higher than for TNF-β 5.5/10.5 kb heterozygotes.IL-1β and TNF-α responses of Mo from males (18–35 years) with newly diagnosed (n= 10) and long-standing IDDM (n= 10) and from age- and HLA-DR-matched healthy males (n= 10) were studied. LPS, gamma interferon (IFN), and TNF-α-stimulated Mo cultures were investigated. No significant differences were found between Mo responses of IDDM patients and controls. IFN (1000 U/ml) in the presence of LPS significantly potentiated LPS-stimulated Mo TNF-α secretion and reduced the levels of IL-β immunoreactivity in Mo lysates. IFN and TNF-α did not have any effects on LPS-stimulated Mo secretion of IL-1 β immunoreactivity.We conclude that Mo IL-1β and TNF-α production is normal in patients with recent-onset and long-standing IDDM. The interindividual differences in monokine responses may be accounted for by the diallelic human TNF-β gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain H LA haplotypes with autoimmune phenomena and disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3083.1990.tb02924.x
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