Determinants of IDDM and Perinatal Mortality in Children of Diabetic Mothers

Warram, James H.; Królewski, A. S.; Kahn, C. Ronald

doi:10.2337/diab.37.10.1328

Cited by 49 publications

(22 citation statements)

References 17 publications

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“…Results from the Joslin Diabetes Center, Boston, Mass., USA show that perinatal mortality of diabetic pregnancies was 23 % before 1961. After a dramatic drop in 1961 it stabilized around 14 % until 1975, and since then it has decreased to 4 % [22]. It has been shown that half of the fetal deaths occur due to poor metabolic control of mothers with IDDM or gestational diabetes, HbA 1 c (assessed by chromatographic methods with ranges of 5-8 % representing healthy metabolism) also has a significant and independent effect on severe neonatal morbidity [23,24].…”

Section: Discussionmentioning

confidence: 99%

Incidence trends in childhood onset IDDM in four countries around the Baltic sea during 1983-1992

Padaiga

Tuomilehto²,

Karvonen³

et al. 1997

Diabetologia

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Incidence of childhood insulin-dependent diabetes mellitus (IDDM) is rising in many areas of the world [1,2]. Despite the role of HLA genetics in the aetiology of IDDM being well known [3,4] the role of putative environmental factors is not yet understood [5][6][7]. Epidemiologically based standardized surveillance systems provide information on the pattern of IDDM incidence which make comparison of IDDM incidence between countries within close geographical areas possible, thus offering an "indirect" way to trace potential environmental factors in the aetiology of IDDM. A collaborative study on the childhood IDDM incidence in countries around the Baltic Sea was started in 1989 named "DIABALT". Short-term data have demonstrated a wide variation in the incidence of IDDM between countries around the Baltic Sea [8,9], from the highest incidence in the world in Finland to one of the lowest within Europe in Poland. In order to obtain more standardized rates for comparison of secular trends in incidence of IDDM in Finland, Estonia, Latvia and Lithuania the analyses of the data were carried out for the period 1983 to 1992. Subjects and methodsGeographically the Baltic States of Estonia, Latvia and Lithuania are located on the south-east coast, while Finland is on the northern coast of the Baltic Sea. Genetically and culturally, the population of Finland is homogeneous [10], while Estonia Diabetologia (1997) 40: 187-192 Incidence trends in childhood onset IDDM in four countries around the Baltic sea during 1983-1992 Summary We present secular trends of childhood onset insulin-dependent diabetes mellitus (IDDM) in Finland, Estonia, Latvia and Lithuania during the period of [1983][1984][1985][1986][1987][1988][1989][1990][1991][1992]. Incidence data were obtained from the national IDDM registries. The average agestandardized incidence per 100 000/year was 35.0 in Finland, followed by 10.2 in Estonia, 7.1 in Lithuania and 6.5 in Latvia. A male excess in incidence was recorded in Finland (1.15) and Latvia (1.01). In all countries, the highest age-specific risk of IDDM was observed in the 11-13 year age range. The large difference in incidence between Finland and other Baltic countries was seen even in 1-2-year-old children. During the 10-year study period overall changes in incidence of IDDM were relatively small in these four countries. The incidence increased in Finland and Lithuania on average by 1 % and 1.4 % per year, respectively. A statistically significant increase was recorded only in 0-4 year old children in Finland, at 5.6 % per year. In Estonia, an 8.3 % increase in this age group, however, was not statistically significant. The different trends in the age-group specific incidence rates were confirmed in Finland. In conclusion, from 1983 to 1992 the incidence of childhood onset IDDM was increasing in Finland and Lithuania, while in Latvia and Estonia it was stable. There are still great differences in IDDM incidence between the countries around the

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Section: Discussionmentioning

confidence: 99%

Incidence trends in childhood onset IDDM in four countries around the Baltic sea during 1983-1992

Padaiga

Tuomilehto²,

Karvonen³

et al. 1997

Diabetologia

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“…Although the hypothesis of a maternal event (presumably during pregnancy) seems biologically more attractive, the possible involvement of the paternal DR4 can be proposed on the basis of two still poorly understood aspects of the inheritance of Type 1 diabetes: (1) the increased transmission of DR4 from diabetic parents to their diabetic offspring [16,17] which may be explained by a dominant transmission of the DR4-associated susceptibility factor; (2) the increased risk for diabetes in offspring of diabetic fathers compared with that of diabetic mothers [26,27]. Overtransmission of a dominant, DR4 associated predisposing allele from diabetic fathers could indeed explain a higher occurrence of diabetes in their offspring, namely in those who have in addition received DR3 from the mother.…”

Section: Discussionmentioning

confidence: 99%

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive Type 1 (insulin-dependent) diabetic patients

et al. 1990

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Summary. The susceptibility determinants of Type 1 (insulindependent) diabetes mellitus are known to be associated with both HLA-DR3 and DR4. In our study we wished to determine if the parental origin of these antigens could influence susceptibility to the disease. We analysed the inheritance of DR3 and DR4 haplotypes from the father or mother (DR3p, DR4p, DR3m and DR4m, respectively), in the index cases and in the affected and non-affected siblings of 246 diabetic simplex and 41 multiplex families without affected parents. An independent series of 80 multiplex families (GAW 5) was also studied. Among the DR3,4 positive index cases and affected siblings, the paternal and maternal DR3 and DR4 antigens were not distributed randomly: 62% and 72%, respectively, had received DR4 from their father and DR3 from their mother (DR4p/DR3m), while only 38% and 28%, respectively, had received a paternal DR3 together with a maternal DR4 (DR3p/DR4m). This differed significantly from the 50% expected ratio (p < 0.01) and was not observed in unaffected siblings. No excess of maternal DR3 in the absence of DR4 and no excess of paternal DR4 in the absence of DR3 were observed. The finding suggests that some maternal DR3 related event (presumably during pregnancy) might play an enhancing role in the pathogenesis of Type 1 diabetes. It also implies that siblings with both DR4p and DR3m have a significantly higher risk for disease than those with DR3p and DR4m.Key words: Type 1 (insulin-dependent) diabetes mellitus, HLA DR3, 4, shared haplotypes, segregation, multiple affected siblings, risk for siblings, maternal effect.Susceptibility to Type 1 (insulin-dependent) diabetes mellitus is associated with the HLA antigens, DR3 and DR4 [1][2][3][4] in Caucasian populations. The risk for disease is greater in both unrelated subjects and in siblings of diabetic children [1-8] with a heterozygous DR3, DR4 phenotype. These observations have led to the hypothesis that two susceptibility genes associated with the DR3 and DR4 haplotype are involved in the inheritance of the disease [2, 9-13]. Though, the exact nature of the molecule(s) responsible, and their role in the pathogenesis of the disease has not been elucidated, strong evidence suggests an autoimmune mechanism, probably triggered by environmental factors [14].It has long been supposed that DR3 and DR4 associated susceptibility genes play different roles in the pathology of Type 1 diabetes, determining the clinical and genetic heterogeneity of the disease [15]. Recent data do indeed suggest that they probably do not have equivalent effects on susceptibility [16][17][18].In this study we present evidence for the different effects of the paternal or maternal origin of DR3 and DR4 antigens on the risk for siblings of diabetic children. Subjects and methodsAmong 325 unrelated, Causasian French families of Type I diabetic patients who had been consecutively ascertained for HLA typing since 1978 (Herold series), 287 families were selected according to the following criteria: (1) unaffected pa...

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“…Possibilities include, firstly, diabetes-prone fetuses of diabetic mothers could be miscarried more often than non-diabetes-prone fetuses; secondly, diabetes-prone fetuses of diabetic mothers could be protected against development of pancreatic autoimmunity and diabetes; and thirdly, diabetespredisposing genes could be less diabetogenic when inherited from mothers than when inherited from fathers (imprinting). One study has shown no relation between pre/perinatal death rates and frequency of diabetes in children of diabetic mothers, arguing against the selective loss mechanism [9]. Additional investigations are needed into this intriguing natural difference in diabetes risk for children of diabetic mothers compared with fathers, as it could suggest ways to artificially reduce the risk through medical intervention.…”

Section: Evidence For a Genetic Basis: Family And Twin Studies Of Typmentioning

confidence: 99%

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

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Type I diabetes (formerly called insulin-dependent diabetes mellitus) results from the autoimmune destruction of the insulin-producing beta cells of the pancreas. It is now known that Type I diabetes is a genetically complex disease, i. e. a disease caused by multiple genes interacting with non-genetic (environmental and stochastic) factors. Family studies have clearly shown a genetic basis but inheritance of the disease does not follow a simple mendelian single-locus pattern. Population and family studies also suggest that most (perhaps all) affected individuals are genetically predisposed to Type I diabetes, particularly through HLA region genes. However, non-genetic factors appear to be required to precipitate the disease in these genetically susceptible persons because in monozygote (MZ) twin pairs in which one twin has Type I diabetes the MZ twin concordance rate is less than 100 %. It is not clear whether there are any purely genetic cases of Type I Diabetologia (2002) AbstractFamily and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies. [Diabetologia (2002) 45: 21±35]

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Determinants of IDDM and Perinatal Mortality in Children of Diabetic Mothers

Cited by 49 publications

References 17 publications

Incidence trends in childhood onset IDDM in four countries around the Baltic sea during 1983-1992

Incidence trends in childhood onset IDDM in four countries around the Baltic sea during 1983-1992

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive Type 1 (insulin-dependent) diabetic patients

Genetic linkage and association studies of Type I diabetes: challenges and rewards

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