Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis

Dahlquist, Gisela

doi:10.1007/s00125-005-0076-4

Cited by 159 publications

(150 citation statements)

References 53 publications

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“…Increased insulin demand has been suggested to have an important role in the pathogenesis of autoimmunity in type 1 diabetes [4][5][6][7][8]. In the present study we aimed to obtain evidence supporting this hypothesis by analysing two known causes of insulin demand, BMI and HOMA-IR (as a marker of insulin sensitivity), in islet autoantibodypositive and -negative children who were prospectively followed from birth.…”

Section: Discussionmentioning

confidence: 90%

“…Roles for impaired insulin action and increased insulin demand in the pathogenesis of autoimmune type 1 diabetes have been proposed [4,5]. There are consistent reports indicating that decreased insulin sensitivity leads to the earlier development of diabetes in islet autoantibody-positive relatives, particularly when they show a concomitant decrease in beta cell function [6][7][8].…”

Section: Introductionmentioning

confidence: 95%

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Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes?

et al. 2009

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Aims/hypothesis It has been suggested that metabolic demand and insulin resistance play a role in the development of type 1 diabetes, including the onset of autoimmunity. The aim of the present study was to determine whether insulin demand is increased in children with islet autoantibodies. Methods BMI standard deviation score (BMI-SDS) was measured from 2 years of age in 1,650 prospectively followed children of mothers or fathers with type 1 diabetes, including 135 who developed persistent islet autoantibodies. HOMA of insulin resistance (HOMA-IR) was determined using fasting samples from 777 of the children starting from age 5 years. Results An increased HOMA-IR was associated with female sex (p=0.0004), older age (p<0.0001) and increased BMI-SDS (p<0.0001). Children with islet autoantibodies did not have an increased HOMA-IR compared with agematched islet autoantibody-negative children (age 8 years: mean 0.61 vs mean 0.72, respectively, p=0.21; age 11 years: mean 0.96 vs mean 1.21, respectively, p=0.07). Furthermore, after correction for age and sex, autoantibody positivity was associated with decreased HOMA-IR values (p=0.01). BMI-SDS was similar between islet autoantibodypositive and -negative children at age 2 (mean 0.07 vs mean 0.16, respectively), 5 (mean 0.06 vs 0.08, respectively), 8 (mean −0.09 vs mean 0.02, respectively), and 11 years (mean 0.22 vs mean 0.16, respectively) and similar to that of national reference values. Conclusions/interpretation Islet autoantibody-positive children in the BABYDIAB cohort are not insulin resistant and do not have an increased BMI around and early after islet autoantibody seroconversion. These findings are inconsistent with the notion that insulin resistance is a risk factor for islet autoimmunity.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 95%

Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes?

et al. 2009

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“…2 (mean ± SEM) in the reference population [24]. The overall contribution of height, weight and BMI to the risk of childhood type 1 diabetes has been estimated at about 20% [25].…”

Section: Does the Hypothesis Fit The Facts?mentioning

confidence: 99%

To boldly go—or to go too boldly? The accelerator hypothesis revisited

Gale

2007

Diabetologia

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“…In particular, the HLA DR4_DQB1*0302 haplotype, which is strongly associated with type 1 diabetes, was found to be associated with increased birthweight in the Swedish population [12]. Such relationships have fuelled interest and debate on a possible central role of nutrition and childhood weight status in the pathogenesis of type 1 and type 2 diabetes [14,15].…”

Section: Introductionmentioning

confidence: 99%

Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions

et al. 2007

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Aims/hypothesis Intrauterine growth in non-diabetic pregnancies is reported to be influenced by type 1 diabetes susceptibility genes. In particular, the high-risk HLA DR4_DQB1*0302 haplotype is associated with increased birthweight. The aim of this study was to determine whether HLA DR4 was associated with increased birthweight in a maternal diabetes environment and whether effects persisted during early childhood. Subjects and methods Birthweight and gestational age were obtained in singleton births from mothers with type 1 diabetes (n=1161) or whose fathers or siblings have type 1 diabetes (n=872). Weight and height at ages 2 and 5 years were obtained from paediatric records. Data were adjusted for (gestational) age and sex and expressed as percentiles of German reference data. HLA DR typing was obtained for all children and 1090 children also had insulin gene (INS) variable number of tandem repeats (VNTR) typing. Results Maternal type 1 diabetes was associated with increased birthweight, gestational age and birthweight percentiles (all p<0.0001). In children of mothers with type 1 diabetes, birthweight percentile was further related to maternal HbA 1c during pregnancy (r=0.26; p<0.0001) and was independently increased if children had HLA DR4 alleles (76th vs 64th percentile; p<0.0001). HLA DR4 was not associated with birthweight in children of non-diabetic mothers. Birthweight was not associated with INS VNTR genotypes. High birthweight, but not HLA DR4 was associated with increased weight and BMI at ages 2 and 5 years (p<0.0001). Conclusions/interpretation Our findings are consistent with the hypothesis that a diabetic intrauterine environment interacts with gene(s) marked by the type 1 diabetes susceptibility HLA DR4 alleles to increase fetal growth.

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Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis

Cited by 159 publications

References 53 publications

Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes?

Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes?

To boldly go—or to go too boldly? The accelerator hypothesis revisited

Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions

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