HHEX-IDE polymorphism is associated with low birth weight in offspring with a family history of type 1 diabetes.

Context: The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion also reduce birth weight, and an association of low birth weight and the type 2 diabetes risk alleles at the HHEX-IDE and CDKAL1 loci were recently reported.

Objective: Here, we examined the relationship between type 2 diabetes risk alleles and birth weight in a diabetic environment presented in children of mothers with type 1 diabetes.

Research Design And Methods: Birth weight and genotyping of single nucleotide polymorphisms (SNPs) at the CDKAL1, HHEX-IDE, and SLC30A8 loci was obtained and analyzed in 729 singleton full-term children of mothers with type 1 diabetes born in Germany.

Influence of early nutritional components on the development of murine autoimmune diabetes.

Background/aims: Infant diet is suggested to modify autoimmune diabetes risk. The aim of this study was to determine whether infant food components affect diabetes development in the nonobese autoimmune diabetes (NOD) mouse.

Methods: A basal low-diabetogenic diet was identified by feeding litter-matched female NOD mice standardized diets with and without casein and wheat proteins after weaning.

Blood glucose levels regulate pancreatic beta-cell proliferation during experimentally-induced and spontaneous autoimmune diabetes in mice.

Background: Type 1 diabetes mellitus is caused by immune-mediated destruction of pancreatic beta-cells leading to insulin deficiency, impaired intermediary metabolism, and elevated blood glucose concentrations. While at autoimmune diabetes onset a limited number of beta-cells persist, the cells' regenerative potential and its regulation have remained largely unexplored. Using two mouse autoimmune diabetes models, this study examined the proliferation of pancreatic islet ss-cells and other endocrine and non-endocrine subsets, and the factors regulating that proliferation.

Dynamic changes in pancreatic endocrine cell abundance, distribution, and function in antigen-induced and spontaneous autoimmune diabetes.

Objective: Insulin deficiency in type 1 diabetes and in rodent autoimmune diabetes models is caused by beta-cell-specific killing by autoreactive T-cells. Less is known about beta-cell numbers and phenotype remaining at diabetes onset and the fate of other pancreatic endocrine cellular constituents.

Research Design And Methods: We applied multicolor flow cytometry, confocal microscopy, and immunohistochemistry, supported by quantitative RT-PCR, to simultaneously track pancreatic endocrine cell frequencies and phenotypes during a T-cell-mediated beta-cell-destructive process using two independent autoimmune diabetes models, an inducible autoantigen-specific model and the spontaneously diabetic NOD mouse.

SLC30A8 (ZnT8) Polymorphism is Associated with Young Age at Type 1 Diabetes Onset.

It was recently shown that the major allele of the SLC30A8 (zinc transporter 8, ZnT8) single nucleotide polymorphism (SNP) rs13266634 was associated with type 2 diabetes and with reduced insulin secretion in non-diabetic relatives. Because of its role in beta-cell function, we hypothesized that this candidate SNP may confer increased susceptibility for beta-cell destruction in type 1 diabetes. We analyzed SLC30A8 genotypes in 874 patients with type 1 diabetes and 1021 control subjects.

Immunomodulation of autoimmune diabetes by dendritic cells.

The biology and properties of dendritic cells (DCs) have been intensely studied in the research areas of infectious diseases, tumor immunology, and vaccine development. This unique subset of immune cells has recently also moved to the center of interest for basic and clinical research in autoimmunity, owing not only to the extraordinary importance of DCs in the initiation and sustenance of adaptive immune responses, but also to more recent discoveries about their profound ability to control and downregulate ongoing T-cell responses. We review current progress of using DCs in mice for induction and propagation of autoimmune T-cell responses and their therapeutic potential to dampen or even stop beta-cell-specific autoimmunity.

Identification of insulin autoantibodies of IgA isotype that preferentially target non-human insulin.

Insulin autoantibodies (IAA) precede clinical type 1 diabetes in children. Immunization events leading to IAA are unknown. The aim of this study was to determine whether some IAA result from mucosal immunization.

Natural history of type 1 diabetes.

The natural history of autoimmune type 1 diabetes in children is associated with the appearance of islet autoantibodies early in life, which is influenced by genetic and environmental factors. Once islet autoantibodies have developed, the progression to diabetes in antibody-positive individuals is determined by the age of antibody appearance and by the magnitude of the autoimmunity, in turn related to the age of the subject. Characteristics that describe the magnitude of the autoimmunity can stage progression to type 1 diabetes in islet autoantibody-positive subjects regardless of genetic background or age.

Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes.

Children at risk for type 1 diabetes can develop early insulin autoantibodies (IAAs). Many, but not all, of these children subsequently develop multiple islet autoantibodies and diabetes. To determine whether disease progression is reflected by autoantibody maturity, IAA affinity was measured by competitive radiobinding assay in first and subsequent IAA-positive samples from children followed from birth in the BABYDIAB cohort.

Delayed exposure to wheat and barley proteins reduces diabetes incidence in non-obese diabetic mice.

Dietary gluten, vitamin D3, and fish-oil are suggested to influence the incidence of autoimmune diabetes. To determine whether modification of their intake could reduce diabetes incidence and autoimmunity in mice, pups from female non-obese diabetic (NOD) mice were fed diets modified for protein source, fatty acid content, and/or vitamin D3 content and were followed for diabetes development, insulin autoantibodies (IAA), and insulitis. Replacement of wheat and barley with poultry as the major protein source significantly affected diabetes development.

Transmission of maternal islet antibodies and risk of autoimmune diabetes in offspring of mothers with type 1 diabetes.

It is suggested that the maternal transmission of islet autoantibodies increases the risk of autoimmune diabetes in mice. The aim of this study was to determine whether fetal exposure to islet autoantibodies modified the risk of type 1 diabetes in humans. Islet autoantibodies were measured at birth in 720 offspring of mothers with type 1 diabetes.

Characterization of antibody responses to endogenous and exogenous antigen in the nonobese diabetic mouse.

It is suggested that a T-helper cell 2 (Th2) shift and Th2 spreading of autoimmunity following immunization with beta-cell antigen causes diabetes protection. To address this, antibody titer and subclass to insulin, glutamic acid decarboxylase (GAD)65, IA-2, and IA-2beta proteins were measured by radiobinding assays in untreated or immunized female nonobese diabetic mice. Untreated nonobese diabetic mice developed autoantibodies to insulin (IAA), but not GAD or IA-2/IA-2beta, and IAA-positive mice had increased diabetes risk (P < 0.

Two distinctly HLA-associated contiguous linear epitopes uniquely expressed within the islet antigen 2 molecule are major autoantibody epitopes of the diabetes-specific tyrosine phosphatase-like protein autoantigens.

The related tyrosine phosphatase-like proteins islet Ag (IA)-2 and IA-2beta are autoantigens of type 1 diabetes in humans. Autoantibodies are predominantly against IA-2, and IA-2-specific epitopes are major autoantibody targets. We used the close homology of IA-2 and IA-2beta to design chimeras and mutants to identify humoral IA-2-specific epitopes.