14 research outputs found
Identification, characterization and application of autoantigens in type 1 diabetes mellitus
Type 1 diabetes mellitus or insulin dependent diabetes mellitus is a disease
characterized by the selective destruction of insulin producing B-cells in the islets of
Langerhans. The exact cause of this destruction is unknown, but is mediated by
cells of the immune system. The immune system has a remarkable ability to recognize
self from non-self, thereby providing a constant surveillance-mechanism
that protects us for foreign invaders. This mechanism has failed in type 1 diabetes
and attacks and destroys B-cells. The autoimmune basis of type 1 diabetes is described
in chapter 1. The central problem in autoimmunity is why and how the immune
system sometimes fails to distinguish between self and non-self. Re-instructing
the immune system or blocking faulty immune reactions could result in primaryor
secondary prevention of type 1 Diabetes Mellitus. This requires however, the
molecular dissection of the process, including the identification of B-cell proteins
involved in the autoimmune reactions. This thesis aims to contribute to this by the
identification and characterization of two humoral autoantigens in type 1 Diabetes
Mellitus, a 64kD and a 38kD protein. These aims are specified as follows:
1. Identification of the 64kD autoantigen in type 1 Diabetes Mellitus.
2. Biochemical and Cell biological characterization of the 64kD protein.
3. Identification of the 38kD autoantigen in type 1 Diabetes Mellitus.
4. Biochemical and Cell biological characterization of the 38kD protein.
5. Analysis of the frequencies of autoantibodies to the 64kD and the 38kD autoantigen
at clinical diagnosis and in the prediabetic period.
6. Assessment of the predictive value of these autoantibodies, in particular in
relation to other markers of autoimmune B-cell destruction
Skin autofluorescence is increased in young people with type 1 diabetes exposed to secondhand smoking
Highlights • Skin autofluorescence is increased in diabetes, rises with age, and predicts diabetes-related complications. • Exposure to secondhand smoke, because one or more family members are smokers, further increases skin auto- fluorescence in children and young adults with type 1 diabetes. • Elimination of passive smoking should be a goal in diabetes education
Islet cell cytoplasmic antibody reactivity in midgestational human fetal pancreas
The reactivity of islet cell cytoplasmic antibodies (ICA)-positive and ICA-negative sera of recent onset type 1 diabetic patients was studied in human fetal pancreata of 12-18 weeks' gestation and compared with the reactivity of these sera in adult human control pancreata. The aims of the study were: (1) to observe the presence of ICA staining in human fetal islet cells; (2) to compare endpoint titres (in Juvenile Diabetes Foundation units) of ICA-positive patient sera in fetal pancreata and adult human control pancreata. Ten ICA-positive sera and eight ICA-negative sera from newly diagnosed diabetic patients and four sera from healthy controls were tested on three human adult and eight human fetal pancreata. As in the adult control pancreata. ICA-positive sera reacted to insulin-, glucagon-, and somatostatin-positive cells of fetal pancreata of all gestational ages. This was observed both in single cells and in cells in islet-like cell clusters. Dilution of a reference serum gave similar results in both adult and fetal pancreata. In contrast, the ICA-positive patient sera yielded a striking heterogeneity in fetal as well as in adult pancreata. However, end-point titres between adult and fetal pancreata did not differ significantly (P>0.05). In conclusion, ICA-positive sera from recent onset diabetic patients show that the expression of molecules to which ICA react is present in all islet cells and starts before week 12 of gestation
Glutamic acid decarboxylase antibodies in screening for autoimmune diabetes: influence of comorbidity, age, and sex on specificity and threshold values
Residual C-peptide secretion and hypoglycemia awareness in people with type 1 diabetes
INTRODUCTION: This study aimed to assess the association between fasting serum C-peptide levels and the presence of impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed a cross-sectional study among 509 individuals with type 1 diabetes (diabetes duration 5-65 years). Extensive clinical data and fasting serum C-peptide concentrations were collected and related to the presence or absence of IAH, which was evaluated using the validated Dutch version of the Clarke questionnaire. A multivariable logistic regression model was constructed to investigate the association of C-peptide and other clinical variables with IAH. RESULTS: In 129 (25%) individuals, residual C-peptide secretion was detected, while 75 (15%) individuals reported IAH. The median (IQR) C-peptide concentration among all participants was 0.0 (0.0-3.9) pmol/L. The prevalence of severe hypoglycemia was lower in people with demonstrable C-peptide versus those with absent C-peptide (30% vs 41%, p=0.025). Individuals with IAH were older, had longer diabetes duration, more frequently had macrovascular and microvascular complications, and more often used antihypertensive drugs, antiplatelet agents and cholesterol-lowering medication. There was a strong association between IAH and having a severe hypoglycemia in the preceding year. In multivariable regression analysis, residual C-peptide, either continuously or dichotomous, was associated with lower prevalence of IAH (p=0.040-0.042), while age at diabetes onset (p=0.001), presence of microvascular complications (p=0.003) and body mass index (BMI) (p=0.003) were also independently associated with the presence of IAH. CONCLUSIONS: Higher BMI, the presence of microvascular complications and higher age at diabetes onset were independent risk factors for IAH in people with type 1 diabetes, while residual C-peptide secretion was associated with lower risk of this complication
Distinct monocyte gene-expression profiles in autoimmune diabetes
OBJECTIVE-There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes. RESEARCH DESIGN AND METHODS-We studied patterns of inflammatory gene expression in monocytes of patients with type 1 diabetes (juvenile onset, n = 30; adult onset, n = 30) and latent autoimmune diabetes of the adult (LADA) (n = 30) (controls subjects, n = 49; type 2 diabetic patients, n = 30) using quantitative PCR. We tested 25 selected genes: 12 genes detected in a prestudy via whole-genome analyses plus an additional 13 genes identified as part of a monocyte inflammatory signature previously reported. RESULTS-We identified two distinct monocyte gene expression clusters in autoimmune diabetes. One cluster (comprising 12 proinflammatory cytokine/compound genes with a putative key gene PDE4B) was detected in 60% of LADA and 28% of adult-onset type 1 diabetic patients but in only 10% of juvenile - onset type 1 diabetic patients. A second cluster (comprising 10 chemotaxis, adhesion, motility, and metabolism genes) was detected in 43% of juvenile-onset type 1 diabetic and 33% of LADA patients but in only 9% of adult-onset type 1 diabetic patients. CONCLUSIONS-Subgroups of type 1 diabetic patients show an abnormal monocyte gene expression with two profiles, supporting a concept of heterogeneity in the pathogenesis of autoimmune diabetes only partly overlapping with the presently known diagnostic categories
Diabetes IN develOpment (DINO): the bio-psychosocial, family functioning and parental well-being of youth with type 1 diabetes: a longitudinal cohort study design
The relationship between parenting stress and parent–child interaction with health outcomes in the youngest patients with type 1 diabetes (0–7 years)
Carbohydrate metabolism during long-term growth hormone (GH) treatment and after discontinuation of GH treatment in girls with Turner syndrome participating in a randomized dose-response study. Dutch Advisory Group on Growth Hormone
To assess possible side-effects of GH treatment with supraphysiological
doses on carbohydrate (CH) metabolism in girls with Turner syndrome (TS)
during long term GH treatment and after discontinuation of GH treatment,
the results of oral glucose tolerance tests and hemoglobin A1c
measurements were analyzed in 68 girls with TS participating in a
randomized dose-response trial. These previously untreated girls, aged
2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4
IU/m2 x day (-0.045 mg/kg x day); group B, first year ,4 IU/m2 day;
thereafter, 6 IU/m2 x day (approximately 0.0675 mg/kg x day); group C,
first year, 4 IU/m2 x day; second year, 6 IU/m2 x day; thereafter, 8 IU/m2
x day (approximately 0.090 mg/kg x day). After the first 4 yr, girls 12 yr
of age or older started with 5 microg/kg BW-day 17beta-estradiol for
induction of puberty. To assess the effects of long term high dose GH
treatment on CH metabolism, the 7-yr data from the oral glucose tolerance
tests in 9 girls of group C were evaluated (group C1). To determine
whether the changes in CH metabolism during GH treatment would persist
after discontinuation of GH treatment, the data for 28 girls who had
reached adult height (group A, n = 9; group B, n = 10; group C, n = 9)
were evaluated at baseline, after 4 yr of GH treatment, and 6 months after
discontinuation of GH. Seven-year data for group C1 showed that glucose
levels did not significantly change during GH treatment, whereas fasting
insulin levels as well as glucose-induced insulin levels increased
significantly. The data for the 28 girls who were treated with GH for a
mean (SD) period of 85.3 (13.3) months demonstrated that the GH-induced
higher insulin levels decreased to values close to or equal to
pretreatment values after discontinuation of GH treatment. Changes in CH
variables were not significantly related to the GH dose. Hemoglobin A1c
levels never showed an abnormal value. The prevalence of impaired glucose
tolerance was low, and none of the girls developed diabetes mellitus. In
conclusion, long term GH treatment with dosages up to 8 IU/m2 x day in
girls with TS has no adverse effects on glucose levels, but induced higher
levels of insulin, indicating relative insulin resistance. The increased
insulin levels during long term GH treatment decreased after
discontinuation of GH treatment to values close to or equal to
pretreatment values. Although the reversibility of the effects of long
term GH is reassuring, the consequence of long term hyperinsulinism is
still unknown
Discovery of a selective islet peptidome presented by the highest-risk HLA-DQ8trans molecule
Transplantation and autoimmunit