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

Increased skin autofluorescence of children and adolescents with type 1 diabetes despite a well-controlled HbA1c:results from a cohort study

BACKGROUND: Early identification of children and adolescents with type 1 diabetes at high risk for development of complications is important, as early intervention may prevent further deterioration. Here we investigate the applicability of assessing skin advanced glycation end products (sAGEs) by skin autofluorescence (SAF) as a potential surrogate risk marker. METHODS: This study included a cross-sectional analysis of SAF in 77 patients with type 1 diabetes mellitus and 118 healthy controls across age categories (11–12, 13–14, 15–16, and 17–19 years old). In patients, the impact of current and historical glycated hemoglobin (HbA1c) values, age, and duration of diabetes on SAF was studied in a retrospective cohort study and analyzed with multivariable analyses. RESULTS: SAF was significantly and similarly higher in patients when compared with controls across all age categories (P ≤0.009). For patients, age, duration of diabetes, and current and historical HbA1c were associated with SAF in univariate analysis. Multivariate analysis showed no association between HbA1c and SAF. A subgroup of patients with a HbA1c-within-target (≤7.5 %/59 mmol/mol) were observed to have high SAF. CONCLUSION: Children and adolescents with type 1 diabetes show higher SAF than controls. The presumed correlation of high HbA1c with high SAF does not exist in all patients. Thus, use of this non-invasive measure may provide a surrogate marker for diabetic complications, additional to HbA1c

Losing Track of Lipids in Children and Adolescents with Type 1 Diabetes:Towards Individualized Patient Care

Aim To assess 1) the prevalence of children and adolescents with type 1 diabetes (T1D) changing from low-risk into borderline-high-risk lipid levels or from borderline-high-risk into high-risk lipid levels ('lose track of lipids') and 2) the power of a risk score including the determinants HbA1c, body mass index (BMI), gender, age, diabetes duration and ethnicity in predicting which patients lose track of lipids. Methods 651 children and adolescents with T1D were included in this longitudinal retrospective cohort study. Lipid dynamics and the impact of the risk score on losing track of lipids were evaluated. Kaplan-Meier analysis was used to estimate screening intervals. Results 31-43% percent of the patients had lost track of one or more lipids at the next lipid measurement. This happened more frequently in patients with a low-risk lipid level at start. Depending on the lipid parameter, 5% of patients with low-risk lipid levels lost track of lipids after 13-23 months. The risk score based on concomitant information on the determinants was moderately able to predict which patients would lose track of lipids on the short term. Conclusions A considerable number of children and adolescents with T1D loses track of lipids and does so within a 2-year screening interval. The predictive power of a risk score including age, BMI, gender, HbA1c, diabetes duration and ethnicity is only moderate. Future research should focus on another approach to the determinants used in this study or other determinants predictive of losing track of lipids on the short term

Effects of Peri-Conception and Pregnancy Glycemic Variability on Pregnancy and Perinatal Complications in Type 1 Diabetes:A Pilot Study

Background Not much is known about the effects of glycemic variability (GV) during the pre- and periconception period on pregnancy/perinatal complications. GV could potentially contribute to identification of high-risk pregnancies in women with type 1 diabetes. Methods An explorative retrospective cohort study was conducted between January 2014 and May 2019. Glucose data were retrieved from electronic patient charts. Pre-/periconceptional GV and GV during all three trimesters was expressed as mean glucose, standard deviation (SD), Coefficient of Variation (CV), High Blood Glucose Index (HBGI), Low Blood Glucose Index (LBGI) and Average Daily Risk Range (ADRR). Maternal and neonatal complications were summarized using a composite total complication score. Binary logistic regression analyses were conducted to assess associations between the GV measures and a total complication score>3, a maternal complication score>1 and a neonatal complication score>1. Results Of 63 eligible women, 29 women (38 pregnancies) were included. Women in the group with a total complication score>3 had a significantly higher ADRR at conception (OR 1.1, CI 1.0–1.2, p=0.048). No statistically significant correlations between complication score and any other GV metric besides the ADRR were found. Although not significant, in the group with a complication score>3, odds ratios>1 were found for SD in trimester 1 (OR 1.6, CI 0.6–4.5, p=0.357) and trimester 2 (OR 1.8, CI 0.5–6.2, p=0.376). Conclusions Presence of a positive association between GV and pregnancy and perinatal complications depends on which pregnancy period is assessed and the GV metrics that are used

Differences in lipid and blood pressure measurements between individuals with type 1 diabetes and the general population:a cross-sectional study

OBJECTIVES: Cardiovascular disease (CVD) is a precarious complication of type 1 diabetes (T1D). Alongside glycaemic control, lipid and blood pressure (BP) management are essential for the prevention of CVD. However, age-specific differences in lipid and BP between individuals with T1D and the general population are relatively unknown.DESIGN: Cross-sectional study.SETTING: Six diabetes outpatient clinics and individuals from the Lifelines cohort, a multigenerational cohort from the Northern Netherlands.PARTICIPANTS: 2178 adults with T1D and 146 22 individuals without diabetes from the general population.PRIMARY AND SECONDARY OUTCOME MEASURES: Total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), systolic BP (SBP) and diastolic BP (DBP), stratified by age group, glycated haemoglobin category, medication use and sex.RESULTS: In total, 2178 individuals with T1D and 146 822 without diabetes were included in this study. Total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in individuals with T1D in comparison to the background population. When stratified by age and medication use, total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in the T1D population. Men with T1D achieved lower LDL-cholesterol levels both with and without medication in older age groups in comparison to women. Women with T1D had up to 8 mm Hg higher SBP compared with the background population, this difference was not present in men.CONCLUSIONS: Lipid and BP measurements are not comparable between individuals with T1D and the general population and are particularly unfavourable for BP in the T1D group. There are potential sex differences in the management of LDL-cholesterol and BP.</p

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