Moving from Insulin Substitution to the Treatment of the Underlying Autoimmune Disease in Type 1 Diabetes.

Currently, a paradigm change occurs in type 1 diabetes from insulin substitution to the treatment of the underlying autoimmune disease. Teplizumab, a humanized monoclonal anti-CD3 antibody, is the first FDA-approved disease-modifying treatment of preclinical stage 2 diabetes. Research of drugs like golimumab, a monoclonal antibody specific for TNF alpha, baricitinib, a tyrosine kinase inhibitor, or frexalimab, a monoclonal antibody against the CD40 ligand, is still ongoing. Repurposing drugs that have been used in other indications like the calcium channel blocker verapamil, antithymocyte globulin (ATG), an antibody preparation used in solid organ transplantation, glucagon-like peptide-1 agonists utilized in type 2 diabetes and obesity, or the antiviral drugs pleconaril and ribavirin have shown positive effects in preserving beta-cell function. While new therapies to halt autoimmunity and restore beta cells in stages one to three are being developed, replacing beta-cell function via inducible pluripotent stem cells have shown glucose control and insulin independence in long-standing type 1 diabetes, albeit with concomitant immunosuppression. Multicenter multinational initiatives developing a clinical trial network like INNODIA or a research platform with the goal of stopping type 1 diabetes in its early stages like EDENT1FI will be instrumental to study these new strategies.

Intermittent Use of Continuous Glucose Monitoring: A New Paradigm in Treatment of Type 2 Diabetes.

OBJECTIVES: To suggest how continuous glucose monitoring (CGM) may be used intermittently in individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The use of CGM is largely in those with type 1 diabetes (T1D), in whom it makes sense to use CGM continuously as CGM provides a valuable tool to not only adjust their insulin doses but also to match it with their diet, physical activity, and other lifestyle modifications. In the case of T2D, however, especially for those not on insulin, the use of CGM may not be needed on a continuous basis. The use of CGM on an intermittent basis is rarely discussed in the literature. This article tries to provide clinical situations where CGM can be used intermittently. RESULTS: Intermittent use of CGM defined as the "use of CGM once in 2 or 3 months or a fixed frequency," and may be useful in several situations in those with T2D. We suggest the following indications for the intermittent use of CGM in T2D-newly diagnosed patients where treatment is being started, uncontrolled diabetes where treatment is being altered, starting intensive lifestyle modification, during infections, during preoperative control, in children and adolescents with T2D, as a motivational tool to improve behavioral modification, after metabolic surgery, and in patients on steroids, apart from other indications. CONCLUSION: Intermittent use of CGM in T2D can be useful in special situations and can also be cost saving particularly in resource-constrained regions of the world.

An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria.

BACKGROUND: The FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany. METHODS: German patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared. RESULTS: Overall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT's albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible. CONCLUSIONS: Certain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.

Direct LDL-C estimation in preschoolers: Practicable first step for FH screening.

BACKGROUND: Individuals with FH develop cardiovascular disease due to lifelong cumulative exposure to elevated LDL-C. Effective screening for FH is not yet established. OBJECTIVE: To evaluate the practicability of a FH screening by measuring directly the LDL-C in preschoolers. METHODS: LDL-C measurement through capillary blood sampling during the compulsory routine check-ups by the pediatrician in children aged 2 to 6 years including information on family history as dyslipidemia and/or premature cardiovascular disease in first and second grade of pedigrees. RESULTS: 15,009 children (52.2% males, median age 3.9 years [IQR 3.0-5.1]) participated in the study. Positive family history for hyperlipidemia was stated in 40.9% cases, in 12.0% also in at least one 1st degree relative. In the total cohort, median LDL-C was 93 mg/dL [IQR 79-109 mg/dL]. Boys had significantly higher LDL-C levels than girls (p < 0.0001), whereas there was no difference regarding their age (p = 0.757). Children from families with a positive history for hypercholesterolemia/dyslipidemia had significantly higher LDL-C levels (p < 0.001) and were more frequently among those with LDL-C values above 135 mg/dL (3.5 mmol/L, 96th percentile; 53.2% vs. 40.3%, p < 0.001) and those with LDL-C levels above 160 mg/dL (4.1 mmol/L, 99th percentile; 45.3% vs. 40.7%, p < 0.001) than children without positive family history. CONCLUSIONS: Direct measurement of LDL-C levels in children at ages 2-6 years during the compulsory routine check-ups as well as at any voluntary visits to the pediatrician's office is practicable and delivers reliable information, which can be used for a FH screening strategy in the general population.

Validation of a risk prediction model for early chronic kidney disease in patients with type 2 diabetes: Data from the German/Austrian Diabetes Prospective Follow-up registry.

AIM: To validate a recently proposed risk prediction model for chronic kidney disease (CKD) in type 2 diabetes (T2D). MATERIALS AND METHODS: Subjects from the German/Austrian Diabetes Prospective Follow-up (DPV) registry with T2D, normoalbuminuria, an estimated glomerular filtration rate of 60 ml/min/1.73m2 or higher and aged 39-75 years were included. Prognostic factors included age, body mass index (BMI), smoking status and HbA1c. Subjects were categorized into low, moderate, high and very high-risk groups. Outcome was CKD occurrence. RESULTS: Subjects (n = 10 922) had a mean age of 61 years, diabetes duration of 6 years, BMI of 31.7 kg/m2 , HbA1c of 6.9% (52 mmol/mol); 9.1% had diabetic retinopathy and 16.3% were smokers. After the follow-up (~59 months), 37.4% subjects developed CKD. The area under the curve (AUC; unadjusted base model) was 0.58 (95% CI 0.57-0.59). After adjustment for diabetes and follow-up duration, the AUC was 0.69 (95% CI 0.68-0.70), indicating improved discrimination. After follow-up, 15.0%, 20.1%, 27.7% and 40.2% patients in the low, moderate, high and very high-risk groups, respectively, had developed CKD. Increasing risk score correlated with increasing cumulative risk of incident CKD over a median of 4.5 years of follow-up (P < .0001). CONCLUSIONS: The predictive model achieved moderate discrimination but good calibration in a German/Austrian T2D population, suggesting that the model may be relevant for determining CKD risk.

Universal screening for familial hypercholesterolemia in 2 populations.

PURPOSE: In Europe, >2 million individuals with familial hypercholesterolemia (FH) are currently undiagnosed. Effective screening strategies for FH diagnosis in childhood are urgently needed. We assessed the overall performances of 2 different FH screening programs in children: universal screening program with opt-out and opt-in type participation. METHODS: We analyzed the data from 2 independent populations based on >166,000 individuals screened for hypercholesterolemia. Genetic analyses of FH-related genes were finalized in 945 children and 99 parents. RESULTS: A total of 305 (32.3%) children were genotyped as positive or with a variant of uncertain significance in FH-related genes. For low-density lipoprotein cholesterol levels of 3.5 mmol L (135.3 mg/dL), the overall sensitivity and specificity for confirming FH were 90.5% and 55.3%, respectively. As part of child-parent screening, in >90% of the families, the parent with reported higher cholesterol levels was positive for the familial genetic variant. The cohort-based prevalence of FH from the opt-out universal screening program was estimated to be 1 in 431 individuals (95% CI = 1/391-1/472). CONCLUSION: Universal 3-step FH screening approach in children enabled detection of most children and their parents in every generation screened at reasonable costs. Opt-out screening strategy might be preferable over opt-in screening strategy.

Add-on therapy with dapagliflozin under full closed loop control improves time in range in adolescents and young adults with type 1 diabetes: The DAPADream study.

AIM: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on glucose levels overnight and during the following day after two unannounced meals under full closed loop (FCL) conditions. MATERIALS AND METHODS: For this single-centre, double-blind, randomized, placebo-controlled, cross-over trial, non-obese persons with type 1 diabetes (T1D) were studied twice (10 mg dapagliflozin bid vs. placebo) for 24 hours with two unannounced mixed meal tests 6 hours apart under FCL conditions. Primary outcome was sensor glucose time in range (TIR; 3.9-10 mmol/L). For safety evaluation, ß-hydroxybutyrate (BHB), glucagon, insulin and gastric inhibitory polypeptide were measured. RESULTS: Fifteen adolescents (aged 15.4 ± 1.6 years, diabetes duration 10.0 ± 3.4 years, HbA1c 8.4% ± 0.9% [67.7 ± 10.1 mmol/mol]) and 15 young adults (aged 18.7 ± 0.8 years; diabetes duration 12.5 ± 3.6 years; HbA1c 8.3% ± 0.9% [68.5 ± 11.2 mmol/mol]) completed the trial. TIR was significantly higher in the intervention group compared with placebo (68% ± 6% vs. 50% ± 13%; P < .001); nocturnal glucose was significantly lower with dapagliflozin (6.2 ± 0.7 vs. 7.3 ± 1.7 mmol/L; P = .003) without an increase in time at less than 3.9 mmol/L (3.3% ± 6.0% vs 3.1% ± 5.2%; P = .75). Urinary glucose excretion was increased 3-fold using dapagliflozin (149 ± 42 vs. 49 ± 23 g/24 hours) with a total insulin reduction of 22% (39.7 ± 12.7 vs. 30.6 ± 10.4 U; P = .004). No abnormal elevated BHB values were observed. CONCLUSIONS: In adolescents and adults with T1D, dapagliflozin significantly increased TIR on average by 259 minutes/day while reducing glycaemic variability during FCL control without any signs of hypoglycaemia or ketosis.

Patient and disease characteristics of type-2 diabetes patients with or without chronic kidney disease: an analysis of the German DPV and DIVE databases.

BACKGROUND: To evaluate the characteristics of type 2 diabetes (T2DM) patients with or without chronic kidney disease (CKD) in Germany. METHODS: Using combined DPV/DIVE registry data, the analysis included patients with T2DM at least ≥ 18 years old who had an estimated glomerular filtration rate (eGFR) value available. CKD was defined as an eGFR < 60 mL/min/1.73 m2 or eGFR ≥ 60 mL/min/1.73 m2 and albuminuria (≥ 30 mg/g). Median values of the most recent treatment year per patient are reported. RESULTS: Among 343,675 patients with T2DM 171,930 had CKD. Patients with CKD had a median eGFR of 48.9 mL/min/1.73 m2 and 51.2% had a urinary albumin level ≥ 30 mg/g. They were older, had a longer diabetes duration and a higher proportion was females compared to patients without CKD (all p < 0.001). More than half of CKD patients (53.5%) were receiving long-acting insulin-based therapy versus around 39.1% of those without (p < 0.001). CKD patients also had a higher rate of hypertension (79.4% vs 72.0%; p < 0.001). The most common antihypertensive drugs among CKD patients were renin-angiotensin-aldosteron system inhibitors (angiotensin converting enzyme inhibitors 33.8%, angiotensin receptor blockers 14.2%) and diuretics (40.2%). CKD patients had a higher rate of dyslipidemia (88.4% vs 86.3%) with higher triglyceride levels (157.9 vs 151.0 mg/dL) and lower HDL-C levels (men: 40.0 vs 42.0 mg/dL; women: 46.4 vs 50.0 mg/dL) (all p < 0.001) and a higher rate of hyperkalemia (> 5.5 mmol/L: 3.7% vs. 1.0%). Comorbidities were more common among CKD patients (p < 0.001). CONCLUSION: The results illustrate the prevalence and morbidity burden associated with diabetic kidney disease in patients with T2DM in Germany. The data call for more attention to the presence of chronic kidney disease in patients with diabetes, should trigger intensified risk factor control up and beyond the control of blood glucose and HbA1c in these patients. They may also serve as a trigger for future investigations into this patient population asking for new treatment options to be developed.

New approach for detection of LDL-hypercholesterolemia in the pediatric population: The Fr1dolin-Trial in Lower Saxony, Germany.

BACKGROUND AND AIMS: Lipid disorders are often detected very late, particularly in affected young children. We evaluated the feasibility of a screening for LDL-hypercholesterolemia (highLDL) among toddlers and preschoolers. METHODS: Population-based screening has been offered to all children (2-6 years) living in the State of Lower Saxony, Germany, with capillary blood sampling for detection of elevated LDL-cholesterol (LDL-C ≥ 135 mg/dL). Positive results were confirmed by a second measurement. Follow-up in specialized centers, including disease specific counselling and extended diagnostics, as well as evaluation of psychological distress of the parents, is carried out longitudinally. RESULTS: Up to March 2018, 5656 children have participated in the screening program. 5069/5656 children have completed the screening for highLDL (52.0% boys; median age: 4.0 years [Interquartile range, IQR 3.0-5.1]; mother age: 35 years [IQR 31-38]; father's age: 37 years; [IQR 33-42]). HighLDL was identified in 112 children (2.2%; 40.2% boys; LDL-C 157.6 ±â€¯29.5 mg/dL, mean ±â€¯SD). In the total cohort, parents stated in 40.9% of the cases a positive family history for hyperlipidemia and in 29.9% a premature cardiovascular event. Children with highLDL had more often both risk factors in their family history; however, in 37% of them none of these factors were reported. CONCLUSIONS: The first results of the screening program showed its feasibility and revealed high prevalence of highLDL in the general population. Furthermore, a large proportion of families of affected children were not aware about their lipid disorders.

Lean diabetes in middle-aged adults: A joint analysis of the German DIVE and DPV registries.

AIMS: To assess differences in demographics, treatment and outcome of lean (LD) compared to overweight and obese people with diabetes clinically classified as type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We combined data from the German DIVE (Diabetes Versorgungs-Evaluation) and DPV (Diabetes-Patienten-Verlaufsdokumentation) databases to produce a large cohort of people with T2DM. The characteristics of people with Body Mass Index (BMI) <25 kg/m2, ≥25-30 kg/m2 and ≥30 kg/m2 aged 30 to 50 years were compared, including demographics, cardiovascular (CV) risk factors, comorbidities and outcomes. RESULTS: A total of 37,870 people were included in the analysis, 3,191 of these (8.4%) had a BMI < 25 kg/m2. LD reported more nicotine (41.6% of 2,070 vs. 38.1% of 6,070 and 33.4% of 16,823; P<0.001)and alcohol consumption (12.0% of 1,282, 10.3% of 3,594 and 6.6% of 9,418; P<0.001)compared to overweight and obese people. More LD were treated with insulin in comparison to the other subgroups (short acting insulin 33.1% of 3,191 vs. 28.4% of 9,234 and 28.0% of 25,445; P <0.001; long acting insulin 31.3% of 3,191 vs. 28.9% of 9,234 and 29.3% of 25,445; P = 0.043). Regression models adjusted for age, gender and diabetes duration showed a 2.50 times higher odds ratio (OR) for hypoglycemia and a 2.52 higher OR for mortality in LD compared to the BMI subgroup ≥30 kg/m2. CONCLUSIONS: LD is associated with an increased risk of hypoglycaemia and death. Patients are characterized by male gender, lifestyle habits as smoking and alcohol consumption while cardiovascular comorbidities are less important. In comparison to patients of the other weight groups they are treated with insulin more often and considerably less with metformin.

Improvement of BMI after Lifestyle Intervention Is Associated with Normalisation of Elevated ELF Score and Liver Stiffness in Obese Children.

BACKGROUND: Noninvasive tools to diagnose nonalcoholic fatty liver disease (NAFLD), including transient elastography (TE) and enhanced liver fibrosis panel (ELF), have only been evaluated in children with biopsy-proven NAFLD. We evaluated the prevalence of ELF and TE abnormalities in obese children without clinical liver disease and examined the effects of BMI stabilization on ELF and TE in a longitudinal approach. METHODS: 39 obese children (17 m, age 12.3 (7.6-17.4) years) who participated in a 12-month lifestyle-intervention program underwent TE and ELF testing at baseline and at completion of the program. Results were compared with data from a nonobese paediatric cohort. RESULTS: TE and ELF at baseline were significantly elevated compared to controls (TE: 5.9 (3.4-8.3) kPa versus 4.45 (2.45-8.85) kPa, P < 0.01; ELF: 9.0 (7.87-9.60) versus 8.6 (7.33-11.52), P = 0.033). All children with elevated TE and ELF results had normal transaminases. After the program, ELF and TE normalized. Reduction of ELF and TE was associated with a decrease in BMI centile. CONCLUSION: Abnormal TE and ELF results in obese children suggest presence of NAFLD even when transaminases are normal. TE and ELF might be used as monitoring tools for NAFLD. BMI stabilisation normalizes TE and ELF, underlining the impact of lifestyle intervention.

Transcriptional regulation of the human KiSS1 gene.

Kisspeptin, the product of the KiSS1 gene, has emerged as a key component of the mechanism by which the hypothalamus controls puberty and reproductive development. It does so by stimulating the secretion of gonadotropin releasing hormone (GnRH). Little is known about the transcriptional control of the KiSS1 gene. Here we show that a set of proteins postulated to be upstream components of a hypothalamic network involved in controlling female puberty regulates KiSS1 transcriptional activity. Using RACE-PCR we determined that transcription of KiSS1 mRNA is initiated at a single transcription start site (TSS) located 153-156bp upstream of the ATG translation initiation codon. Promoter assays performed using 293 MSR cells showed that the KiSS1 promoter is activated by TTF1 and CUX1-p200, and repressed by EAP1, YY1, and CUX1-p110. EAP1 and CUX-110 were also repressive in GT1-7 cells. All four TFs are recruited in vivo to the KiSS1 promoter and are expressed in kisspeptin neurons. These results suggest that expression of the KiSS1 gene is regulated by trans-activators and repressors involved in the system-wide control of mammalian puberty.

Risk of celiac disease in children with type 1 diabetes is modified by positivity for HLA-DQB1*02-DQA1*05 and TNF -308A.

OBJECTIVE: The overlap between genetic susceptibility to celiac disease (CD) and to type 1 diabetes is incomplete; therefore, some genetic polymorphisms may significantly modify the risk of CD in subjects with type 1 diabetes. This study aimed to investigate whether the susceptibility to CD in diabetic children is modified by positivity for HLA-DQB1*02-DQA1*05 and DQB1*0302-DQA1*03 and by alleles of single nucleotide polymorphisms within the genes encoding CTLA4, transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1, IL-2, IL-6, and IL-10. RESEARCH DESIGN AND METHODS: Genotypic data were compared between 130 case subjects (children with type 1 diabetes and CD diagnosed using endomysium antibodies) and 245 control subjects (children with type 1 diabetes only, optimally two per case, matched for center, age at type 1 diabetes onset, and type 1 diabetes duration). The subjects were recruited from 10 major European pediatric diabetes centers performing regular screening for CD. The polymorphisms were determined using PCR with sequence-specific primers, and the risk was assessed by building a step-up conditional logistic regression model using variables that were significantly associated with CD in the univariate analysis. RESULTS: The best-fitted model showed that risk of CD is increased by presence of HLA-DQB1*02-DQA1*05 (odds ratio 4.5 [95% CI 1.8-11], for homozygosity, and 2.0 [1.1-3.7], for a single dose) and also independently by TNF -308A (1.9 [1.1-3.2], for phenotypic positivity), whereas IL1-alpha -889T showed a weak negative association (0.6 [0.4-0.9]). CONCLUSIONS: The results indicate that the risk of CD in children with type 1 diabetes is significantly modified both by the presence of HLA-DQB1*02-DQA1*05 and by a variant of another gene within the major histocompatibility complex, the TNF -308A.

Identification of urinary protein pattern in type 1 diabetic adolescents with early diabetic nephropathy by a novel combined proteome analysis.

Diabetic nephropathy is the main cause of morbidity and mortality in patients with Type 1 diabetes mellitus. Microalbuminuria has been established as a risk factor for the development and the progression of diabetic renal disease. A strong demand exists for better technologies to provide accurate diabetic nephropathy risk estimates before renal functional or structural disturbances already become established. Here, we present the application of a novel proteomics technology identifying urinary polypeptides and proteins. In this pilot study, we investigated 44 Type 1 diabetic patients with more than 5 years of diabetes duration compared with an age-matched control group. Random spot urine samples were examined utilizing high-resolution capillary electrophoresis (CE), coupled to mass spectrometry (MS). More than 1000 different polypeptides, characterized by their separation time and mass, were found between 800 Da and 66.5 kDa. Mathematical analysis revealed specific clusters of 54 polypeptides only found in Type 1 diabetic patients and an additional 88 polypeptides present or absent in patients with beginning nephropathy defined by the albumin-to-creatinine ratio (ACR; >35 mg/mmol). We observed polypeptide patterns characteristic for healthy controls and diabetic patients and subdivision of patients according to the excretion of polypeptides typical for diabetic nephropathy. Our study revealed that the urinary proteome contains a much greater variety of polypeptides than previously recognized and demonstrated the successful application of a novel high-throughput technology towards the human urinary proteome. Future prospective studies with the application of this technique may enable the earlier and more accurate detection of individuals at high risk to develop diabetic nephropathy.

Prevalence of 20S proteasome, anti-nuclear and thyroid antibodies in young patients at onset of type 1 diabetes mellitus and the risk of autoimmune thyroiditis.

Patients with type 1 diabetes mellitus (DM1) are at high risk to develop further autoimmune disorders, which are mostly characterized by the presence of organ-specific antibodies in serum and a subclinical disease course. Diabetes-related (glutamic acid decarboxylase, tyrosine phosphatase, IA-2) and thyroid-specific (thyroperoxidase, thyroglobulin) as well as antibodies to 20S proteasome, and anti-nuclear antibodies, were measured at DM1 onset in 147 children and adolescents. Patients were followed prospectively for the development of autoimmune thyroiditis (TSH elevation and/or sonographic thyroid gland enlargement in the presence of thyroid antibodies) up to 12 years, median observation time 4.4 years. Eight of 147 (5.4%) patients developed autoimmune thyroiditis. The cumulative incidence (+/-SE) at 5 years was 0.08+/-0.03. The prevalence of thyroid antibodies was 16.7%, of DM-related 88.4%, 20S proteasome 21.9%, and anti-nuclear antibodies 20.0%. There was a positive correlation between thyroid and anti-nuclear antibodies (p <0.001). Clinical course of DM1 and remission duration were not influenced by the presence of autoantibodies. However, in contrast to patients without antibodies, those with positive antibodies had significantly (p <0.001) elevated cumulative incidence of autoimmune thyroiditis at 5 years: thyroperoxidase 0.40+/-0.13, thyroglobulin 0.38+/-0.15, and anti-nuclear antibodies 0.29+/-0.12, respectively. These data underline that autoimmunity in patients with DM1 is not only restricted to beta-cell antigens at the onset of disease. In particular, patients with positive thyroid and anti-nuclear antibodies are at high risk to develop autoimmune thyroiditis during the first 5 years of DM1.