Aims/hypothesis The variants of transcription factor 7-like 2 (TCF7L2) gene have been proposed to be associated with latent autoimmune diabetes in adults (LADA). We sought to confirm the possible association in Europeans and to examine the interaction between one gene variant and clinical data. Methods The TCF7L2 rs7903146 C-to-T polymorphism was genotyped in 211 LADA, 1,297 type 2 diabetic, 545 type 1 diabetic and 1,497 control individuals from Hungary. A meta-analysis of our and previously published studies was performed to evaluate the size and the heterogeneity of the gene effect.Results The meta-analysis yielded a significant effect of TCF7L2 T allele (OR 1.28; p<0.0001) on LADA risk without heterogeneity among Europeans. The T allele conferred equally strong susceptibility to LADA and type 2 diabetes. In the Hungarian dataset, the T allele was associated with LADA and type 2 diabetes, but not with type 1 diabetes.T allele carriers had significantly lower BMI than patients with the CC genotype in the LADA and type 2 diabetes groups (p=0.0021 and p=0.0013, respectively). In both diseases, the diabetes risk was significantly higher in the non-overweight than in the overweight BMI category (p=0.0013 and p<0.0001, respectively); susceptibility to LADA was increased by 2.84-fold in non-overweight individuals compared with overweight ones. Conclusions/interpretation The meta-analysis demonstrates that TCF7L2 rs7903146 polymorphism is a populationindependent susceptibility locus for LADA in Europeans. The effect size is similar for LADA and type 2 diabetes. The gene effect on diabetes risk may be modulated by BMI, such that the lower the BMI, the higher the gene effect.

Aims/hypothesis The rs1990760 polymorphism (Ala946Thr) of interferon induced with helicase C domain 1 (IFIH1) has been proposed to associate with type 1 diabetes. In this study, association between IFIH1 Ala946Thr and type 1 diabetes was investigated in two distinct white populations, the Hungarians and Finns. Methods The rs1990760 polymorphism was genotyped in 757/509 Hungarian/Finnish childhood-onset cases, 499/250 Hungarian/Finnish control individuals and in 529/924 Hungarian/Finnish nuclear family trios. Disease association was tested using case-control and family-based approaches. A meta-analysis of data from 9,546 cases and 11,000 controls was also performed.

The goal of the treatment for Type I (insulin-dependent) diabetes mellitus is to achieve near-normal glycaemia as early as possible in as many patients as is safely possible. Hypoglycaemia is the most common and dangerous side effect of insulin treatment and the prevalence of severe episodes remains a major obstacle in attempts to prevent long-term diabetic complications with intensive insulin therapy. The Diabetes Control and Complications Trial has recently shown that intensification of insulin therapy increases threefold the risk of severe hypoglycaemia in adolescent and adult Type I patients [1,2]. Undesirable consequences of hypoglycaemia are particularly important in children, and primarily in young children, because severe hypoglycaemic events may impair normal brain development and neuropsychologic functioning [3,4,5,6]. The perception of symptoms of hypoglycaemia (hypoglycaemia awareness) is the first line of defence mechanisms against blood glucose decline: it alerts the patient to the early development of Diabetologia (1998) Summary To establish whether impaired hypoglycaemic awareness is associated with increased rate of severe hypoglycaemia and to assess clinical predictors of severe episodes without warning symptoms a prospective study of 130 insulin-dependent diabetic children and adolescents was undertaken for 1 year. Using a structured questionnaire, 48 patients reported impaired awareness and 82 reported normal awareness of hypoglycaemia at baseline of the study. The two groups did not differ regarding clinical and metabolic characteristics. Episodes of severe hypoglycaemia were recorded for 1 year. The rate of severe hypoglycaemia was higher in the group with impaired awareness than in the group with normal awareness (p < 0.0001). Of the severe hypoglycaemic episodes, 34.0 % developed without warning symptoms. Patients with impaired awareness experienced more severe episodes without warning symptoms than those with normal awareness (p = 0.0054). Severe hypoglycaemia occurred more frequently in patients with impaired awareness aged 6 years and less (p = 0.0041) than in older counterparts. Impaired awareness reported at baseline [adjusted odds ratio (OR): 5.8; p = 0.0021], age 6 years or less (3.4; p = 0.0121), previous severe episode (4.8; p = 0.0043) and more than 5 % of home blood glucose readings 3.3 mmol/l or less in the preceding month (4.2; p = 0.0211) proved to be independently predictive of severe hypoglycaemic events without warning symptoms. In conclusion, impaired hypoglycaemic awareness is associated with an increased rate of severe hypoglycaemia in diabetic children and adolescents. One third of severe episodes developed without warning symptoms. Impaired awareness, young age and recent biochemical or severe hypoglycaemias are independent risk factors for such episodes. Avoidance of hypoglycaemia should be a priority in preschool children with diabetes. [Diabetologia (1998) 41: 898±903]

The aim of the present study was to investigate peripheral sensory nerve function in diabetic children and adolescents without neurological symptoms. Ninety-two children and adolescents with Type 1 (insulin-dependent) diabetes mellitus (mean +/- SD age: 14.2 +/- 2.1 years, diabetes duration: 5.8 +/- 3.0 years) and 80 healthy control subjects (age: 13.8 +/- 2.2 years) matched for age, sex, body mass index, and height standard deviation score were involved in the study. Using a sine-wave transcutaneous stimulator, current perception threshold (CPT) testing at 2000, 250 and 5 Hz was performed on the left median and peroneal nerves. Diabetic children had increased CPT at 2000 Hz on both nerves as compared to the control group (median (interquartile range), median nerve: 2.43 (2.20-3.43) vs 1.80 (1.51-2.60) mA, p = 0.02; peroneal nerve: 3.51 (2.81-4.82) vs 2.70 (2.04-3.70) mA, p = 0.01). Twenty-one (23%) of patients had CPT values higher than that of any healthy individual. Of these, elevated CPT was observed in 9 (9.8%) patients on the median nerve, in 8 (8.7%) patients on the peroneal nerve, and in 4 (4.3%) patients on both median and peroneal nerves. Using multiple logistic regression analysis, worse long-term metabolic control and advanced puberty were independently predictive of peripheral sensory nerve dysfunction as the dependent variable (adjusted OR (95% CI): 3.4 (1.2-6.2), p = 0.01, and 2.8 (1.1-5.6), p = 0.03, respectively). In conclusion, evidence of peripheral sensory nerve dysfunction is not rare in children and adolescents with diabetes and can be demonstrated by CPT testing in asymptomatic patients. Poor metabolic control is a risk factor for such subclinical neuropathy, and pubertal development may be involved in the pathogenesis of diabetic peripheral neuropathy.

Autoimmune diseases are initiated by interaction between genetic and environmental factors and caused by the loss of immunologic tolerance to self-antigens. They cluster within families and individuals, but the aggregation in a triad is quite rare. We report a case of a young girl affected by three organ-specific autoimmune disorders, from which type 1 diabetes developed first, then Hashimoto's thyroiditis and juvenile rheumatoid arthritis were diagnosed. Hitherto unreported detailed genetic studies included genotyping of HLA class II, CTLA4, and PTPN22 gene regions. These genes have been associated with autoimmunity in general and some of their variants confer increased risk to all three diseases. Our results - with the limitation of reporting only on a single patient - contribute to the complex genetic background of these clustering organ-specific autoimmune diseases and the analysis of further similar cases might help to reveal how the major and minor genetic factors determine the individual clinical phenotype.