Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes

in European Journal of Endocrinology (2007), 156(6), 663-671

Objective: The ATP-dependent K+-channel (KATP) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine α- and β-cells. Gastrointestinal endocrine L- and K-cells ... [more ▼]

Objective: The ATP-dependent K+-channel (KATP) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine α- and β-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the KATP channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu2Lys, exerts a functional impact on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes. Design and methods: Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in 257 children at 1, 6 and 12 months after diagnosis. Genotyping for the Glu23Lys variant was by PCR-restriction fragment length polymorphism. Results: Kir6.2 and SUR1 co-localise with GLP-1 in L-cells and with GIP in K-cells in human ileum tissue. Children with type 1 diabetes carrying the hyperactive Glu23Lys variant had higher HbA1c at diagnosis (coefficient= 0.61%, P= 0.02) and 1 month after initial insulin therapy (coefficient= 0.30%, P=0.05), but later disappeared. However, when adjusting HbA1c for the given dose of exogenous insulin, the dose-adjusted HbA1c remained higher throughout the 12 month study period (coefficient= 0.42%, P=0.03). Conclusions: Kir6.2 and SUR1 co-localise in the gastrointestinal endocrine L- and K-cells. The hyperactive Glu2Lys variant of the KATP channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control in children with type 1 diabetes. © 2007 Society of the European Journal of Endocrinology. [less ▲]

Effect of 2 years of high-dose growth hormone therapy on cognitive and psychological development in short children born small for gestational age

in European Journal of Endocrinology (2007), 156(2), 195-201

Objective and design: Children born small for gestational age (SGA) are not only at risk for short stature, but also for neurodevelopmental and behavioral problems. In this study, we analyzed the effects ... [more ▼]

Objective and design: Children born small for gestational age (SGA) are not only at risk for short stature, but also for neurodevelopmental and behavioral problems. In this study, we analyzed the effects of high-dose GH therapy on cognitive development and psychosocial functioning in 34 prepubertal (3-8 years) short SGA children, equally randomized into a GH-treated group (TRG) and an untreated group (UTRG). Methods: At start and after 2 years, children underwent standardized tests measuring the intellectual abilities (Wechsler Preschool and Primary Scale of Intelligence-Revised, or Wechsler Intelligence Scale for Children-Revised); their parents completed a standardized questionnaire evaluating psychosocial functioning (Child Behavior Checklist; CBCL). Results: At start, total IQ scores were significantly (P<0.05) lower in the SGA group than in the general population: 32% of the SGA patients had scores below 85. After 2 years, IQ scores remained unchanged in the TRG, but increased significantly (P<0.05) in the UTRG. After exclusion of children with developmental problems, however, no significant changes in IQ scores occurred in the UTRG as well as the TRG. At baseline, 24% (8/34) children had problematic CBCL total problems scores, equally distributed among the two groups; no significant changes in the different subscale scores occurred after 2 years. Conclusion: No beneficial effect of 2 years of GH therapy on cognitive and behavioral profile could be observed in a cohort of rather young short SGA children presenting a variable degree of developmental delay and behavioral problems. Subsequent follow-up could reveal potential long-term effects of GH therapy on development and behavior. © 2007 Society of the European Journal of Endocrinology. [less ▲]

The TRIGR Trial: Testing the Potential Link between Weaning Diet and Type 1 Diabetes

in Immunology, Endocrine and Metabolic Agents - Medicinal Chemistry (2007), 7

Support for young people with diabetes

in The BMJ (2006), 333(7558), 55-56

Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: Reduced insulin antibody titres and preserved beta cell function

in Diabetologia (2006), 49(1), 71-74

Aims/hypothesis: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin ... [more ▼]

Aims/hypothesis: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin gene (INS). We investigated the association between INS VNTR class III alleles (-23HphIA/T) and both insulin antibody presentation and residual beta cell function during the first year after diagnosis in 257 children with type 1 diabetes. Materials and methods: To estimate C-peptide levels and autoantibody presentation, patients underwent a meal-stimulated C-peptide test 1, 6, and 12 months after diagnosis. The insulin -23HphIA/T variant was used as a marker of class III alleles and genotyped by PCR-RFLP. Results: The insulin antibody titres at 1 and 6 months were significantly lower in the class III/III and class I/III genotype groups than in the class I/I genotype group (p = 0.01). Class III alleles were also associated with residual beta cell function 12 months after diagnosis and independently of age, sex, BMI, insulin antibody titres, and HLA-risk genotype group (p = 0.03). The C-peptide level was twice as high among class III/III genotypes as in class I/I and class I/III genotypes (319 vs 131 and 166 pmol/l, p=0.01). Furthermore, the class III/III genotype had a 1.1% reduction in HbA1c after adjustment for insulin dose (p = 0.04). Conclusions/interpretation: These findings suggest a direct connection in vivo between INS VNTR class III alleles, a decreased humoral immune response to insulin, and preservation of beta cell function in recent-onset type 1 diabetes. © Springer-Verlag 2005. [less ▲]

Incidence and trends of Childhood Type 1 diabetes worldwide 1990-1999

in Diabetic Medicine: A Journal of the British Diabetic Association (2006), 23(8), 857-866

AIM: To examine incidence and trends of Type 1 diabetes worldwide for the period 1990-1999. METHODS: The incidence of Type 1 diabetes (per 100 000/year) was analysed in children aged <or= 14 years from ... [more ▼]

AIM: To examine incidence and trends of Type 1 diabetes worldwide for the period 1990-1999. METHODS: The incidence of Type 1 diabetes (per 100 000/year) was analysed in children aged <or= 14 years from 114 populations in 112 centres in 57 countries. Trends in the incidence of Type 1 diabetes were analysed by fitting Poisson regression models to the dataset. RESULTS: A total of 43,013 cases were diagnosed in the study populations of 84 million children. The age-adjusted incidence of Type 1 diabetes among 112 centres (114 populations) varied from 0.1 per 100,000/year in China and Venezuela to 40.9 per 100,000/year in Finland. The average annual increase in incidence calculated from 103 centres was 2.8% (95% CI 2.4-3.2%). During the years 1990-1994, this increase was 2.4% (95% CI 1.3-3.4%) and during the second study period of 1995-1999 it was slightly higher at 3.4% (95% CI 2.7-4.3%). The trends estimated for continents showed statistically significant increases all over the world (4.0% in Asia, 3.2% in Europe and 5.3% in North America), except in Central America and the West Indies where the trend was a decrease of 3.6%. Only among the European populations did the trend in incidence diminish with age. CONCLUSIONS: The rising incidence of Type 1 diabetes globally suggests the need for continuous monitoring of incidence by using standardized methods in order to plan or assess prevention strategies. [less ▲]

Evolution du traitement médicamenteux du diabète au Luxembourg.

in Bulletin de la Société des Sciences Médicales du Grand-Duché de Luxembourg (2006), (1), 29-35

OBJECTIVES: The aims of the study were to estimate the prevalence of diabetes in Luxembourg in 2002, to compare it to the prevalence reported in 1991 and to evaluate if prescription attitudes have changed ... [more ▼]

OBJECTIVES: The aims of the study were to estimate the prevalence of diabetes in Luxembourg in 2002, to compare it to the prevalence reported in 1991 and to evaluate if prescription attitudes have changed since 1991. METHODS: The prevalence of diabetes was estimated using the drug sales data. The key parameters, total amount of antidiabetic drugs sold in one year and the average daily dose or Prescribed Daily Dose (PDD), have been obtained from the National Social Security Organization and by a standardized questionnaire sent to all general practitioners and all internists and endocrinologists of the country. RESULTS: The PDD was calculated on 2,402 questionnaires on individual diabetic patients. By this mean, the proportion of patients only treated with appropriate diet could also be obtained. Compared to 1991, the total amount of antidiabetic drugs showed a four-fold increase in biguanides tablet prescriptions. A high percentage of combined treatments was found. The prevalence of diabetes in Luxembourg was found to be 3.05% of the total population. CONCLUSIONS: Compared to the status in 1991, prevalence of diabetes increased by 63%, which seems mainly due to type 2 diabetic patients as orally-treated diabetic patients almost doubled (2.11% vs 1.16%). A substantial change in prescriptions for diabetes has occurred, suggesting a positive influence of studies like the United Kingdom Prospective Diabetes Study (UKPDS). [less ▲]

Changes in diabetes prevalence and treatment in the last ten years in Luxembourg. A lesson from the United Kingdom prospective diabetes study?

in Diabetes and Metabolism (2005), 31(5), 499-502

Objectives: The aims of the study were to estimate the prevalence of diabetes in Luxembourg in 2002, to compare it to the prevalence reported in 1991 and to evaluate if prescription attitudes have changed ... [more ▼]

Objectives: The aims of the study were to estimate the prevalence of diabetes in Luxembourg in 2002, to compare it to the prevalence reported in 1991 and to evaluate if prescription attitudes have changed since 1991. Methods: The prevalence of diabetes was estimated using the drug sales data. The key parameters, total amount of antidiabetic drugs sold in one year and the average daily dose or Prescribed Daily Dose (PDD), have been obtained from the National Social Security Organization and by a standardized questionnaire sent to all general practitioners and all internists and endocrinologists of the country. Results: The PDD was calculated on 2, 402 questionnaires on individual diabetic patients. By this means, the proportion of patients only treated with appropriate diet could also be obtained. Compared to 1991, the total amount of antidiabetic drugs showed a four-fold increase in metformine tablet prescriptions. A high percentage of combined treatments was found. The prevalence of diabetes in Luxembourg was found to be 3.05% of the total population. Conclusions: Compared to the status in 1991, prevalence of diabetes increased by 63%, which seems mainly due to type 2 diabetic patients as orally-treated diabetic patients almost doubled (2.11% vs 1.16%). A substantial change in prescriptions for diabetes has occurred, suggesting a positive influence of studies like the United Kingdom Prospective Diabetes Study (UKPDS). © 2005 Masson, all rights reserved. [less ▲]

Seasonality of birth in patients with childhood type 1 diabetes in nineteen European regions

in Diabetologia (2001), 44(3), 67-74

AIMS/HYPOTHESIS: Differences in seasonality of birth patterns between the general population and the group who develop Type I (insulin-dependent) diabetes mellitus indicate that environmental factors ... [more ▼]

AIMS/HYPOTHESIS: Differences in seasonality of birth patterns between the general population and the group who develop Type I (insulin-dependent) diabetes mellitus indicate that environmental factors operating around the antenatal and perinatal period could be important. We investigated whether the same unsual patterns in seasonality of birth observed in children with Type I diabetes in Great Britain could also be found in other European populations. METHODS: Population-based incidence cohorts of children diagnosed with Type I diabetes under 15 years of age from 1989 onwards were analysed. Previously reported data sets from Great Britain were also included together with data on children diagnosed over an additional 5 year period (1988-1992). To assess the role of seasonality in diabetes, we used the method of Walter and Elwood to examine monthly birth figures for each country or region. RESULTS: Outside of Great Britain, no seasonality of birth was seen for any single or combination of European countries. Significant sinusoidal patterns were observed in Scotland, Yorkshire and Leicester, although the peak for Leicester appeared around autumn rather than spring. There was little evidence that sex or age at diagnosis played a part in differences in seasonal patterns, either overall or for any individual country. CONCLUSIONS/INTERPRETATION: We found no uniform seasonal pattern of birth in childhood diabetes patients across European populations, either overall or according to sex and age. This study provides no consistent evidence that environmental factors, which vary from season to season, have any influence on the fetal or neonatal life to determine the onset of Type I diabetes. However, a study of seasonality that takes into account possible changes both over time and over geographical areas could provide more insights. [less ▲]

Is childhood onset type1 diabetes a wealth-related disease. An ecological analysis of European incidence rates

in Diabetologia (2001), 44