Harry Dorchy

Insulin management and metabolic control of Type 1 diabetes mellitus in childhood and adolescence in 18 countries

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross‐sectional, non‐population‐based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4–6.3 %, mean 5.4 %). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 ± 1.3 % (mean ± SD) compared with 8.9 ± 1.8 % in those aged 12–18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg−124 h−1) in children aged 2–9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37 % (n = 1071) used three or more. Of those on two or three injections daily, 37 % used pre‐mixed insulins, either alone or in combination with short‐ and intermediate‐acting insulin. Pre‐adolescent children on pre‐mixed insulin showed similar HbA1c levels to those on a combination of short‐ and long‐acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long‐acting insulin. Among adolescent boys, lower HbA1c was related to use of more short‐acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.

Continuing Stability of Center Differences in Pediatric Diabetes Care: do advances in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood Diabetes

OBJECTIVE—To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis. RESEARCH DESIGN AND METHODS—This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11–18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005. RESULTS—Mean A1C was 8.2 ± 1.4%, with substantial variation between centers (mean A1C range 7.4–9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 ± 2.0% vs. 8.2 ± 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C. CONCLUSIONS—Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.

Insulin injection regimens and metabolic control in an international survey of adolescents with type 1 diabetes over 3 years: Results from the Hvidore study group

Abstract. The optimal insulin regimen for paediatric patients with type 1 diabetes remains controversial. Therefore this multicentre study was performed in adolescents over a 3-year period to assess metabolic control, severe hypoglycaemia, and weight gain in relation to insulin injection regimens. Out of 2873 children and adolescents in an international survey in 1995, 872 adolescents (433 boys, 439 girls, mean age in 1995 11.3±2.2 years) were restudied in 1998, relating insulin regimens to HbA1c measured in a central laboratory. In addition, the daily dose of insulin, changes in body mass index (BMI), and events of severe hypoglycaemia were evaluated. Over 3 years, the use of multiple injection regimens increased from 42% to 71%: 251 patients remained on twice daily insulin, 365 remained on multiple injections and 256 shifted from twice daily insulin to multiple injections. In all three subgroups an increase in insulin dose, a deterioration of metabolic control, and an increase in BMI were observed. Metabolic control deteriorated less than expected over 3 years during adolescence (HbA1c 1995: 8.7±1.6%; 1998 observed: 8.9±1.6%, HbA1c expected for 1998: 9.0%). BMI increased more than expected, the increase was greatest in patients switching from twice daily to multiple injections, and higher in females compared to males. Conclusion: in this international study, metabolic control was unsatisfactory in many adolescents with type 1 diabetes irrespective of the insulin regimen. No improvement in metabolic control was observed in this cross-sectional survey, over 3 years in any of the subgroups. Even the group switching from twice to multiple injections did not improve blood glucose control and the increase in body mass index was most pronounced in this group. Conclusive evidence, however, should be based on prospectively planned, randomised therapeutic trials in paediatric patients.

Glycated Hemoglobin and Related Factors in Diabetic Children and Adolescents Under 18 Years of Age: a Belgian Experience

OBJECTIVE To determine, in an unselected population of diabetic children and adolescents < 18 years of age, which HbA1c levels can be achieved, and to examine the relationships with insulin regimen, insulin dose, sex, diabetes duration, BM1, and frequency of home blood glucose monitoring (HBGM) and outpatient clinic attendance. RESEARCH DESIGN AND METHODS A total of 144 unselected subjects (73 boys and 71 girls) aged 11.8 ± 3.7 years (mean ± SD) were included in the study over a 6-month period. They had diabetes durations ranging from 5 months to 15 years (4.0 ± 3.0). They were followed by the same pediatric diabetologist and the same nurse. The yearly frequency of visits was 8.9 ± 2.0, and the monthly frequency of HBGM was 111 ± 27. Of the patients, 129 were treated with two daily insulin injections of an individualized mixture of rapid- and intermediate-acting insulins, and 15 adolescents were treated with four injections using the basal-bolus regimen. The patients were divided into two subgroups according to diabetes duration: ≤ 2 years (n = 53) and > 2 years (n = 91), i.e., outside the honeymoon period. HbA1c was measured by a high-pressure liquid chromatography method (normal values 3.9–5.5%). RESULTS The mean ± SD HbA1c level in the 144 children and adolescents was 6.6 ± 1.2% using our method. In 62% of the patients, it was possible to obtain an HbA1c level under the normal mean value plus 5 SD. HbA1c was not related to sex, number of insulin injections, or age, i.e., it was not poorer at adolescence. The mean daily insulin dose was 0.9 U/kg body wt, being lower during the first 2 years of diabetes and reaching 1 U at adolescence. HbA1c levels were lower during the first 2 years of diabetes (6.2 ± 1.0%) than afterwards (6.9 ± 1.2%), but the frequencies of outpatient visits and HBGM were higher. After 2 years, HbA1c was negatively correlated with the frequency of HBGM. The yearly incidence rate of severe hypoglycemic episodes was 0.2. After the age of 13 years, BM1 was significantly higher in girls and in adolescents on four daily injections. CONCLUSIONS In nearly two-thirds of diabetic children and adolescents, it is possible to obtain HbA1c levels under the normal mean plus 5 SD, which is considered satisfactory and close to that of the adult cohort of the Diabetes Control and Complications Trial (DCCT) with intensive treatment. There is no difference between the children on only two daily insulin injections and the adolescents on four injections. After 2 years of diabetes, increased frequency of HBGM helps reduce HbA1c levels, taking into account the “intensive” education of the patients and their families. Adolescent girls on four injections must pay attention to the risk of becoming overweight.

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes

Aims  To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries.

HLA-DR 3 is associated with a more slowly progressive form of Type 1 (insulin-dependent) diabetes

SummaryThe presence of HLA-DR 3 was analysed in 745 patients with Type 1 (insulin-dependent) diabetes with age at diagnosis between 1–19 years. HLA-DR 3 and/or 4 was found in 678/745 (91%) of the patients. Presence of DR 2 with neither DR 3 nor 4 was demonstrated in 15 patients. Patients with HLA-DR 3 without DR 4 presented with Type 1 diabetes more evenly over the year; they also presented without incidence peaks at 7 years or 10–11 years, as seen especially in DR 3/4 patients. The DR 3 patients more often had mild disease with less ketonuria at diagnosis, less often ketoacidotic symptoms and more often a subsequent partial remission. The apparently more severe disease among diabetic girls may, at least to some extent, be explained by their higher prevalence of HLA-DR4. The differences found were similar in North America and Europe. The results suggest that Type 1 diabetes is a genetically heterogenous disease and that HLA-typing may be a useful marker of this heterogeneity.

Target setting in intensive insulin management is associated with metabolic control: The Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005

Swift PGF, Skinner TC, de Beaufort CE, Cameron FJ, Åman J, Aanstoot H‐J, Castaño L, Chiarelli F, Daneman D, Danne T, Dorchy H, Hoey H, Kaprio EA, Kaufman F, Kocova M, Mortensen HB, Njølstad PR, Phillip M, Robertson KJ, Schoenle EJ, Urakami T, Vanelli M, Ackermann RW, Skovlund SE for the Hvidoere Study Group on Childhood Diabetes. Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005.

Isodisomy of chromosome 6 in a newborn with methylmalonic acidemia and agenesis of pancreatic beta cells causing diabetes mellitus.

Isodisomy (ID) is a genetic anomaly defined as the inheritance of two copies of the same genetic material from one parent. ID in an offspring is a rare cause of recessive genetic diseases via inheritance of two copies of a mutated gene from one carrier parent. We studied a newborn female with a mut(o) of methylmalonic acidemia and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus. The patient died 2 wk after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal ID, involving at least a 25-centiMorgan portion of the chromosome pair that encompasses the MHC. ID probably caused methylmalonic acidemia by duplication of a mutated allele of the corresponding gene on the chromosome 6 inherited from the father. It is also very likely that ID was etiologically related to the agenesis of beta cells and consequent insulin-dependent diabetes mellitus in our patient. We thus speculate on the existence of a gene on chromosome 6 involved in beta cell differentiation.

Associations of GAD65- and IA-2-Autoantibodies With Genetic Risk Markers in New-Onset IDDM Patients and Their Siblings. The Belgian Diabetes Registry

OBJECTIVE To investigate the association of GAD (65-kDa) autoantibodies (GAD65-Abs) and IA-2 autoantibodies (IA-2-Abs) with human leukocyte antigen (HLA)-DQ and insulin gene (INS) risk markers in patients with recent-onset IDDM and their siblings. RESEARCH DESIGN AND METHODS Blood was sampled from 608 recent-onset IDDM patients and 480 siblings, aged 0–39 years and consecutively recruited by the Belgian Diabetes Registry, to determine GAD65- and IA-2-Ab (radiobinding assay), HLA-DQ- (allele-specific oligonucleotyping), and INS-genotypes (restriction fragment length polymorphism analysis; siblings, n = 439). RESULTS At the onset of IDDM, GAD65-Abs were preferentially associated with two populations at genetic risk but only in the 20- to 39-year age-group: 1) their prevalence was higher in carriers of DQA1*0301-DQB1*0302 (88 vs. 73% in non[DQA1*0301-DQB1*0302], P = 0.001), and 2) an association was found in patients lacking this haplotype but carrying DQA1*0501-DQB1*0201, together with INS I/I (87 vs. 54% vs. non[INS I/I], P = 0.003). Siblings of IDDM patients also presented the association of GAD65-Abs with DQA1*0301-DQB1*0302 (13 vs. 2% non[DQA1*0301-DQB1*0302], P < 0.001), while associations with the second genetic risk group could not yet be assessed. At the onset of IDDM, IA-2-Ab prevalence was higher in carriers of DQA1*0301-DQB1*0302 (69 vs. 39% non[DQA1*0301-DQB1*0302], P < 0.001) but not of DQA1*0501-DQB1*0201 or INS I/I. This association was present in both the 0- to 19- and the 20- to 39-year age-groups. It was also found in siblings of IDDM patients (4 vs. 0% non[DQA1*0301-DQB1*0302], P < 0.001). CONCLUSIONS Both GAD65- and IA-2-Abs exhibit higher prevalences in presence of HLA-DQ- and/or INS-genetic risk markers. Their respective associations differ with age at clinical onset, suggesting a possible usefulness in the identification of subgroups in this heterogeneous disease.

EEG Abnormalities in Diabetic Children Influence of Hypoglycemia and Vascular Complications

The effect of diabetic control upon EEC has seldom been studied. In the present investigation, a significant positive correlation between EEC ab normalities and degree of diabetic control was found, but no definite increase was noted in relation to the duration of diabetes. Eighty per cent of our patients having more than 5 severe hypoglycemic attacks showed evidence of abnormal EEG, suggesting that hypoglycemic coma or convulsions are closely related to EEC abnormalities (minor hypoglycemic episodes had no effect on the EEG). With the sensitive technique of fluorescein angiography, we demonstrated a clear correlation between incipient retinal angiopathy and EEC abnormalities. The factors that most positively relate to pathologic electrocerebral (EEG) activity in diabetic children are frequent and severe hypoglycemic attacks, comas and/or convulsions, and vascular changes in the retina.