Yearbook of Pediatric Endocrinology 2011

J. -C. Carel, Z. Hochberg

• Publisher: S. Karger
• Year: 2011
• ISBN:
  9783805598606
• Topic: Medicina
• Subtopic: Endocrinología y metabolismo

The body of knowledge in most medical specialties is rapidly expanding, making it virtually impossible to follow all advances in clinical and basic sciences that are relevant to a given field. This is particularly true in pediatric endocrinology, at the cross-road of pediatrics, endocrinology, development and genetics. Providing abstracts of articles that report the year's breakthrough developments in the basic sciences and evidence-based new knowledge in clinical research and clinical practice that are relevant to the field, the Yearbook of Pediatric Endocrinology 2011 keeps busy clinicians and scientists, pediatric endocrinologists, and also pediatricians and endocrinologists informed on new advances. Twelve Associate Editors and their co-authors selected from several thousand papers those that brought the most meaningful new information, summarized them and provided comments to put them into perspective. The papers are classified into those that identify new genes involved in diseases, new hormones, concepts revised or re-centered, important observations for clinical practice, large-scale clinical trials, new mechanisms, new paradigms, important review articles, new fears and new hopes. Because the Yearbook is endorsed by the European Society for Paediatric Endocrinology (ESPE), its publication is linked to the annual meeting of the ESPE. The Yearbook of Pediatric Endocrinology 2011 covers the medical and scientific literature from June 2010 through May 2011.

Type 1 Diabetes: Clinical and Experimental

Francesco Chiarelli and M. Loredana Marcovecchio

Department of Pediatrics, University of Chieti, Chieti, Italy

The rising incidence in type 1 diabetes (T1D) continues to stimulate experimental and clinical studies aiming at understanding the pathogenesis of the disease and developing new preventive and therapeutic strategies. This trend in T1D incidence appears to be too rapid to be simply justified by the genetic background, whereas it seems more likely to be due to changes in environmental factors [1], such as enteroviruses, early life nutrition and vitamin D deficiency. Interestingly, over the last year there has been a particular focus in trying to understand whether these factors directly trigger the autoimmune process or mainly influence the progression from autoimmunity to clinical manifest T1D. With regard to genetic studies in T1D, a further step after the genome-wide association (GWA) era has been the attempt to integrate GWA data with gene expression profiles in order to translate genetic associations into biological function, as well as the assessment of the interaction between genetic and environmental factors to fully characterize the complex etiology of T1D. Prevention is a fundamental issue in the context of diabetes and several ongoing studies are assessing the role of dietary interventions started early in life. Studies focusing on a way of improving the success of islet transplantation and on the development of new non-invasive biomarkers of insulinitis offer new hopes and food for thought.

Last but not least, when considering childhood-onset T1D, one aspect which needs to be carefully considered is related to its acute and chronic complications, which contribute to the burden of the disease. New data based on long-term follow-up of a cohort with childhood-onset T1D have been published in 2010-2011 and indicate that mortality among people with T1D is still higher than in the general population. A better understanding of the pathogenesis of T1D complications represents the starting point for new intervention strategies which could improve the prognosis of patients. All the above-mentioned aspects are the focus of the articles chosen for this year's chapter on T1D.

Clinical trials, new treatments
Early interventions to prevent auto immunity

Dietary intervention in infancy and later signs of ß-cell autoimmunity

Knip M, Virtanen SM, Seppa K, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hamalainen AM, Paronen J, Dosch HM, Hakulinen T, Akerblom HK

Hospital for Children and Adolescents, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

[email protected]

N Engl J Med 2010;363:1900-8.

Background: Early exposure to complex dietary proteins may increase the risk of ß-cell autoimmunity and T1D. In the present study the effect of supplementing breast milk with highly hydrolyzed milk formula on the incidence of diabetes-associated autoantibodies was assessed in children with genetic susceptibility.

Methods: In a double-blind, randomized trial, 230 infants with HLA-conferred susceptibility to T1D and at least 1 family member with T1D were assigned to receive either a casein hydrolysate formula (intervention) or a conventional, cow’s-milk-based formula (control) during the first 6-8 months of life. T1D autoantibodies were analyzed during a median observation period of 10 years. Children were monitored for incident T1D until the age of 10 years.

Results: The unadjusted hazard ratio (HR) for positivity for one or more autoantibodies in the intervention formula group was 0.54 (95% confidence interval (CI) 0.29-0.95), compared with the control group, and the adjusted HR for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI 0.28-0.91). The unadjusted HR for positivity for ≥2 autoantibodies was 0.52 (95%CI 0.21-1.17), and the adjusted HR was 0.47 (95% CI 0.19-1.07). The rate of reported adverse events was similar in the two groups.

Conclusions: Dietary intervention during infancy appears to have a long-lasting effect on markers of ß-cell autoimmunity.

There is increasing evidence suggesting that ß-cell autoimmunity is a phenomenon deriving from the interaction of genetic and environmental factors, which may be induced early in life and potentially even during prenatal life [2]. Animal and human studies have shown that reduced breastfeeding and an early introduction of complex dietary proteins can influence the development of ß-cell autoanti-bodies [3]. These observations represented the starting point for the present study, which assessed whether the composition of two different formulas given to infants was associated with seroconversion to T1D autoantibodies. In a randomized double-blind study, 230 at term newborn with genetic susceptibility were assigned to receive either an extensively hydrolyzed casein-based formula (intervention formula) or a control formula, composed of 80% intact milk protein and 20% hydrolyzed milk protein. Interestingly, the intervention formula was associated with a significant reduced risk of seroconversion to one or more autoantibodies: 17% of babies in this group developed at least one autoantibody vs. 30% in the control formula group. Although there were some differences in the time when the two formulas were introduced and in the duration of their implementation, the results remained consistent after adjusting for these potential confounders. The mechanisms behind the effect of the intervention formula is not clear, although it has been hypothesized that this could be due to effects on the gut and the microbiota, such as reduced gut permeability, modification of the gut microflora, induction of the maturation of regulatory T cells in the gut-associated lymphoid tissue, as well as to the elimination of early exposure to bovine insulin [3]. Although further studies are required to confirm the findings of the present study, these results highlight the feasibility of preventive dietary interventions started early in life as a tool to manipulate ß-cell autoimmunity. Early nutritional interventions represent indeed an appealing strategy for preventing T1D because they could be easily applicable as a public health strategy.

New concerns Looking for an explanation for the increasing T1D incidence?

Accelerated progression from islet autoimmunity to diabetes is causing the escalating incidence of type 1 diabetes in young children

Ziegler AG, Pflueger M, Winkler C, Achenbach P, Akolkar B, Krischer JP, Bonifacio E

Institute of Diabetes Research, Forschergruppe Diabetes e.V. at Helmholtz Center Munich, Neuherberg, Germany.

J Autoimmun 2011;37:3-7

Background: This study was performed to determine whether the incidence of islet autoimmunity or the rate of progression from autoimmunity to diabetes onset has changed over a 20-year period in children genetically predisposed to T1D.

Methods: Between 1989 and 2010, children who were first-degree relatives of patients with T1D and who were born in Germany were prospectively followed from birth without intervention. A total of 324 children (BABYDIAB study) born between 1989 and 2000 and 216 children (TEDDY study) born between 2004 and 2010 with matched HLA genotypes were recruited before age 3 months and included for analysis. Children were followed for the development of T1D autoantibodies and for progression to diabetes.

Results: The cumulative frequency of T1D by age 4 years was 2.5% (95% CI 0.8-4.2%) in BABYDIAB children and 6.2% (95% CI 2.3-10.1%) in TEDDY children (p = 0.03). The cumulative frequency of islet autoantibodies by age 4 years was similar in the children from both studies (11.3 vs. 13.9%). Progression to diabetes from the appearance of islet autoantibodies was markedly increased in children from the more recently recruited TEDDY cohort than in BABYDIAB children: 50% progression within 9.6 vs. 85.2 months; p = 0.009. This difference persisted even when children were further selected on the basis of high-risk HLA genotypes or the development of autoantibodies to multiple islet antigens (p = 0.01).

Conclusions: The recent increasing incidence of T1D in young children could be due to weakening of mechanisms that normally regulate autoimmune destruction of islet ß cells.

The escalating increase in new cases of T1D observed during the last decades, particularly in children younger than 5 years, continues to stimulate studies aiming at understanding the underlining mechanisms. One important issue to clarify is whether this trend reflects an increase in the incidence of early autoimmunity against the pancreatic ß cells or a faster progression from the appearance of autoimmunity to clinical manifest T1D. This was the key aspect investigated in the study reported by Ziegler et al., where children at risk of developing diabetes, as defined by having a first-degree relative with T1D and a high-risk HLA haplotype, were followed from birth up to 20 years. These children were recruited to two large ongoing studies, BABYDIAB and TEDDY, which have been assessing auto-immunity and progression to T1D in children with an increased genetic susceptibility. For the BABYDIAB cohort, recruitment of at risk newborn was conducted between 1989 and 2000, whereas TEDDY represents a more recent cohort established between 2004 and 2010. One of the main study findings was that the percentage of positivity for autoantibody by age 4 was similar in both cohorts: 11.3% in BABYDIAB vs. 13.9% in TEDDY. In contrast, the time for progression to T1D, calculated from the first appearance of autoantibodies, was more rapid in the more recent TEDDY cohort than in the BABYDIAB cohort: 50% progression occurred within 9.6 months in the TEDDY vs. 85 months in the BABYDIAB children. This suggests that the current increasing incidence of diabetes in young children could be related to mechanisms implicated in the progression from autoimmunity to T1D progression, which therefore represent specific targets for the development of future interventions.

New concerns
Discovering the vascular effects of hypoglycemia

Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals

Gogitidze Joy N, Hedrington MS, Briscoe VJ, Tate DB, Ertl AC, Davis SN

University of Maryland School of Medicine, Baltimore, Md.,USA.

[email protected]

Diabetes Care 2010;33:1529-35.

Background: Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. The aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with T1D and healthy individuals.

Methods: 35 healthy volunteers (19 male, age 32 ± 2 years, BMI 26 ± 2 kg/m², A1C 5.1 ± 0.1%) and 24 with T1D (12 male, age 33 ± 3 years, BMI 24 ± 2 kg/m², A1C 7.7 ± 0.2%) were studied during either a 2-hour hyperinsulinemic euglycemic or hypoglycemic clamp or both.

Results: Insulin levels were similar (602 ± 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 ± 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both T1D subjects and healthy control subjects (2.9 ± 0.1 mmol/l). Plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (p < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in ...