BETA-JUDO

Beta-cell function in juvenile diabetes and obesity

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 Obiettivo del progetto (Objective)

'The number of individuals with obesity and type 2 diabetes mellitus (T2DM) is increasing. An alarming aspect is decline in age of onset of T2DM, which is coupled to rise in childhood obesity. Accentuated insulin secretion is observed early in young obese individuals. In many subjects insulin hypersecretion is evident when insulin sensitivity is essentially normal. Based on these observations we propose insulin hypersecretion as an etiological factor promoting lipid deposition, insulin resistance, cellular dysfunction and death in insulin-producing beta-cells and insulin-target brown adipocytes. Pharmacology-based treatment strategies are limited for this growing patient group and the aim of the proposal is to identify novel strategies reducing insulin hypersecretion, which has not been considered a target for intervention in young obese individuals. To address the issue, pediatric obesity clinics and academic centres with focus on beta-cell biology, brown adipocyte imaging, transcript and protein profiling, genetics, epidemiology and bioinfomatics have formed a consortium with two SMEs specialized on biomarker discovery and clinical trials and one large drug company. In the project well-characterized European patient cohorts of more than 3000 obese children will be further characterized with regard to insulin secretion and brown adipocyte mass. Currently used drugs and new principles of intervention based on novel genes, idenitifed in the project and linked with insulin hypersecretion, will be examined for effects on insulin hypersecretion in translational work including the young obese subjects and isolated human islets. Following comprehensive analysis candidate compounds/principles attenuating insulin hypersecretion will be selected, from which novel therapeutic strategies are expected to emerge. Such therapeutic strategies will be of importance for afflicted individuals and European health economy and lead to new opportunities for European industry.'

Introduzione (Teaser)

Type 2 diabetes mellitus (T2DM) is increasingly prevalent among children due to a concomitant rise in obesity. Obtaining insight into the interplay between the two conditions could lead to the development of much-needed therapeutic interventions.

Descrizione progetto (Article)

T2DM is a metabolic disorder where the body is unable to produce or utilise insulin effectively. Since high insulin levels favour storage rather than combustion of energy, individuals with accentuated insulin responses could be at risk of developing obesity and T2DM.

To delineate if high insulin levels is an early phenomenon that dictates obesity development, the EU-funded 'Beta-cell function in juvenile diabetes and obesity' (http://www.betajudo.org (BETA-JUDO)) project is pursuing a translational approach. By bringing together researchers and clinicians across Europe, the project hopes to answer key questions regarding elevated insulin levels in young obese individuals. Additional objectives of the study include the elucidation of genetic predisposition factors alongside the development of pharmacological interventions.

Scientists are performing oral glucose tolerance tests in obese and normal weight children to characterise insulin secretion. Genetic analysis aims at identifying genes potentially associated with insulin traits in obese children. When obese children with high insulin levels were followed up, a drop in insulin levels could be observed. Some of these individuals developed T2DM.

A considerable part of the BETA-JUDO work is focused on the molecular mechanisms responsible for insulin hypersecretion from human pancreatic islets. An in vitro model for insulin hypersecretion, where islet cells are cultured, has been established and partners are in the process of evaluating various drugs that could normalise the aberrant phenotype. Additional characteristics associated with insulin hypersecretion are also being evaluated such as circulating levels of free fatty acids, as well as white and brown fat cells.

Taken together, the BETA-JUDO study will generate important knowledge on the association between insulin hypersecretion and childhood obesity. Project activities should help reduce obesity rates in Europe through increased awareness about the dismal outcome of childhood obesity and the importance of intervention strategies.