Executive summary, entire project

The project “Beta-cell function in Juvenile Diabetes and Obesity” (Beta-JUDO) aimed at investigating the role of the insulin-producing beta-cell in development of obesity and type 2 diabetes mellitus (T2DM) in children. The rationale behind the project was that accentuated insulin response (insulin hypersecretion) is an early phenomenon promoting development of overweight and insulin resistance, since high insulin levels favours storage rather than combustion of energy. Individuals with this secretory phenotype are therefore at risk of developing obesity and T2DM. The project was organised in a translational approach involving studies of obese children and beta-cells from isolated human islets of Langerhans. In Beta-JUDO, paediatric obesity clinics and academic centres with focus on treatment of obese children, beta-cell biology, protein and transcript profiling, genetics, and bioinformatics formed a consortium together with a large drug company and small companies (SMEs) specialized on biomarker discovery and clinical trials.

The overall aim of the project was to identify new pharmacological approaches to normalize the high insulin levels observed in obese children and children of risk to become obese. The aim was addressed by, firstly, defining factors and molecular mechanisms that contribute to insulin hypersecretion, and secondly, to address ways to counteract insulin hypersecretion by investigating pharmacological principles potentially targeting insulin hypersecretion in both isolated islets and in obese children.

Factors contributing to insulin hypersecretion included high circulating levels of the free fatty acid (FFA) palmitate, which were high in obese children with accentuated insulin hypersecretion. Correspondently, in isolated islets such elevated palmitate levels caused accentuated glucose-stimulated insulin secretion. The findings supported a role of elevated levels of palmitate as an underlying factor contributing to insulin hypersecretion. We found that palmitate enhanced islet respiration, which was closely linked with islet insulin hypersecretion. In obese children raised glucagon levels were compatible with a role of altered glucagon response in obese children contributing to hyperinsulinemia. In genetic studies using large obesity cohorts we identified a number of genes that are associated with insulin hypersecretion, such as the gene PCSK1 that is involved in insulin processing. Further underlying factors for islet insulin hypersecretion were found by generating extensive protein and transcript expression patterns.

Strategies to counteract insulin hypersecretion included free fatty acid receptor 1 (FFAR1) antagonism, which normalized insulin hypersecretion from isolated islets exposed to palmitate. FFAR1 may represent a prevention strategy/therapy in subjects with high palmitate levels, but no FFAR1 antagonists are currently available for clinical use. GLP-1 receptor agonism showed promise in normalizing insulin hypersecretion. There are several available clinical intervention options using GLP-1 agonism. Indeed, we have conducted the first extended placebo-controlled, double-blinded intervention trial, where the GLP-1 analogue exenatide was administered to obese adolescents. Significant reduction in weight was observed with no rise in adverse events compared to placebo. The trial will potentially supply this patient group a novel pharmacological alternative.

The Beta-JUDO project has developed a cohort counting to about 700 obese children with detailed phenotype and blood samples collected over time including subjects that develop T2DM. The cohort provides unique possibilities to delineate early events in obesity-related T2DM and identify prognostic markers for subjects at risk. A definition of insulin hypersecretion in obese children has been proposed, which was used when genetic markers for insulin hypersecretion were identified.