Insulin Secretion Defect in Children and Adolescents with Obesity: Clinical and Molecular Genetic Characterization.

Introduction: Childhood obesity is increasing worldwide and presents as a global health issue due to multiple metabolic comorbidities. About 1% of adolescents with obesity develop type 2 diabetes (T2D); however, little is known about the genetic and pathophysiological background at young age. The objective of this study was to assess the prevalence of impaired glucose regulation (IGR) in a large cohort of children and adolescents with obesity and to characterize insulin sensitivity and insulin secretion.

HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion.

Background: Studying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating β-cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis.

Methods: We performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease-causing HDAC4 variant (p.

Alu elements and human common diseases like obesity.

In the past few years the epigenetic impact on human diseases has been studied extensively. However, a controversial debate remains about the influence of environmental factors on the genetic determination of DNA methylation patterns. Although DNA methylation defects have been described in imprinting diseases and linked to cancer development, its impact on common diseases like obesity has yet to be elucidated.

An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity.

The individual risk for common diseases not only depends on genetic but also on epigenetic polymorphisms. To assess the role of epigenetic variations in the individual risk for obesity, we have determined the methylation status of two CpG islands at the POMC locus in obese and normal-weight children. We found a hypermethylation variant targeting individual CpGs at the intron 2-exon 3 boundary of the POMC gene by bisulphite sequencing that was significantly associated with obesity.

Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets.

Leptin inhibits insulin secretion from pancreatic β-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion.