The PARK2 gene is involved in the maintenance of pancreatic beta-cell functions related to insulin production and secretion

Abstract

Several association studies have implicated the PARK2 gene that encodes parkin - the key molecule orchestrating the mitochondrial quality control system - as a candidate susceptibility gene for diabetes. A total of 7551 unrelated Korean KARE cohort subjects were analyzed to investigate the association between the PARK2 single nucleotide polymorphism (SNP) and quantitative glycemic traits. Two SNPs, rs10455889 and rs9365294, were significantly associated with fasting plasma glucose level (p = similar to 1.2 x 10(-4)) and insulin secretion indices (p = similar to 7.4 x 10(-5)) in male KARE subjects. Parkin was expressed predominantly in the rat pancreatic islets. Downregulation of the Park2 gene in rat INS-1 beta-cells resulted in a significant decrease in the glucose-stimulated insulin secretion, intracellular insulin gene expression, and intracellular ATP level. The Park2-depleted beta-cells also exhibited increased mitochondrial fragmentation and ROS production and decreased mitochondrial membrane potential. Both population-based statistical evaluation and experimental evidence demonstrated a fundamental role of the PARK2 gene in the maintenance of beta-cell function. (C) 2013 Elsevier Ireland Ltd. All rights reserved.