The PARK2 gene is involved in the maintenance of pancreatic β-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= approximately

1.2x10(-4)) and insulin secretion indices (p= approximately 7.4x10(-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.