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

• Published in: Molecular and cellular endocrinology Vol. 382; no. 1; pp. 178 - 189
• Main Authors: Jin, Hyun-Seok, Kim, Jeonghyun, Lee, Soo-Jin, Kim, Kyunga, Go, Min Jin, Lee, Jong-Young, Lee, Hye-Ja, Song, Jihyun, Jeon, Byeong Tak, Roh, Gu Seob, Kim, Sung-Jun, Kim, Bo-Young, Hong, Kyung-Won, Yoo, Young-Hyun, Oh, Beomseok, Kang, Yup, Jeong, Seon-Yong
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 25.01.2014
• Subjects: Adenosine Triphosphate - metabolism; Adult; Aged; Animals; ATP; Cohort Studies; Gene Expression Profiling; Gene Knockdown Techniques; Genes; Genetic association; Glucose; Humans; Insulin; Insulin - biosynthesis; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Maintenance; Male; Males; Middle Aged; Mitochondria; Mitochondria - metabolism; Nucleotides; Pancreatic β-cell; PARK2; Polymorphism, Single Nucleotide - genetics; Quantitative Trait, Heritable; Rats; Secretions; Type 2 diabetes; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Type 2 diabetes; Mitochondria; Pancreatic β-cell; Genetic association; PARK2; Insulin secretion
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2013.09.031

•Two PARK2 SNPs are associated with fasting blood glucose and insulin secretion.•The Park2-depleted rat β-cells exhibit decreased insulin production and secretion.•Knockdown of Park2 gene by RNAi causes mitochondrial alterations in rat INS-1 β-cells.•PARK2 gene plays an important role in the maintenance of pancreatic β-cell function. 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=∼1.2×10−4) and insulin secretion indices (p=∼7.4×10−5) in male KARE subjects. Parkin was expressed predominantly in the rat pancreatic islets. Downregulation of the Park2 gene in rat INS-1 β-cells resulted in a significant decrease in the glucose-stimulated insulin secretion, intracellular insulin gene expression, and intracellular ATP level. The Park2-depleted β-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 β-cell function.