Type 2 diabetes (T2D) is characterized by decreased insulin secretion and action. Although many studies have reported the genetic loci/genes for susceptibility to T2D, the vast majority of genetic factors in T2D are still unknown. Mitophagy, a selective elimination system for impaired mitochondria, plays a key role in mitochondrial quality control. Defects in mitophagy that contribute to causing mitochondrial dysfunction have been recently suggested to be involved in the pathogenesis of T2D as well as in neurodegenerative diseases.
By performing a candidate-gene association analysis of the single nucleotide polymorphisms (SNPs) in the 28 mitophagy-related genes with glucose- and insulin-related quantitative traits in the Korean study cohort (7,551 subjects), I found that two SNPs, rs10455889 and rs9365294, in the PARK2 gene encoding an E3 ubiquitin-protein ligase (parkin) were significantly associated with fasting plasma glucose levels and insulin secretion indices in response to glucose stimulation in men (3,747 subjects). Replication analysis in two other Korean cohorts and a European-descendent cohort revealed that genetic variants in the PARK2 gene were associated with glucose homeostasis-related quantitative traits in three cohorts. One variant showed a meaningful linkage disequilibrium correlation to the two discovered PARK2 SNPs.
The PARK2 gene is known to be mutated in certain cases of familial Parkinson’s disease. Nevertheless, my results indicated a close relationship between the PARK2 gene and pancreatic β-cell dysfunction-related T2D. In order to prove this finding experimentally, I first investigated whether the PARK2 gene is expressed in the pancreatic tissues. Gene expression profiling of the Park2 gene in rats showed its predominant expression in the pancreatic islets as well as in the brain, skeletal muscle, and liver tissues. Next, I performed a functional analysis to investigate whether the alterations in PARK2 gene expression have an influence on insulin-producing pancreatic β-cell functions. Downregulation of the Park2 gene by RNA interference in rat INS-1 β-cells resulted in a significant decrease in the transcriptional and translational insulin gene (Ins1) expression levels and glucose-stimulated insulin secretion. The mRNA levels of the genes Pdx1, Mafa, Mafb, Nkx2-2, Nkx6-1, Pax4, and Irs1 that encode the pancreatic transcription factors were significantly decreased in the Park2-depleted INS-1 β-cells. In addition, the INS-1 β-cells lacking parkin exhibited decreased intracellular ATP level and mitochondrial membrane potential (m∆ψ) but increased reactive oxygen species production and mitochondrial fragmentation.
This finding is particularly important because I have provided both population-based statistical and experimental evidence to support the claim that the mitophagy-regulating PARK2 gene plays an important role in the maintenance of pancreatic β-cell function as well as in the maintenance of neuronal cell function.
