Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems: Pgc1b knock-out hearts

Type 2 diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting that a crosstalk between mitochondria and the insulin-signaling cascade could be involved in the etiology of TD2 and insulin resistance. In this study, we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the largest genome-wide meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found significant enrichment of T2D-associated SNPs in the genomic context of our linker genes, including four already confirmed and 14 additional SNPs, which when combined were also associated with increased fasting glucose levels according to MAGIC genome-wide meta-analysis (p = 2.8 x 10-7). This study highlights the potential of combining systems biology, experimental, and genome-wide meta-analyses mining for identifying novel genetic variants that increase vulnerability to complex diseases.

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