Abstract
The pathogenic mechanisms causing type 2 diabetes (T2D) are still poorly understood; a greater awareness of its causation can lead to the development of newer and better antidiabetic drugs. In this study, we used a network-based approach to assess the cellular processes associated with protein–protein interaction subnetworks of glycemic traits—HOMA-β and HOMA-IR. Their subnetworks were further analyzed in terms of their overlap with the differentially expressed genes (DEGs) in pancreatic, muscle, and adipose tissue in diabetics. We found several DEGs in these tissues showing an overlap with the HOMA-β subnetwork, suggesting a role of these tissues in β-cell failure. Many genes in the HOMA-IR subnetwork too showed an overlap with the HOMA-β subnetwork. For understanding the functional theme of these subnetworks, a pathway-to-pathway complementary network analysis was done, which identified various adipose biology-related pathways, containing genes involved in both insulin secretion and action. In conclusion, network analysis of genes showing an association between T2D and its intermediate phenotypic traits suggests their potential role in beta cell failure. These genes enriched the adipo-centric pathways and were expressed in both pancreatic and adipose tissue and, therefore, might be one of the potential targets for future antidiabetic treatment.
Highlights
The current epidemic of diabetes presents a challenge to the global healthcare system
This large difference in the number of genes between HOMA-β and HOMA-IR strengthens the hypothesis that defects in insulin secretion are caused by a large number of genes and may have a large genetic component, while insulin resistance may largely be induced by environmental factors [15]
A total of 1360 HOMA-β-associated genes overlapped with the type 2 diabetes (T2D) interactome showing that almost 61% of the network nodes are functionally associated with the insulin secretion-related trait of T2D, while only 24 HOMA-IR (∼8%) genes were mapped to the T2D interactome network
Summary
The current epidemic of diabetes presents a challenge to the global healthcare system. It has been speculated that by 2045 over 629 million people will have diabetes [1], and as per the International Diabetes Federation, type 2 diabetes (T2D) would account for over 90% of these patients This alarming situation can be attributed to our inadequate understanding of the diverse pathogenic processes involved at the molecular level that converge into two well-defined intermediate glycemic traits—impaired insulin secretion by the pancreatic beta cells and insulin resistance in peripheral tissues. Understanding these underlying mechanisms wouldhugely benefit in the designing of better antidiabetic agents to treat T2D and its associated micro-vascular (nephropathy, neuropathy, and retinopathy) and macro-vascular (atherosclerosis and cardiovascular) complications. Even though several hundred susceptibility loci for T2D have been identified using genome-wide association studies (GWAS), the y account for only about 20%–30% of the heritability of T2D, with the remaining “missing heritability” being attributed to rare or small effect variants, epistasis, gene–environment interaction epigenetic changes, etc. [2]
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