Network analysis to trace the common key gene (s) involved in antihyperglycemic effects mediated through co-supplementation of Vitamin D and Metformin

Metformin, an antihyperglycemic drug has been known for centuries as the first treatment for diabetes mellitus. Likewise, vitamin D is also recognized for its role in boosting insulin action and improving insulin sensitivity. There is also evidence supporting their combined effect as an antihyperglycemic agent. However, key genes associated with their combined antihyperglycemic effect have not been explored yet. Thus, our in-silico study aims to explore the key genes associated with metformin and VDR signaling that could aid in managing hyperglycemia as well as explore other health benefits. We have used a systems biology approach for the construction of the metformin-VDR network and it was found to be hierarchical scale-free in nature. The statistical parameters including node degree distribution, and clustering coefficient, were calculated. Out of the several prominent hubs, which served as the network's backbone and contained several critical regulators as well as potential target genes, we were able to identify a few key regulators. Modules with comparable functions were also identified. We found the top 14 key regulators namely G0S2, DDIT4, IL6, PRKAA1, EGFR, mTOR, PPARGC1A, CYBA, CYBB, NCF1, NCF2, NCF4, NOX1 and NOX3. While reviewing the function of these key genes and their association with vitamin D and/or metformin, most of these genes were analyzed to be involved in regulating glucose levels as well as alleviating hyperglycemia-induced inflammation and oxidative stress. Based on the prediction from our study, these key regulatory genes may be proposed to be involved in the combined antihyperglycemic effects of vitamin D and metformin. These genes mayfurther be explored as a probable therapeutic target for the management of diabetes as well as accompanying disorders.