Identification of Probucol as a candidate for combination therapy with Metformin for Type 2 diabetes

Type 2 Diabetes (T2D) is often managed with metformin as the drug of choice. While it is effective overall, many patients progress to exhibit complications. Strategic drug combinations to tackle this problem would be useful. We constructed a genome-wide protein-protein interaction network capturing a global perspective of perturbations in diabetes by integrating T2D subjects' transcriptomic data. We computed a 'frequently perturbed subnetwork' in T2D that captures common perturbations across tissue types and mapped the possible effects of Metformin onto it. We then identified a set of remaining T2D perturbations and potential drug targets among them, related to oxidative stress and hypercholesterolemia. We then identified Probucol as the potential co-drug for adjunct therapy with Metformin and evaluated the efficacy of the combination in a rat model of diabetes. We find Metformin-Probucol at 5:0.5 mg/kg effective in restoring near-normal serum glucose, lipid, and cholesterol levels.

Automated summary

Type 2 Diabetes (T2D) is commonly treated with metformin, but many patients still develop complications. By analyzing transcriptomic data of T2D subjects, we constructed a protein-protein interaction network that captures the global perturbations in diabetes. We identified possible drug targets related to oxidative stress and hypercholesterolemia and proposed Probucol as a potential co-drug with metformin. In a rat model of diabetes, the combination of metformin and Probucol at 5:0.5 mg/kg effectively restored near-normal levels of glucose, lipids, and cholesterol.