Precision Medicine in Patients with Differential Diabetic Phenotypes: Novel Opportunities from Network Medicine

Introduction: Diabetes mellitus (DM) comprises differential clinical phenotypes ranging from rare monogenic to common polygenic forms, such as type 1 (T1DM), type 2 (T2DM), and gestational diabetes, which are associated with cardiovascular complications. Also, the high- -risk prediabetic state is rising worldwide, suggesting the urgent need for early personalized strategies to prevent and treat a hyperglycemic state. Objective: We aim to discuss the advantages and challenges of Network Medicine approaches in clarifying disease-specific molecular pathways, which may open novel ways for repurposing approved drugs to reach diabetes precision medicine and personalized therapy. Conclusion: The interactome or protein-protein interactions (PPIs) is a useful tool to identify subtle molecular differences between precise diabetic phenotypes and predict putative novel drugs. Despite being previously unappreciated as T2DM determinants, the growth factor receptor-bound protein 14 (GRB14), calmodulin 2 (CALM2), and protein kinase C-alpha (PRKCA) might have a relevant role in disease pathogenesis. Besides, in silico platforms have suggested that diflunisal, nabumetone, niflumic acid, and valdecoxib may be suitable for the treatment of T1DM; phenoxybenzamine and idazoxan for the treatment of T2DM by improving insulin secretion; and hydroxychloroquine reduce the risk of coronary heart disease (CHD) by counteracting inflammation. Network medicine has the potential to improve precision medicine in diabetes care and enhance personalized therapy. However, only randomized clinical trials will confirm the clinical utility of network- oriented biomarkers and drugs in the management of DM.