Disease-modifying pharmacological treatments of type 1 diabetes (T1D): Molecular mechanisms, target checkpoints and possible combinatorial treatments.

After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet β-cells, significant research has recently demonstrated that β-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. SIGNIFICANCE STATEMENT: This research delves into the underlying causes of T1D and identifies critical mechanisms governing β-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting β-cells, (3) compounds that act simultaneously on both immune cell and β-cell pathways, and (4) combinations of compounds simultaneously targeting immune and β-cell pathways.