Metabolic interventions as adjunctive therapies to insulin in type 1 diabetes: Current clinical landscape and perspectives.

Type 1 diabetes (T1D) is classically characterized as an autoimmune disease wherein the immune system erroneously attacks insulin-producing pancreatic β-cells, causing insulin insufficiency and severe metabolic dysregulation. However, intensive investigation and numerous clinical trials with immunotherapies have been largely unable to significantly alter the course of disease. Currently, there is no effective way to prevent or cure T1D, and insulin remains the cornerstone of T1D treatment. In recent years, a growing body of research suggests that β-cells actively contribute to the immune response and to disease development. Factors including glucotoxicity, lipotoxicity, inflammation, endoplasmic reticulum (ER) and oxidative stress can induce β-cell apoptosis and senescence, further promoting insulitis. Recent studies highlight the importance of targeting metabolic control for T1D management and treatment. Metabolic interventions, through their direct and indirect impacts on β-cells, have shown promise in preserving β-cell function. These interventions can reduce glucose toxicity, alleviate oxidative stress and inflammation, enhance insulin sensitivity, and indirectly mitigate the autoimmune responses. By preserving β-cell function, individuals with T1D attain better glycaemic control, reduced complication risks and exhibit improved overall metabolic health. Here, we provide an overview of insights from clinical studies, systematic reviews and meta-analyses that collectively demonstrate that adjunctive metabolic interventions can enhance glycaemic control, reduce insulin requirements and mitigate adverse effects associated with insulin monotherapy. They also show potential for halting disease progression, preserving residual β-cell function and improving long-term outcomes for newly diagnosed individuals. Future research should focus on optimizing these treatment strategies and establishing their long-term efficacy and safety.