Type 1 diabetes mellitus (T1DM) is caused by autoimmune β-cell destruction, with insulin as the mainstay of treatment, while adjunctive oral hypoglycemic agents (OHGAs) are not routinely recommended due to limited evidence and safety concerns. Mitochondrial dysfunction is increasingly recognized as a key contributor to β-cell loss and disease progression. This scoping review aims to comprehensively examine the existing literature on the role of OHGAs in T1DM, with a particular focus on mitochondrial dysfunction. By integrating molecular insights with clinical data, this review seeks to clarify the potential therapeutic benefits and risks of OHGAs in T1DM. This approach may help inform future research directions and clinical practice.

This review was conducted according to Preferred Reporting Items for Scoping Reviews and Meta-Analyses (PRISMA) guidelines, with systematic searches of PubMed, SCOPUS, BIOSIS, and Web of Science up to June 2025 using terms related to T1DM, mitochondria, and OHGAs. Two reviewers independently screened and extracted data on study design, populations, OHGAs, and mitochondrial outcomes. Eligible studies addressed either T1DM–mitochondrial links or OHGAs effects on mitochondria. A summary of the overall selection process is presented in the PRISMA flow diagram (Figure 1).

Out of 984 screened articles, 26 studies were included: 16 on mitochondrial dysfunction in T1DM and 10 on the effects of OHGAs on mitochondria. T1DM studies highlighted key mechanisms such as oxidative stress, impaired ATP production, apoptosis, disrupted proteostasis, altered mitochondrial dynamics, and dysregulated miRNAs. OHGAs—including imeglimin, thiazolidinediones, sulfonylureas, metformin, SGLT2 inhibitors, and GLP-1 receptor agonists—demonstrated mitochondrial benefits by improving bioenergetics, reducing oxidative stress, preserving membrane potential, and modulating metabolic pathways. These findings suggest potential therapeutic roles for OHGAs in mitigating mitochondrial dysfunction in T1DM.

Mitochondrial dysfunction in T1DM contributes to β-cell failure and diabetes-related complications through impaired ATP production, oxidative stress, disrupted calcium handling, altered dynamics, and proteostasis. While insulin remains the primary treatment, OHGAs—such as metformin, imeglimin, pioglitazone, and GLP-1 receptor agonists—show potential to mitigate mitochondrial dysfunction by enhancing bioenergetics, reducing oxidative stress, and promoting mitochondrial biogenesis. Evidence is largely preclinical or derived from type 2 diabetes mellitus (T2DM) models, with limited clinical trials in T1DM, often using surrogate endpoints. Further well-designed in vitro and clinical studies are needed to clarify mechanisms, assess efficacy, and explore OHGAs as mitochondrial-targeting therapies in T1DM.