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In animal models, C2 supplementation promoted neuroplasticity, synthesis of neurotrophic factors, modulation of glutamatergic dysfunction, reversal of neuronal atrophy in regions like the hippocampus and amygdala, and improvement in depression-like behavioral symptoms [20, 30, 57, 58]

Key Points As several mechanisms lead to -cell failure in type 1 diabetes mellitus (T1DM), strategies combining different molecules could target different pathways involved in the pathogenesis of T1DM Different combination therapies have been tested in preclinical studies with encouraging results, but results from clinical trials have not matched expectations Heterogeneity in the age of patients with T1DM and the low rate of human -cell regeneration are possible explanations for the negative results of clinical trials that should be addressed in future studies Proton pump inhibitors and incretin-based agents can stimulate -cell regeneration, so future trials in patients with T1DM should investigate their potential in combination with immunomodulatory compounds The issue of patient heterogeneity can be addressed by designing trials evaluating the relative effectiveness of interventions in specific subgroups of patients Abstract Immunotherapies for type 1 diabetes mellitus (T1DM) have been the focus of intense basic and clinical research over the past few decades

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