Optimizing Stage 2 T1DM Management: Assessing the Impact of GLP-1Ra on Metabolic Outcomes in Patients Receiving Teplizumab

This proposal aims to explore the metabolic advantages and mechanisms of glucagon-like peptide-1 receptor agonists (GLP-1Ra) in individuals with stage 2 type 1 diabetes (T1DM) undergoing treatment with teplizumab, an immunomodulatory therapy. Stage 2 T1DM represents a critical juncture where interventions could potentially slow β-cell decline, delay the need for exogenous insulin therapy, and improve long-term outcomes. Our study seeks to address current knowledge gaps concerning the role of GLP-1Ra in modifying the disease progression of T1DM. We are particularly interested in understanding how the insulinotropic and glucagonostatic effects of GLP-1Ra can rectify metabolic derangements during this early stage in T1DM. Our study's significance lies in challenging the current treatment paradigm, primarily centered on immunomodulation, by proposing an innovative combination of GLP-1Ra and teplizumab in stage 2 T1DM. The capacity of GLP-1Ra to enhance glucose-dependent insulin secretion and suppress glucagon release could present beneficial metabolic outcomes for T1DM patients, especially when combined with teplizumab. Addressing the current knowledge gaps about this combined therapy could pave the way for the development of more effective and personalized treatment strategies. Our proposal introduces several novel elements in the treatment of early-stage T1DM and the understanding of disease mechanisms. The research explores a new use of GLP-1Ra in early-stage T1DM, repurposing a treatment initially developed for T2DM. By investigating the potential benefits of combining these therapies in a population where their combined effects have not been fully explored, our study contributes to shifting the prevailing paradigm of early-stage T1DM treatment. To achieve our objectives, we have designed a randomized, double-blind, placebo-controlled, mechanistic crossover study. We will quantify postprandial hyperglycemia, disposition index, and nitric-oxide mediated endothelial function during mixed meal tolerance test studies. We will recruit volunteers from Vanderbilt's Type 1 Diabetes Immunotherapy Clinic. The goals of this study will yield novel insights into GLP-1Ra’s insulinotropic and glucagonostatic effects and their individual contributions to improving metabolism outcomes in stage 2 T1DM patients. As a pilot and feasibility study, this research will provide key information and experience for the design of a future, fully-powered study. This includes refining the recruitment process, optimizing the study design, and generating preliminary data to inform the full-study’s data analysis plan. Our findings will help address the Dual Derangements of diminishing insulin secretion and detrimental hyperglucagonemia present in stage 2 T1DM, guiding the development of more effective, personalized treatment strategies. Thus, our research will lay the groundwork for future therapies and significantly contribute to the broader field of T1DM management.