Abstract
Diabetes and obesity are a growing healthcare and socioeconomic crisis of unprecedented proportions. Driven in part by the westernization of diets around the world, the prevalence of individuals with type 2 diabetes alone is projected to exceed 1.3 billion by 2050. Glucagon-like peptide 1 (GLP1) receptor agonists offer transformative therapeutic potential but are challenged by gastrointestinal side effects due to pharmacokinetic spikes from repeated injections, resulting in discontinuation rates which approach 70% by the first anniversary of treatment initiation. To overcome the repeat-injection nature of current GLP1 therapies, we developed a novel, subcutaneously injectable, lipid nanoparticle-based DNA delivery system to administer and express exendin 4 (EX4) or a modified natural GLP1 peptide in obese diabetic mice. The treatment was well tolerated, durable, and the transgene remained localized to the subcutaneous area of injection for over 6 months. The expressed EX4 and GLP1 promoted weight loss and decreased food intake, while reducing insulin resistance and improving glycemic control. Changes in the transcriptomic profile indicated that efficacy was mediated via the GLP1 receptor pathway, and blood-based biomarkers of liver and pancreatic function, systemic inflammation, and muscle injury confirmed that the treatment was systemically well tolerated.