MANATEE-T1D: Metformin ANd AutomaTEd insulin delivery system Effects on renal vascular resistance, insulin sensitivity, and cardiometabolic function in youth with Type 1 Diabetes

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PROJECT SUMMARY/ABSTRACT: Diabetic kidney disease (DKD) and cardiovascular disease (CVD) remain the leading causes of morbidity and mortality in people with type 1 diabetes (T1D) and are exacerbated with longer duration of diabetes and time outside goal glycemic range. Yet, T1D is a complex disease with pathophysiology that extends beyond -cell injury and insulin deficiency to include insulin resistance (IR) and renal vascular resistance (RVR), factors that accelerate CVD risk. We have shown that metformin improved peripheral insulin sensitivity (IS) and vascular stiffness in youth with T1D on multiple daily insulin injections (MDI) or standard insulin pumps. However, metformin’s effect on kidney and endothelial outcomes, and the effects of T1D technologies, with or without metformin, on any CV or kidney outcome, remains unknown. Automated insulin delivery (AID) systems combine an insulin pump, continuous glucose monitor (CGM), and control algorithm to modulate background insulin delivery and decrease peripheral insulin exposure while improving time in target range and reducing hypoglycemia. We hypothesize that AID systems, particularly when combined with metformin, may modulate RVR and IS, thereby impacting cardiometabolic function. MANATEE-T1D is a randomized, double-blind, placebo-controlled trial of 4 months of metformin 2,000 mg daily in 30 youth aged 12-21 years with T1D on AID systems vs. 15 control youth with T1D on MDI/CGM which will assess for changes in calculated RVR and gold standard measures of whole-body and adipose IS, arterial stiffness, and endothelial function. As an Instructor/Fellow in Pediatric Endocrinology with a strong publication and grant funding record, I am establishing myself in the burgeoning field of T1D technologies by developing a unique niche studying the effects of diabetes technologies, with or without combination pharmacological therapies, on IS and kidney and cardiovascular complications in youth with T1D. A K23 would support the following research goals: 1) define longitudinal differences in RVR by p-aminohippurate clearance and IS by hyperinsulinemic-euglycemic clamp in youth with T1D on metformin and AID systems, 2) test for associations between RVR and IS, 3) evaluate for in vivo and ex vivo endothelial function changes with metformin and AID systems. My career development plan includes dedicated time to 1) train in the performance and analysis of gold standard translational research methods for RVR, IS, arterial stiffness, and endothelial function, 2) gain experience conducting patient-oriented research studies including study design and execution, data collection and analysis, and personnel management, 3) work with a multidisciplinary team of experts in Endocrinology, Nephrology, and Biostatistics, and 4) establish the foundation for an independent research career aimed at developing novel technologies while leveraging existing therapies to mitigate the risk for DKD and CVD across the lifespan. My training environment will be outstanding with mentorship from Drs. Kristen Nadeau (Professor, Ped. Endocrinology) and Jessica Kendrick (Professor, Nephrology), experts in clinical trials, diabetes, IS, DKD, and CVD.