Sarm1 and diabetic complications in adolescents with type 1 diabetes
Erica Scheller   (Saint Louis, MO)
In America, there are 1.6 million people living with type 1 diabetes (T1D), including nearly 200,000 children and adolescents. Young adults with T1D often have difficulty maintaining adequate glycemic control relative to other age groups, putting them at increased risk for early development of diabetic complications in systems including nerve and bone. Therapies that can be used to simultaneously prevent or to reverse multiple diabetic complications during times of glycemic instability, beginning in childhood and adolescence and continuing throughout the lifespan, are needed to promote lifelong health and healthy aging in patients with T1D. Sarm1 (sterile a and TIR motif-containing protein-1) is homomultimeric cytoplasmic protein with NADase and ADP-ribosyl cyclase activity. Sarm1 is a metabolic biosensor that is activated by injury, inflammation, and oxidative stress. When activated, Sarm1 promotes the progression of diabetic peripheral neuropathy. In addition, we have recently discovered that Sarm1 drives bone loss and skeletal instability in mice with T1D. Progression of DPN often tracks with fracture risk, suggesting shared underlying mechanisms of development and/or direct relationships between nerve and bone health. In humans, as in mice, we hypothesize that increases in Sarm1 expression and activation occur in adolescents with poorly controlled T1D in response to inadequate glycemic control, contributing to the early onset and progression of diabetic complications in nerve and bone. To test this hypothesis while obtaining foundational preliminary data for future longitudinal studies, we will pursue two specific aims. First, we will quantify Sarm1 expression and activation in adolescents with T1D relative to non-diabetic controls. Second, we will explore the relationship between Sarm1, neuropathy, and bone quality. This is timely because Sarm1 inhibitors are currently in preclinical development for treatment of peripheral nerve damage. Our goal is to define young patients with T1D that may benefit from future use of Sarm1 inhibitors as a clinical strategy to prevent diabetic complications across multiple systems including nerve and bone.