Pre-transplant Aerobic Exercise Improves Glycemic Outcomes After Marginal Islet Mass Transplantation in Rats

Pancreatic islet transplantation (ITx) improves glycemic management and prevents severe hypoglycemia in select individuals with type 1 diabetes (T1D). However, insulin independence cannot be guaranteed due to transplant and recipient-specific factors, limiting broad application. Exercise improves insulin sensitivity, reduces chronic inflammation, increases insulin-independent glucose uptake, and can decrease the risk of surgery-related complications. Therefore, we examined the utility of pre-transplant exercise in the context of ITx on metabolic and immune outcomes. Streptozotocin (STZ)-induced diabetic rats performed voluntary, 1-hour wheel-running exercise in an overnight-fasted state on three non-consecutive days weekly for four weeks preceding transplantation. Exercised (RUN, n=7) and sedentary (SIT, n=6) rats underwent marginal syngeneic ITx. Graft efficacy was compared with non-fasted blood glucose readings and a 4-week intraperitoneal glucose challenge. At four weeks post-transplant, 100% (7/7) of RUN rats became euglycemic compared to 66% (4/6) in the SIT condition ( P<0.05). RUN recipients demonstrated superior non-fasting blood glucose and weight gain ( P<0.05) and comparable glucose tolerance to naïve rats, while SIT rats had inferior clearance ( P<0.05), despite comparable proportions of insulin and glucagon graft-positive cells. Reduction in RUN adipose tissue macrophages suggests lower inflammation levels alongside greater insulin sensitivity based on QUICKI ( P<0.01). Moreover, the soleus muscle of RUN recipients had lower levels of pyruvate dehydrogenase phosphorylation at serine 232 ( P<0.05), and increased levels of phosphorylated glycogen synthase kinase ( P<0.05), suggestive of increased carbohydrate oxidation and insulin signaling, respectively. Altogether, we demonstrate that pre-transplant exercise may enhance glycemic outcomes in ITx due to lower inflammation levels and increased carbohydrate oxidation.