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DiaComp Funded Abstracts

Program Application Abstract
Role of insulin signaling in the development of insulin neuritis
Hu, Rebecca   (University of California San Diego)
The most common complication of long-­term diabetes is neuropathy, and approximately 30% of diabetic patients with neuropathy develop chronic neuropathic pain. A significant percentage of these patients develop insulin neuritis, also called acute painful diabetic neuropathy of rapid glycemic control (APDNRGC), a distinct acute and severe form of neuropathic pain. This debilitating condition is refractory to all currently available therapeutic interventions used to treat classical diabetic painful neuropathy. There are no targeted treatments, in part because of the condition’s uncertain pathophysiology. We have developed a model of insulin neuritis for type 1 diabetes. Streptozotocin (STZ)-­diabetic mice were treated daily with 1U of insulin and tactile responses to von Frey filaments were measured 24 hours following the last injection. The onset of tactile allodynia was observed in mice after 8 days of daily insulin treatment and persisted up to 50 days. Ex-­vivo incubations of STZ-­diabetic rat sciatic nerve with different doses of insulin (0.0, 0.1 or 1.0 nM) showed that 3 months of untreated diabetes led to sensitization of insulin receptors while total insulin receptor protein levels remained unchanged. To test our hypothesis that insulin neuritis results from enhanced insulin signaling, AKT inhibitor IV (2 mg/kg intraperitoneal) was injected along with the daily dose of insulin in STZ-­diabetic mice and found to have an acute, but not chronic, effect on alleviating tactile allodynia. We are currently testing whether inhibiting other elements of the insulin signaling pathway, such as glycogen synthase kinase 3 (GSK3), are effective at alleviating insulin-­induced allodynia. In parallel, we are validating whether our model is representative of the human condition by testing gabapentin, one of the first line treatments for classical diabetic painful neuropathy that has a limited efficacy for patients suffering from insulin neuritis. Additionally, ongoing studies are being conducted to assess whether the administration of C peptide, an endogenous peptide released at equimolar concentration with insulin in non-­ diabetic conditions and lacking in type 1 diabetes, alters the development of insulin neuritis.