Peripheral Neuropathy (PN) is one of the most common complications of diabetes worldwide, affecting up to 60% of diabetic patients. Despite strict glycemic control, the risk of PN persists in approximately 30% of type 1 diabetic (T1D) patients. Understanding the role of insulin in PN is therefore critical to designing adjunct therapies that can slow or reverse disease progression. In this study, we aimed to determine the effect of insulin replacement therapy on nerve function and identify metabolic and molecular changes in plasma and nerves of T1D mice that are not improved following euglycemia. Terminal metabolic and neuropathy phenotyping was performed in Streptozotocin (STZ)-induced T1D mice, treated with insulin for 12 weeks. Oxidative stress was quantified in plasma and sciatic nerve. DNA methylation and protein expression of key insulin signaling markers were also determined in dorsal root ganglia (DRG). T1D mice developed hyperglycemia, hypertriglyceridemia, reduced plasma insulin, PN, systemic and nerve oxidative stress. Additionally, DRG isolated from T1D mice exhibited hypermethylation and reduced insulin signaling. Insulin replacement therapy normalized glycemia and triglyceride levels, but induced hyperinsulinemia and markers of oxidative stress. While insulin treatment did not reverse large fiber neuropathy, it improved small fiber and sensory nerve function. This protective effect was accompanied with a restoration of methylation levels and insulin signaling markers in DRG. Our findings show that insulin treatment ameliorates small fiber function by correcting methylation and insulin signaling. However, we show that insulin treatment fails to rescue large fiber deficit, which is mediated at least in part by hyperinsulinemia and systemic oxidative stress. Accordingly, these results suggest that in addition to metabolic control, restoring oxidative balance may represent an adjunct therapy to fully prevent PN in T1D.
S. Eid: None. L.M. Hinder: None. J.M. Hayes: None. F. Mendelson: None. E.L. Feldman: Consultant; Self; Novartis Pharmaceuticals Corporation.
American Diabetes Association (7-12-BS-045 to E.L.F.); JDRF; Rose C. and Nathan L. Milstein Family Emerging Scholar Fund; A. Alfred Taubman Medical Research Institute