106-OR: Degludec-Like Insulin Analog Improves Peripheral Neuropathy More than Control Insulin Independent of Glycemic Control in a Rat Model of Type 2 Diabetes

Abstract

Current treatments for type 2 diabetes fail to prevent the development of peripheral neuropathy. To examine insulin degludec’s effect on peripheral neuropathy in rats, we tested insulin 700, an analog identical to insulin degludec with the same pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, but with the absence of the terminal threonine on the B-chain. Rats were fed a high fat diet for 8 weeks and then treated with a low dose of streptozotocin to induce hyperglycemia. After 2 weeks, diabetic rats were treated with I700 or a control basal insulin (IC) with similar PK twice daily for 18 weeks. A healthy reference group fed a chow diet and not subjected to streptozotocin treatment was also included. The endpoints evaluated included sensory and motor nerve conduction velocity, allodynia using von Frey’s test, thermal sensitivity using Hargreaves test and corneal sensitivity. We evaluated innervation of sensory nerves using corneal confocal microscopy and, in the skin, using histological methods. We also tested vascular reactivity of epineurial arterioles using pressure myography. The insulin analogues were equally effective at correcting hyperglycemia as determined by HbA1C levels of 4.1±0.1 and 4.1±0.1% for I700 and IC, respectively. Both insulin analogues improved all neuropathy related parameters. However, I700 was more effective in that by the end of the treatment period there was no difference in thermal sensitivity, corneal sensitivity, corneal nerve fiber length and sensory and motor nerve conduction velocity between the group treated with I700 and the healthy reference rats. Interestingly, vascular relaxation to acetylcholine improved more with IC treatment. In conclusion, this study demonstrates that I700 (a degludec-like insulin analog) is a more effective treatment for diabetic peripheral neuropathy than a comparable control insulin, independent of glycemic control. Disclosure T.C.A.Åkerström: Employee; Novo Nordisk. L.Andreasen: Employee; Novo Nordisk. E.Nishimura: Employee; Novo Nordisk A/S. M.A.Yorek: Consultant; Novo Nordisk.