The Protective Effect And Mechanism Of Wld ~ S On Type 1 Diabetes Mellitus And Its Complications

The C57BL/Wlds mouse carries a dominant mutation that delays Wallerian degeneration in the distal stump of an injured axon. Wlds (also known as Wld) mutation comprises an85kb tandem triplication, which results in overproduction of slow Wallerian degeneration (WLDS) protein. This protein is composed of the N-terminal70amino acids of ubiquitin fusion degradation protein2a (UFD2A), a ubiquitin-chain assembly factor, fused to the complete sequence of nicotinamide mononucleotide adenylyltransferasel (NMNAT1), an enzyme in the NAD biosynthetic pathway that generates NAD. The Wlds mouse has been shown to have protective properties in different types of neurodegenerative disease models with axonal degeneration.Diabetes, a life long progressive disease, is the result of body’s inability to produce insulin or use insulin to its full potential, and is characterized by high circulating glucose. This disease has reached epidemic proportion and has become one of the most challenging health problems of the21st century. It is the fourth leading cause of death by disease globally; every7seconds a person dies from diabetes-related causes. It affects92.4million people in China. It is the leading cause of blindness and visual impairment, non-injury amputation, and end-stage kidney disease in adults in developed countries. Here, we aimed to evaluate the effect of the mutant Wlds gene in experimental diabetes on early experimental peripheral diabetic neuropathy, diabetic retinopathy and diabetic nephropathy.The experiments were performed in four groups of mice:wild-type (WT), streptozotocin (STZ)-induced diabetic WT, C57BL/Wlds and STZ-induced diabetic C57BL/Wlds. In each group, intraperitoneal glucose and insulin tolerance tests were performed; blood glucose, glycated haemoglobin and serum insulin were monitored. These mice were also subjected to the following behavioural tests:grasping test, hot-plate test and von Frey anaesthesiometer test. For some animals, sciatic-tibial motor nerve conduction velocity, tail sensory nerve conduction velocity and eye pattern electroretinogram were measured. At the end of the experiments, islets were isolated to detect glucose-stimulated insulin secretion, ATP content and extent of apoptosis. The NAD/NADH ratio in islets and retinas was evaluated. Surviving retinal ganglion cells were estimated by immunohistochemistry. Urinary and serum variables were also determined. Periodic acid-Schiff staining, Masson staining and Silver staining were performed for histological analyses. The expression of p38and ERK in renal cortical tissues were examined by western blot.We found that the Wlds gene is expressed in islets and protects beta cells against multiple low doses of STZ by increasing the NAD/NADH ratio, maintaining the ATP concentration, and reducing apoptosis. Consistently, significantly higher insulin concentrations, lower blood glucose concentrations, and better glucose tolerance were observed in Wlds mice compared with WT mice after STZ treatment. Furthermore, Wlds alleviated abnormal sensory responses, nerve conduction, retina dysfunction and reduction of surviving retinal ganglion cells in STZ-induced diabetic models. In addition, diabetes-induced renal dysfunction and extracellular matrix accumulation were prevented in diabetic Wlds mice. Wlds inhibited the activation of p38and ERK in renal cortical tissues.We provide the first evidence that expression of the Wlds gene decreases beta cell destruction and preserves islet function in STZ-induced diabetes, thus revealing a novel protective strategy for diabetic models.