The role of nerve inflammation and exogenous iron load in experimental peripheral diabetic neuropathy (PDN)

Abstract

Background

Iron is an essential but potentially toxic metal in mammals. Here we investigated a pathogenic role of exogenous iron in peripheral diabetic neuropathy (PDN) in an animal model for type 1 diabetes.

Methods

Diabetes was induced by a single injection of streptozotocin (STZ) in 4-month-old Sprague–Dawley rats. STZ-diabetic rats and non-diabetic rats were fed with high, standard, or low iron diet. After three months of feeding, animals were tested.

Results

STZ-rats on standard iron diet showed overt diabetes, slowed motor nerve conduction, marked degeneration of distal intraepidermal nerve fibers, mild intraneural infiltration with macrophages and T-cells in the sciatic nerve, and increased iron levels in serum and dorsal root ganglion (DRG) neurons. While motor fibers were afflicted in all STZ-groups, only a low iron-diet led also to reduced sensory conduction velocities in the sciatic nerve. In addition, only STZ-rats on a low iron diet showed damaged mitochondria in numerous DRG neurons, a more profound intraepidermal nerve fiber degeneration indicating small fiber neuropathy, and even more inflammatory cells in sciatic nerves than seen in any other experimental group.

Conclusions

These results indicate that dietary iron-deficiency rather than iron overload, and mild inflammation may both promote neuropathy in STZ-induced experimental PDN.

Introduction

Peripheral diabetic neuropathy (PDN) is a serious complication observed in type 1 and type 2 diabetes mellitus (T1D and T2D) [1], [2]. The pathophysiology of this diabetes-associated neurological disorder includes metabolic, vascular and inflammatory mechanisms but a unifying hypothesis of the culprit pathogenic factors is a matter of debate [3]. Activation of the polyol pathway and phosphokinase C isoforms, oxidative stress and lipid peroxidation, transition metal metabolism disorders, neurotrophic factors, the effects of non-enzymatic glycation and autoimmune mechanisms have all been proposed as contributing factors based on various experimental PDN models and on human nerve tissue investigations [2]. PDN leads to peripheral nerve axonal degeneration and impaired regeneration associated with structural and functional changes in endoneural and epineural microvessels and in Schwann cells [1], [4], [5], [6], [7], [8].

Recently animal models and human studies have shown an association between diabetes and iron metabolism [9], [10], [11], [12], [13], [14], [15]. Increased body iron storage enhances generation of free radicals [16]. Free radicals are highly reactive species promoting often deleterious oxidation of proteins, peroxidation of membrane lipids and modification of nucleic acids [17], [18] and are implicated in the pathogenesis of several neurological diseases [13], [14], [19], [20], [21].

Which role, if any, iron has in the pathogenesis of PDN, is difficult to establish in patients and animal models with T2D because development of PDN is usually slow and may be influenced by pathogenic cofactors such as obesity and inflammation as well as by genetic background [22]. Here we investigated the effects of increased or reduced external iron load on the severity of PDN in a rat model of T1D. In contrast to previous hypotheses suggesting that iron excess might be a crucial pathogenic cofactor [20] we found a functionally relevant, increase in distal peripheral nerve pathology with chronic iron depletion rather than iron overload which had little effects.