Pathogenesis of diabetic polyneuropathy

INTRODUCTION — Involvement of the peripheral and autonomic nervous systems is the most common complication of diabetes. The duration and severity of hyperglycemia and the metabolic syndrome are the two important risk factors for the development of diabetic neuropathy in patients with type 1 or type 2 diabetes.

This topic will address the pathogenesis of diabetic polyneuropathy. Other aspects of diabetic neuropathy are discussed separately. (See "Epidemiology and classification of diabetic neuropathy" and "Screening for diabetic polyneuropathy" and "Management of diabetic neuropathy".)

PATHOLOGY — Axons from motor neurons in the spinal cord relay signals to muscles, while axons from sensory neurons at the dorsal root ganglia receive signals from skin and joints. Supporting these axons presents a unique challenge, as they are frequently 20,000 times longer than their corresponding cell bodies. Schwann cells provide supporting myelin for axons in the peripheral nervous system, but most sensory axons are unmyelinated, making them more susceptible to damage than motor axons.

Distal symmetric polyneuropathy is the most common form of diabetic neuropathy [1]. The cause is a length-dependent "dying back" axonopathy, primarily involving the distal portions of the longest myelinated and unmyelinated sensory axons, with relative sparing of motor axons [2]. Though distal "dying back" is commonly seen, there is also evidence for proximal nerve dysfunction at the sensory ganglia, which may contribute to this phenomenon [3].

Distal symmetric polyneuropathy is morphologically and functionally indistinguishable from many other "metabolic" neuropathies, including uremic neuropathy and alcoholic neuropathy. However, in diabetic neuropathy, morphologic abnormalities of the vasa nervorum are present early in the course of the disease and may parallel the severity of the nerve fiber loss [4]. Thus, the morphologic characteristics of diabetic neuropathy support a vascular component, although most damage is likely secondary to metabolic impairment and loss of required energy in the distal sensory axons [5].

PATHOPHYSIOLOGY — In diabetes, a complex array of metabolic and vascular factors shift the balance between nerve fiber damage and nerve fiber repair in favor of damage [2]. This occurs in a fiber-selective pattern that preferentially affects the more vulnerable distal sensory and autonomic fibers, leading to the progressive loss of sensation that underlies the clinical manifestations of diabetic polyneuropathy.

Understanding of the pathogenesis of diabetic neuropathy has evolved from the idea that one single disrupted metabolic pathway was responsible for disease, to the realization that multiple differentially regulated pathways converge to promote mitochondrial dysfunction with bioenergetic failure and oxidative damage of axons (figure 1). Because mitochondria must travel from the sensory neuron along the entire length of the axon to supply axonal energy requirements, metabolic injury occurs both at the cell body and during mitochondrial trafficking, leading to bioenergetic failure, especially at the most distal portion of the axon. This results in the distal to proximal axonal loss that is the hallmark of diabetic neuropathy (figure 2).

Metabolism

Energy production — Circulating glucose and lipids serve as energy sources for the peripheral nervous system. Glucose, via glycolysis and the tricarboxylic acid (TCA), and lipids, via beta-oxidation, produce two dinucleotide cofactors central to metabolism: reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin adenine dinucleotide (FADH2). These cofactors are shuttled into the mitochondria as a source of cellular energy to produce adenosine triphosphate (ATP) via oxidative phosphorylation [6]. Natural byproducts of oxidative phosphorylation are reactive oxygen species (ROS), including superoxide dismutase, glutathione, and catalase. Produced in low levels, ROS are required for normal physiology with essential roles in immunity and cardiovascular tone [7,8].

People with diabetes have excess circulating glucose and lipids, which overwhelm the normal production of ATP, resulting in increased ROS production, energy failure, and loss of normal cellular function [9]. As an example, increased ROS disrupt endoplasmic reticulum function, leading to protein misfolding and cellular injury [10]. Increased ROS also directly damage mitochondria, disrupt normal cellular signaling, and produce significant cellular damage, resulting in a vicious feed-forward cycle of energy failure and loss of normal function [11-13]. These disrupted processes occur throughout all cell types in the peripheral nervous system in diabetes [2,14]. Importantly, injured mitochondria can no longer travel down the axons, and this disruption in normal mitochondrial axonal trafficking underlies the distal to proximal pattern of axonal damage observed in diabetic neuropathy [15].

Other metabolic pathways — Several other metabolic pathways have been studied in the context of diabetic neuropathy, including as potential therapeutic targets [16,17]. In light of the emerging importance of bioenergetics in the pathogenesis of diabetic neuropathy, future therapeutic efforts will need to address both energy homeostasis and specific metabolic pathway abnormalities.

●Polyol and hexosamine – Excess glucose is metabolized by both the polyol and hexosamine pathways. In the polyol pathway, accumulation of sorbitol leads to depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) [18]. The hexosamine pathway produces excess acetylated dinucleotides [19]. In both cases, these byproducts of energy excess lead to increased ROS, energy loss, and inflammation [18,20].

●Advanced glycation end products – Elevated systemic levels of glucose in diabetes lead to glycation of plasma and tissue proteins and formation of advanced glycation end products (AGEs). This nonenzymatic process forms irreversible AGEs that bind to the cell surface receptor called RAGE (receptor for AGE). Activation of RAGE increases ROS [21], promotes neural inflammation, disrupts cellular signaling, and alters normal gene expression in the peripheral nervous system, further promoting diabetic neuropathy [22].

Unifying mechanism — The concept of oxidative stress provides a unifying mechanism for neural damage and for the onset and progression of diabetic neuropathy. Hyperglycemia and hyperlipidemia disrupt peripheral nervous system energy production and result in ROS, with resulting nerve injury and dysfunction. Changes in the polyol and hexosamine pathways, along with AGE formation, further promote oxidative damage.

Because different metabolic impairments are tightly interrelated, a vicious feed-forward cycle of altered metabolism, ROS accumulation, and reduced antioxidant defense occurs. This leads to peripheral nerve damage and the signs and symptoms of diabetic neuropathy (figure 1 and figure 2) [2,5,16].

In support of a role for oxidative stress in the pathogenesis of peripheral neuropathy, patients with diabetes who are treated with antioxidants show clinically meaningful improvements in neuropathic symptoms and neuropathic deficits [23-25]. (See "Management of diabetic neuropathy".)

Role of ischemia — Nerve ischemia was initially invoked in the pathogenesis of diabetic polyneuropathy because of morphologic evidence on sural nerve biopsies as well as the presence of thickened endoneurial blood vessel walls and vascular occlusions at autopsy [4,26-30]. Ischemia is secondary to well-documented endothelial dysfunction in diabetes, with loss of vasodilation and increased vasoconstriction [31,32].

Ischemic and metabolic factors may operate together [33,34]. Ischemia itself has metabolic consequences that may be exacerbated by insulin deficiency and hyperglycemia [33]. Inflammation, specifically acute-phase reactants and interleukins, may also play a role [35].

Role of nerve fiber repair — Peripheral nerve repair is impaired in diabetes [36,37]. This complication may be due to disease-induced loss of neurotrophic peptides that normally mediate nerve repair, regeneration, and tonic maintenance. These peptides include nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, the insulin-like growth factors, and vascular endothelial growth factor [36]. Additionally, insulin functions as a neurotrophic factor to peripheral neurons, and thus loss of insulin in type 1 diabetes may compromise nerve viability and repair [38].

Studies in laboratory animals suggest that expression of nerve growth factor and other neurotrophic factors may be decreased in diabetes, which could lead to decreased repair and perhaps impaired maintenance of peripheral nerve fibers [39].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Nerve damage caused by diabetes (The Basics)")

●Beyond the Basics topics (see "Patient education: Diabetic neuropathy (Beyond the Basics)")

SUMMARY

●Pathology – Distal symmetric polyneuropathy is the most common form of diabetic neuropathy. The proximate cause is a length-dependent "dying back" axonopathy, primarily involving the distal portions of the longest myelinated and unmyelinated sensory axons, with relative sparing of motor axons. (See 'Pathology' above.)

●Pathogenesis – In diabetes, a complex array of metabolic, vascular, and perhaps hormonal factors shifts the balance between nerve fiber damage and nerve fiber repair in favor of the former. This occurs in a fiber-selective pattern that preferentially affects distal sensory and autonomic fibers, leading to the progressive loss of sensation that underlies the clinical manifestations of diabetic polyneuropathy. (See 'Pathophysiology' above.)

•Energy production failure – Excess circulating glucose and lipids in patients with diabetic polyneuropathy overwhelm the normal production of ATP, resulting in increased reactive oxygen species production, mitochondrial damage, energy failure, and loss of normal cellular function. (See 'Energy production' above.)

•Other metabolic pathways – Byproducts of energy excess in the polyol and hexosamine metabolic pathways also can lead to increased reactive oxygen species (ROS), energy loss, and inflammation contributing to diabetic polyneuropathy. (See 'Other metabolic pathways' above.)

●Role of ischemia – Nerve ischemia has been invoked in the pathogenesis of diabetic polyneuropathy because of the presence of thickened endoneurial blood vessel walls and vascular occlusions at autopsy. This is supported by morphologic and clinical evidence. (See 'Role of ischemia' above.)

●Impaired nerve fiber repair – Loss of neurotrophic peptides that normally mediate nerve repair, regeneration, and tonic maintenance contribute to diabetic polyneuropathy. Additionally, insulin functions as a neurotrophic factor to peripheral neurons, and thus loss of insulin in type 1 diabetes may compromise nerve viability and repair. (See 'Role of nerve fiber repair' above.)