New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain

Abstract

Pre-diabetes and diabetes are a global epidemic, and the associated neuropathic complications create a substantial burden on both the afflicted patients and society as a whole. Given the enormity of the problem and the lack of effective therapies, there is a pressing need to understand the mechanisms underlying diabetic neuropathy (DN). In this review, we present the structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults and then discuss the pathways that contribute to peripheral nerve injury in DN. We also discuss systems biology insights gleaned from the recent advances in biotechnology and bioinformatics, emerging ideas centered on the axon-Schwann cell relationship and associated bioenergetic crosstalk, and the rapid expansion of our knowledge of the mechanisms contributing to neuropathic pain in diabetes. These recent advances in our understanding of DN pathogenesis are paving the way for critical mechanism-based therapy development.

Keywords: Schwann cell; axon-glia crosstalk; bioenergetics; diabetic neuropathy; pain; peripheral nervous system; pre-diabetes; type 1 diabetes; type 2 diabetes.

Figure 1. The peripheral nervous system

The peripheral nervous system (PNS) is comprised of both neurons and Schwann cells (SCs), and the structure, location, and interaction of these components have important implications for PNS function. Efferent axons of motor neurons, whose cell bodies are located in the ventral horn of the spinal cord, carry signals from the central nervous system (CNS) to muscles and glands, whereas afferent axons of sensory neurons, whose cell bodies are located in the dorsal root ganglia, relay information from peripheral sensory receptors to the CNS. Thin and unmyelinated sensory axons, also known as C-fibers or small fibers, are associated with non-myelinating SCs and are grouped as Remak bundles and represent a large portion of the PNS neurons. Myelinated sensory axons, on the other hand, are surrounded by myelin sheaths made by SCs that form distinct nodal domains important for saltatory conduction and a tubular network of myelinic channels that connect the SC cytoplasm with the periaxonal space to provide a source of energy to the axonal compartment

Figure 2. Pathways implicated in diabetic neuropathy pathogenesis

Nerve dysfunction and cell death in DN results from a complex myriad of events that are triggered by the metabolic imbalances associated with diabetes. Hyperglycemia, dyslipidemia, and/or insulin resistance promotes activation of the protein kinase C (PKC), polyol, advanced glycation end-product (AGE), poly (ADP-ribose) polymerase (PARP), and hexosamine pathways, as well as loss of insulin signalling, which culminate in deleterious effects on mitochondrial function and gene expression along with inflammation and oxidative stress.

Figure 3. Bioenergetic mechanisms of nerve injury in diabetes

Glucose enters SCs via Glut3 and LCFA enter via FABP for production of ATP via the TCA cycle and OxPhos. In T2D, excess glucose undergoes glycolysis but excess pyruvate overwhelms the TCA cycle with loss of OxPhos, and the SC enters anaerobic metabolism with increased lactate production. Lactate is shuttled to the axon via the MCT. Glucose can also enter the axon directly via Glut3 on the Node of Ranvier. How the insulin receptor alters glucose entry or nerve viability is unknown. In T2D, excess LCFA can also enter the SC and CPT1 transports the LCFA acyl-CoA esters, along with the carnitine shuttle and CPT2, to the mitochondrial matrix to undergo β-oxidation, with repeat cleavage of 2 carbons to form acetyl-CoA with each cycle. Excess acetyl-CoA overwhelms the TCA cycle with loss of OxPhos, and a secondary increase in large quantities of acylcarnitines, which are shuttled to the axon. Finally, excess lactate and acylcarnitines mediate mitochondrial axonal damage in T2D. Lactate overload results in TCA/OxPhos dysfunction, producing mitochondrial injury, mitochondrial fission, and ROS. Acylcarnitines may trigger flux of extracellular Ca²⁺ into the axon and intracellular Ca²⁺ into the mitochondria, which alters mitochondrial trafficking and induces mitochondrial apoptosis, respectively. Impaired trafficking mechanisms will likely impede the crucial mitophagy clearance pathways that shuttle damaged mitochondria back to the soma via retrograde transport. Cumulative continued substrate excess results in loss of axonal mitochondrial function with subsequent loss of axon structure and function, leading to DN. ACSL1: long chain acyl-CoA synthetase 1; CPT1/2: Carnitine palmitoyltransferase 1/2; FABP: fatty acid binding protein; FFA: Free fatty acids; Glut3: Glucose transporter 3; IMM/OMM: Inner/outer mitochondrial membrane; LCFA: Long chain fatty acids; MCT: Monocarboylase transporter 1 or 4; ROS: Reactive oxygen species.

Figure 4. Peripheral mechanisms contributing to neuropathic pain in diabetic neuropathy

The axons of both unmyelinated (blue) and myelinated axons (brown) undergo length-dependent degeneration (dotted lines). At the terminals of nociceptors, ion channels undergo post-translational modifications, for instance due to increased levels of the reactive metabolite methylglyoxal and enhanced glycosylation, resulting in gain of function. In myelinated axons, the distribution of voltage gated ion channels at the node of Ranvier changes with at the juxtaparanode leading to hyperexcitability. At the reduced expression of shaker type K_v cell body there is increased expression and trafficking of pro-excitatory voltage gated sodium channels such as Na_v1.8. Inheriting rare variants of Na_v1.7 may also confer risk of developing neuropathic pain. The end result of these changes is reflected in hyperexcitability with the development of enhanced stimulus-response and ectopic activity.