Pathogenesis of Distal Symmetrical Polyneuropathy in Diabetes

Abstract

Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying therapies and left the reasons for failed therapies uncertain, which is critical given that current management strategies often fail to achieve long-term efficacy. In this article, the pathogenesis of DSPN is reviewed, covering pathogenic changes in the peripheral nervous system, microvasculature and central nervous system (CNS). Furthermore, the successes and limitations of current therapies are discussed, and potential therapeutic targets are proposed. Recent findings on its pathogenesis have called the definition of DSPN into question and transformed the disease model, paving the way for new research prospects.

Keywords: central nervous system; diabetes; diabetic neuropathy; distal symmetrical polyneuropathy; glycemic control; hyperglycemia; neuropathic pain; pain management; pathogenesis; spinal cord stimulation.

Figure 1

Neuropathological findings of distal symmetrical polyneuropathy in diabetes. Early breakdown of the myelin sheath and Schwann cells occurs. Schwann cells dissociate from axons even in unmyelinated neurons. Axonal transport and signaling are disrupted, potentially also at the axo–glial interface, resulting in decreased neurotrophic factors and, eventually, distal axonal loss that progresses length-dependently.

Figure 2

Metabolic mechanisms of hyperglycemia in distal symmetrical polyneuropathy in diabetes. This cross-sectional diagram of a peripheral myelinated sensory neuron depicts the various hypothesized metabolic mechanisms of hyperglycemia (polyol, glycation, protein kinase C, poly (ADP-ribose) polymerase and hexosamine pathways) and their interconnection, which are critical in DSPN pathogenesis and neuronal dysfunction. As shown, only the glycation pathway via AGEs acts on an extracellular level, while the others act on an intracellular level. Blue labels represent molecules and red labels represent neuropathic outcomes. ↑ refers to an increase and ↓ refers to a decrease. AGEs, advanced glycation end products; ADP, adenosine diphosphate; ATP, adenosine triphosphate; NA⁺, sodium ion; NAD⁺, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide plus hydrogen; Na⁺/K⁺-ATPase, sodium–potassium ATPase; NF-ĸB, nuclear factor kappa B; PARP, poly (ADP-ribose) polymerase; PKC, protein kinase C, RAGEs, receptors for advanced glycation end products; ROS, reactive oxygen species; Sp1, specificity protein 1; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine.