Abstract
Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1.3 and NaV1.7, which are encoded by the sodium voltage-gated channel alpha subunit 3 and 9 (Scn3A and Scn9A) genes, respectively, have been identified in both peripheral nociceptive neurons of dorsal root ganglion (DRG) and pancreatic islet cells. Recent advances in our understanding of tetrodotoxin-sensitive (TTX-S) sodium channels NaV1.3 and NaV1.7 lead to the rational doubt about the cause–effect relation between diabetes and painful neuropathy. In this review, we summarize the roles of NaV1.3 and NaV1.7 in islet cells and DRG neurons, discuss the link between DM and painful neuropathy, and present a model, which may provide a starting point for further studies aimed at identifying the mechanisms underlying diabetes and painful neuropathy.
Highlights
Diabetes mellitus (DM) is a chronic disease that affects more than 382 million people worldwide, and this number is expected to rise beyond 592 million by 2035 [1]
The clinical characteristics of painful diabetic neuropathy (PDN) range from spontaneous pain to allodynia and hyperalgesia [7,8,9]
The small diameter Aδ- and C-fibers of dorsal root ganglion (DRG) neurons, known as pain-sensing sensory neurons, are the target cells of PDN, as they can be sensitized by a variety of mechanisms in response to different pathological conditions associated with diabetes
Summary
Diabetes mellitus (DM) is a chronic disease that affects more than 382 million people worldwide, and this number is expected to rise beyond 592 million by 2035 [1]. With DM becoming increasingly prevalent over time, painful diabetic neuropathy (PDN), as one of its associated major complications, is rapidly rising. PDN affects almost 25% of the diabetic population and covers a wide variety of clinical presentations, which involve a significant risk in the quality of patients’ life [3,4,5,6]. Even with frequent visits to medical professionals and use of prescription medications, it turns out that the clinical treatment of PDN is often unsatisfactory because the use of high doses of drugs is accompanied by abundant side effects. Several pathogeneses, including metabolic, vascular, autoimmune and oxidative stress-related mechanisms for PDN, have been postulated, the precise cause of neuropathic pain in diabetes remains to be elucidated
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