title: Channelopathies, painful neuropathy, and diabetes: which way does the causal arrow point?
abstract: Diabetes mellitus, a major global health problem, is commonly associated with painful peripheral neuropathy, which can substantially erode quality of life. Despite its clinical importance, the pathophysiology of painful diabetic neuropathy is incompletely understood. It has traditionally been thought that diabetes may cause neuropathy in patients with appropriate genetic makeup. Here, we propose a hypothesis whereby painful neuropathy is not a complication of diabetes, but rather occurs as a result of mutations that, in parallel, confer vulnerability to injury in pancreatic β cells and pain-signaling dorsal root ganglion (DRG) neurons. We suggest that mutations of sodium channel NaV1.7, which is present in both cell types, may increase susceptibility for development of diabetes via β cell injury and produce painful neuropathy via a distinct effect on DRG neurons.
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Maastricht, 6202 AZ, The Netherlands.
authors.forename: Janneke G J
authors.initials: JG
authors.lastname: Hoeijmakers
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Maastricht, 6202 AZ, The Netherlands.
authors.forename: Catharina G
authors.initials: CG
authors.lastname: Faber
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Maastricht, 6202 AZ, The Netherlands; Department of Neurology, Spaarne Hospital, Hoofddorp, 2130 AT, The Netherlands.
authors.forename: Ingemar S J
authors.initials: IS
authors.lastname: Merkies
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06515, USA; Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT 06515, USA. Electronic address: stephen.waxman@yale.edu.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D053447:Channelopathies / Q000209:etiology / Q000235:genetics*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D010146:Pain / Q000209:etiology / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000235:genetics*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human
keywords: Na(V)1.7; diabetes mellitus; diabetic neuropathy; painful neuropathy; sodium channelopathy; β cells