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The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the Ins2+/Akita mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in Ins2+/Akita mechanonociceptors compared with wild-type littermates, whereas the function of low-threshold A-fibers was essentially intact. Studies of isolated sensory neurons demonstrated a markedly reduced heat responsiveness in Ins2+/Akita dorsal root ganglion (DRG) neurons, but a mostly unchanged function of cold-sensitive neurons. Restoration of normal glucose control by islet transplantation produced a rapid recovery of nociception, which occurred before normoglycemia had been achieved. Islet transplantation also restored Ins2+/Akita intraepidermal nerve fiber density to the same level as wild-type mice, indicating that restored insulin production can reverse both sensory and anatomical abnormalities of diabetic neuropathy in mice. The reduced rate of action potential discharge in nociceptive fibers and the impaired heat responsiveness of Ins2+/Akita DRG neurons suggest that ionic sensory transduction and transmission mechanisms are modified by diabetes.

Original publication

DOI

10.2337/db17-1306

Type

Journal article

Journal

Diabetes

Publication Date

08/2018

Volume

67

Pages

1650 - 1662

Keywords

Action Potentials, Amino Acid Substitution, Animals, Behavior, Animal, Cells, Cultured, Diabetes Mellitus, Diabetic Neuropathies, Epidermis, Ganglia, Spinal, Heterozygote, Insulin, Islets of Langerhans Transplantation, Kidney, Male, Mechanoreceptors, Mice, Inbred C57BL, Mice, Mutant Strains, Nerve Fibers, Unmyelinated, Pain Measurement, Somatosensory Disorders, Thermoreceptors, Transplantation, Heterotopic