Abstract
Sensory and autonomic neuropathy affects the majority of type II diabetic patients. Clinically, autonomic evaluation often focuses on sudomotor function yet this is rarely assessed in animal models. We undertook morphological and functional studies to assess large myelinated and small unmyelinated axons in the db/db type II diabetes mouse model. We observed that autonomic innervation of sweat glands in the footpads was significantly reduced in db/db mice compared to control db/+ mice and this deficit was greater compared to reductions in intraepidermal sensory innervation of adjacent epidermis. Additionally, db/db mice formed significantly fewer sweat droplets compared to controls as early as 6 weeks of age, a time when no statistical differences were observed electrophysiologically between db/db and db/+ mice studies of large myelinated sensory and motor nerves. The rate of sweat droplet formation was significantly slower and the sweat droplet size larger and more variable in db/db mice compared to controls. Whereas pilocarpine and glycopyrrolate increased and decreased sweating, respectively, in 6 month-old controls, db/db mice did not respond to pharmacologic manipulations. Our findings indicate autonomic neuropathy is an early and prominent deficit in the db/db model and have implications for the development of therapies for peripheral diabetic neuropathy.
Highlights
Contributed to our understanding of pathogenesis of diabetic sensory neuropathy[21,29]
The blood glucose levels were significantly elevated in db/db mice from 4 weeks until 20 weeks of age, at the last recorded time point (Supplementary Fig. 1)
We examined the pathology (intraepidermal nerve fiber density (IENFD)) and function in db/db mice starting at 6 weeks of age to establish the earliest age at which these mice show neuropathy
Summary
Contributed to our understanding of pathogenesis of diabetic sensory neuropathy[21,29]. Whether db/db mice exhibit autonomic neuropathy has not been explored. We describe a combined approach in which pathological assessment of footpad autonomic innervation is measured and correlated with functional assessment of footpad sweating. We observed that small unmyelinated autonomic fibers were preferentially affected early in disease compared to large myelinated fibers and that autonomic fibers innervating sweat glands were more prominently affected than their unmyelinated epidermal sensory counterparts at early time points. Pharmacologic manipulation of sweat production was possible with pilocarpine and glycopyrrolate in db/+animals, db/db animals were unresponsive to such treatments at 6 months of age
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