Experimental diabetic neuropathy with spontaneous recovery: is there irreparable damage?
Progressive diabetic neuropathy has hitherto been irreversible in humans. New approaches raise the question of whether islet cell reconstitution rendering euglycemia can reverse specific features of neuropathy. We evaluated physiological and structural features of experimental neuropathy in a long-term murine model of diabetes induced by streptozotocin. By serendipity, a subset of these diabetic mice spontaneously regained islet function and attained near-euglycemia. Our hypotheses were that this model might better reflect axon loss observed in human disease and that spontaneous recovery from diabetes might identify the features of neuropathy that are reversible. In this model, experimental neuropathy closely modeled that in humans in most critical aspects: declines in motor conduction velocities, attenuation of compound muscle (M waves) and nerve action potentials, axon atrophy, myelin thinning, loss of epidermal axons, and loss of sweat gland innervation. Overt sensory neuron loss in dorsal root ganglia was a feature of this model. In mice with recovery, there was robust electrophysiological improvement, less myelin thinning, and remarkable epidermal and sweat gland reinnervation. There was, however, no recovery of populations of lost sensory neurons. Our findings identify a robust model of human diabetic neuropathy and indicate that overt, irretrievable loss of sensory neurons is one of its features, despite collateral reinnervation of target organs. Sensory neurons deserve unique protective strategies irrespective of islet cell reconstitution.
Kennedy
James M
JM
Department of Clinical Neurosciences and Neuroscience Research Group, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada.
Zochodne
Douglas W
DW
D000200:Action Potentials; D000818:Animals; D001369:Axons / Q000473:pathology; D002452:Cell Count; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000473:pathology / Q000503:physiopathology*; D004817:Epidermis / Q000294:innervation; D005727:Ganglia, Spinal / Q000473:pathology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000294:innervation; D009431:Neural Conduction; D009474:Neurons; D009475:Neurons, Afferent / Q000502:physiology; D012075:Remission, Spontaneous; D013497:Sural Nerve / Q000473:pathology; D013979:Tibial Nerve / Q000473:pathology