The neurological consequences of diabetes exclusively affect the peripheral nervous system (PNS) and are linked to hypermetabolic activity in the sorbitol pathway and intrinsic microvascular changes which have long-term structural consequences. Hyperglycemia is the underlying defect and since nerves are insulin-independent, excess glucose enters the endoneurium being converted into osmotically active polyols. Transport mechanisms which convey hexoses across the blood-nerve barrier also carry sodium into the endoneurium resulting in increased osmotic activity associated with reduced nerve conduction velocity and reduced nerve fiber diameter in the early metabolic phase, during which neuropathy is most amenable to treatment with aldose reductase inhibitors and insulin. Our studies focus i) on the link between increased sodium and electrophysiologic disturbances, ii) fine structural localization of increased sodium in the axon and paranodal region and iii) mechanisms of glycogen accumulation in diabetic axons. In the latter stages of the disease microcirculatory changes become established and have an impact on the nerve fiber in which axonal degeneration and demyelination occur. Microangiopathy, resulting in narrowing of the capillaries, is implicated and the proposed research attaches particular significance to the transperineurial microcirculation which may play a key role in the pathogenesis of endoneurial ischemia. Both hyperglycemia and hypoxia are underlying mechanisms whose contributions to pathogenesis will be individually investigated using new techniques for measurement of nerve blood flow, endoneurial electrolyte analysis by x-ray microprobe, nerve oxygen tension and endoneurial fluid pressure. Biophysical techniques designed to investigate disturbances in the endoneurial microenvironment will be combined with classic morphologic and morphometric methods to determine the pathogenesis of the early changes in diabetic neuropathy knowledge of whose onset is crucial to initiate appropriate treatment before irreversible neuropathic changes supervene.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Pathology A Study Section (PTHA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Shelton, G D; Calcutt, N A; Garrett, R S et al. (1999) Necrotizing myopathy induced by overexpression of interferon-gamma in transgenic mice. Muscle Nerve 22:156-65
Dines, K C; Shelton, G D; Schneider, T et al. (1999) Mast cell-associated Renaut bodies in the peroneal nerve of a dog with a history of mastocytosis. J Peripher Nerv Syst 4:19-26
Dines, K C; Calcutt, N A; Nunag, K D et al. (1999) Effects of hindlimb temperature on sciatic nerve laser Doppler vascular conductance in control and streptozotocin-diabetic rats. J Neurol Sci 163:17-24
Powell, H C; Garrett, R S; Brett, F M et al. (1999) Response of glia, mast cells and the blood brain barrier, in transgenic mice expressing interleukin-3 in astrocytes, an experimental model for CNS demyelination. Brain Pathol 9:219-35
Kalichman, M W; Dines, K C; Bobik, M et al. (1998) Nerve conduction velocity, laser Doppler flow, and axonal caliber in galactose and streptozotocin diabetes. Brain Res 810:130-7
Kalichman, M W; Powell, H C; Mizisin, A P (1998) Reactive, degenerative, and proliferative Schwann cell responses in experimental galactose and human diabetic neuropathy. Acta Neuropathol (Berl) 95:47-56
Castelnau, P A; Garrett, R S; Palinski, W et al. (1998) Abnormal iron deposition associated with lipid peroxidation in transgenic mice expressing interleukin-6 in the brain. J Neuropathol Exp Neurol 57:268-82
Mizisin, A P; Kalichman, M W; Garrett, R S et al. (1998) Tactile hyperesthesia, altered epidermal innervation and plantar nerve injury in the hindfeet of rats housed on wire grates. Brain Res 788:13-9
Dines, K C; Mizisin, A P; Jorge, M C et al. (1997) Effects of body and hindlimb temperature on laser Doppler blood flow and vascular conductance in rat sciatic nerve and skeletal muscle. J Neurol Sci 148:7-13
Mizisin, A P; Li, L; Calcutt, N A (1997) Sorbitol accumulation and transmembrane efflux in osmotically stressed JS1 schwannoma cells. Neurosci Lett 229:53-6

Showing the most recent 10 out of 62 publications