| DIABETES VOL. 46, SUPPLEMENT 2, SEPTEMBER 1997 Metabolic and Vascular Factors in the Pathogenesis of Diabetic Neuropathy Norman E. Cameron Reduced nerve perfusion is an important factor in the
etiology of diabetic neuropathy. Studies in
streptozotocin-induced diabetic rats show that nerve
conduction velocity (NCV) and blood flow deficits are
corrected by treatment with vasodilator drugs, with
angiotensin II and endothelin-1 antagonists being
particularly important. The AT1 antagonist
ZD7155 also prevents diabetic deficits in regeneration
following nerve damage, indicating that hypoperfusion is
an important limitation for nerve repair. Metabolic
changes include high polyol pathway flux, increased
advanced glycosylation, elevated oxidative stress, and
impaired Copyright © 1997 American Diabetes Association Last updated: 8/97 |
-6 essential fatty acid
metabolism. Aldose reductase inhibitors (ARIs) restore
NCV via their effects on perfusion. ARI action probably
depends on blocking the conversion of glucose to
sorbitol, thus preventing depletion of vasa nervorum
glutathione, an important endogenous free radical
scavenger. Free radicals cause vascular endothelium
damage and reduced nitric oxide vasodilation. Inhibition
of advanced glycosylation and autoxidation (autoxidative
glycosylation), major sources of free radicals, by
aminoguanidine or transition metal chelators, corrects
neurovascular dysfunction. Evening primrose oil supplies 
-linolenic acid (GLA) to improve vasodilator
eicosanoid synthesis in diabetes, correcting nerve blood
flow and NCV deficits. Interactions between some of these
mechanisms have therapeutic implications. Thus, combined
ARI and evening primrose oil treatment produced a 10-fold
amplification of NCV and blood flow responses. Similarly,
GLA effects are markedly enhanced when given in
combination with ascorbate as ascorbyl-GLA. Thus,
metabolic abnormalities combine to produce deleterious
changes in nerve perfusion that make a major contribution
to the etiology of diabetic neuropathy. The potential
importance of multi-action therapy is stressed. Diabetes
46 (Suppl. 2):S31S37, 1997