A sodium-pump defect in diabetic peripheral nerve corrected by sorbinil administration: relationship to myo-inositol metabolism and nerve conduction slowing.
Nerve conduction slowing, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by aldose reductase inhibitors such as sorbinil. Recent animal experiments attribute acutely reversible nerve conduction slowing in diabetes to a myo-inositol (MI)-related defect in the nerve Na-K-ATPase (which generates the transmembrane sodium and potassium potentials necessary for nerve impulse conduction and the sodium gradient necessary for sodium-dependent uptake of substrates). This MI-related abnormality in Na-K-ATPase function is currently viewed as a cyclic, metabolic defect involving sequential alteration of Na-dependent MI uptake, MI content, MI incorporation into membrane phospholipids, and phospholipid-dependent Na-K-ATPase function in peripheral nerve. Aldose reductase inhibitors have been shown to normalize both nerve MI content and nerve Na-K-ATPase activity. These observations suggest that the acute effects of aldose reductase inhibitors on nerve conduction in both diabetic animals and patients may be mediated by correction of an underlying MI-related nerve Na-K-ATPase defect. Furthermore, this sorbinil-corrected Na-K-ATPase defect in diabetic nerve may contribute to other biochemical, functional, and structural abnormalities present in patients with diabetic peripheral neuropathy.
Greene
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D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D048289:Imidazolidines; D007294:Inositol / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism / Q000502:physiology*; D009431:Neural Conduction / Q000187:drug effects*; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011913:Rats, Inbred BB; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism
D007093:Imidazoles; D048289:Imidazolidines; D007473:Ion Channels; D007294:Inositol; D013012:Sorbitol; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil