A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.
A myo-inositol-related defect in nerve sodium-potassium ATPase activity in experimental diabetes has been suggested as a possible pathogenetic factor in diabetic neuropathy. Because the sodium-potassium ATPase is essential for other sodium-cotransport systems, and because myo-inositol-derived phosphoinositide metabolites regulate multiple membrane transport processes, sodium gradient-dependent amino acid uptake was examined in vitro in endoneurial preparations derived from nondiabetic and 14-d alloxan diabetic rabbits. Untreated alloxan diabetes reduced endoneurial sodium-gradient dependent uptake of the nonmetabolized amino acid 2-aminoisobutyric acid by greater than 50%. Administration of an aldose reductase inhibitor prevented reductions in both nerve myo-inositol content and endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Myo-inositol supplementation that produced a transient pharmacological elevation in plasma myo-inositol concentration, but did not raise nerve myo-inositol content, reproduced the effect of the aldose reductase inhibitor on endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Phorbol myristate acetate, which acutely normalizes sodium-potassium ATPase activity in diabetic nerve, did not acutely correct 2-aminoisobutyric uptake when added in vitro. These data suggest that depletion of a small myo-inositol pool may be implicated in the pathogenesis of defects in amino acid uptake in diabetic nerve and that rapid correction of sodium-potassium ATPase activity with protein kinase C agonists in vitro does not acutely normalize sodium-dependent 2-aminoisobutyric acid uptake.
Greene
D A
DA
Department of Medicine, School of Medicine, University of Pittsburgh, Pennsylvania 15261.
Lattimer
S A
SA
Carroll
P B
PB
Fernstrom
J D
JD
Finegold
D N
DN
D000596:Amino Acids / Q000378:metabolism*; D000621:Aminoisobutyric Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D011817:Rabbits; D012016:Reference Values; D012964:Sodium / Q000494:pharmacology*; D013979:Tibial Nerve / Q000187:drug effects / Q000378:metabolism*
D000596:Amino Acids; D000621:Aminoisobutyric Acids; D001786:Blood Glucose; D007093:Imidazoles; D048289:Imidazolidines; D007328:Insulin; C100049:2-aminoisobutyric acid; D007294:Inositol; D010042:Ouabain; D012964:Sodium; C026411:sorbinil; D005947:Glucose