Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl-L-carnitine.
The rationale for these experiments is that administration of L-carnitine and/or short-chain acylcarnitines attenuates myocardial dysfunction 1) in hearts from diabetic animals (in which L-carnitine levels are decreased); 2) induced by ischemia-reperfusion in hearts from nondiabetic animals; and 3) in nondiabetic humans with ischemic heart disease. The objective of these studies was to investigate whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic peripheral neuropathy. The major findings in rats with streptozotocin-induced diabetes of 4-6 weeks duration were that 24-h urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%). These changes in carnitine levels/excretion were associated with decreased caudal nerve conduction velocity (10-15%) and sciatic nerve changes in Na(+)-K(+)-ATPase activity (decreased 50%), Mg(2+)-ATPase (decreased 65%), 1,2-diacyl-sn-glycerol (DAG) (decreased 40%), vascular albumin permeation (increased 60%), and blood flow (increased 65%). Treatment with acetyl-L-carnitine normalized plasma and endoneurial L-carnitine levels and prevented all of these metabolic and functional changes except the increased blood flow, which was unaffected, and the reduction in DAG, which decreased another 40%. In conclusion, these observations 1) demonstrate a link between imbalances in carnitine metabolism and several metabolic and functional abnormalities associated with diabetic polyneuropathy and 2) indicate that decreased sciatic nerve endoneurial ATPase activity (ouabain-sensitive and insensitive) in this model of diabetes is associated with decreased DAG.
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
Y
Y
Ido
J
J
McHowat
K C
KC
Chang
E
E
Arrigoni-Martelli
Z
Z
Orfalian
C
C
Kilo
P B
PB
Corr
J R
JR
Williamson
D000108:Acetylcarnitine / Q000627:therapeutic use*; D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002331:Carnitine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000517:prevention & control*; D004075:Diglycerides / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009431:Neural Conduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism
C011439:1,2-diacylglycerol; D004075:Diglycerides; D008055:Lipids; D012710:Serum Albumin, Bovine; D007294:Inositol; D013012:Sorbitol; D000108:Acetylcarnitine; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D002331:Carnitine