Effects of acute, subacute, and chronic diabetes on carbohydrate and energy metabolism in rat sciatic nerve. Relation to mechanisms of peripheral neuropathy.
To address the problem of the pathogenesis of diabetic neuropathy, rats were made diabetic by alloxan administration, and sciatic nerves were sampled for electrolyte and water content and levels of selected carbohydrates and intermediates in energy metabolism at 3, 6, and 26 weeks. Significant increases were seen in the nerve content of glucose, sorbitol, and fructose. Decreases of myo-inositol were not statistically significant. Glucose-6-phosphate was increased at all times; fructose-1,6-bisphosphate was elevated at 6 and 26 weeks. Nerve ATP and phosphocreatine levels were both increased concomitantly, as was the energy charge. Nerve lactate levels increased only at 26 weeks when plasma lactate levels were also high. Plasma ketone bodies were elevated throughout the 26-week experimental interval. It is postulated that ketone bodies were being used as alternative metabolic fuels in diabetic nerve, thereby causing inhibition of pyruvate oxidation and increased aerobic production of lactate. Increased plasma ketone body levels could also inhibit hepatic lactate uptake. There was no other evidence for hypoxia/ischemia. Lactate:pyruvate ratios did not differ from control values at any time in these ketotic hypoinsulinemic animals. Five major hypotheses have been proposed to explain the pathogenesis of diabetic neuropathy: 1) hypoxia/ischemia, 2) hyperglycemic pseudohypoxia, 3) myo-inositol deficiency, 4) fructose and polyol accumulation and osmotic disequilibrium, and 5) nonenzymatic glycation of macromolecules by fructose and glucose. The data obtained in this study seem to fit best with hypotheses 4 and perhaps 5.
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
J H
JH
Thurston
D B
DB
McDougal
R E
RE
Hauhart
D W
DW
Schulz
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D050260:Carbohydrate Metabolism; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000209:etiology*; D004573:Electrolytes / Q000378:metabolism; D004734:Energy Metabolism; D005632:Fructose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D008297:Male; D010523:Peripheral Nervous System Diseases / Q000209:etiology*; D010725:Phosphocreatine / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism
D004573:Electrolytes; D011108:Polymers; C024617:polyol; D010725:Phosphocreatine; D005632:Fructose; D013012:Sorbitol; D000255:Adenosine Triphosphate; D005947:Glucose