Reduced effects of L-carnitine on glucose and fatty acid metabolism in myocytes isolated from diabetic rats.
Depressed glucose utilization and over-reliance of muscle tissues on fat represents a major metabolic disturbance in diabetes. This study was designed to investigate the relationship between fatty acid oxidation and glucose utilization in diabetic hearts and to examine the role of L-Carnitine on the utilization of these substrates in diabetes. 14CO2 release from [1-14C]pyruvate (an index of PDH activity), [2-14C]pyruvate and [6-14C]glucose (an index of acetyl-CoA flux through the Krebs cycle), [U-14C]glucose (an index of both PDH and acetyl-CoA flux through the Krebs cycle), and [1-14C]palmitate oxidation were studied in cardiac myocystes isolated from normal and streptozotocin-injected rats. Palmitate oxidation was increased twofold in diabetic myocytes compared to normal cells (5.4 +/- 1.45 vs 2.35 +/- 0.055 nmol/mg protein/30 min, p > 0.05). L-Carnitine (5 mM) significantly increased palmitate oxidation (60-70%) in normal cells but had no effect on diabetic cells. The activity of PDH and acetyl-CoA flux through the Krebs cycle was severely depressed in diabetes (58.14 +/- 20.27 and 8.63 +/- 0.62 in diabetes vs 128.75 +/- 11.47 and 24.84 +/- 7.81 nmol/mg protein/30 min in controls, p > 0.05, respectively). The efflux of acetylcarnitine, a by-product of PDH activity was also much lower in diabetic cells than in normal cells but had no effect in diabetes. L-Carnitine also had no effect on 14CO2 release from [U-14C]glucose but significantly decreased that from [6-14C]glucose, which reflects oxidative metabolism suggesting that L-Carnitine decreases oxidative glucose utilization. Thus, these data suggest that the overreliance on fat in diabetes may be in part secondary to a reduction of carbohydrate-generated acetyl-CoA through the Krebs cycle.
Abdel-aleem
S
S
Duke University Medical Center, Department of Surgery and Medicine, Durham, North Carolina, USA.
Karim
A M
AM
Zarouk
W A
WA
Taylor
D A
DA
el-Awady
M K
MK
Lowe
J E
JE
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000108:Acetylcarnitine / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D002331:Carnitine / Q000494:pharmacology*; D002952:Citric Acid Cycle; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002250:Carbon Radioisotopes; D005227:Fatty Acids; D011768:Pyruvate Dehydrogenase Complex; D019308:Palmitic Acid; D000108:Acetylcarnitine; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D005947:Glucose; D002331:Carnitine