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 (rebs 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.

Key words

L-Carnitine - Pyruvate dehydrogenase - Fatty acid oxidation - Diabetes - Glucose metabolism