Correlations Between Fatty Acid and Glucose Metabolism: Potential Explanation of Insulin Resistance of Puberty

Abstract

In vivo resistance to the action of insulin on glucose uptake has been documented during puberty. To test the hypothesis that the glucose-fatty acid cycle, as proposed by Randle et al. (Randle PJ, Garland PB, Hales CN, Newsholme EA: The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789, 1963), may be responsible for this phenomenon, we studied nine prepubertal (Tanner I), nine pubertal (Tanner II-IV), and five young adult healthy subjects. The rate of lipolysis was measured with [d-5]glycerol tracer during basal state and during a stepwise hyperinsulinemic (10 and 40 mU·m−2 · min−1)-euglycemic clamp. The rates of insulin-stimulated glucose disposal (Rd) were measured during the clamp, whereas glucose and fat oxidation were measured by using indirect respiratory calorimetry. Basal glycerol rate of appearance (Rα; lipolysis) and fat oxidation were similar between prepubertal and pubertal subjects but higher than adults when the data were expressed per kilogram body weight or per kilogram fat-free mass (FFM; glycerol Rα: 2.5 ± 0.2, 2.6 ± 0.2 vs. 1.6 ± 0.2 μmol · min−1 · kg FFM−1 P < 0.05; fat oxidation: 4.4 ± 0.6, 4.8 ± 0.3 vs. 3.2 ± 0.6 μmol · min−1 · kg FFM−1 P < 0.05). However, when expressed for total body, glycerol Rα and fat oxidation were higher in pubertal versus prepubertal and adult subjects. Insulin-like growth factor I (IGF-I) levels correlated with total-body lipolysis (r = 0.52, P = 0.006) and with total lipid oxidation (r = 0.44, P = 0.016) at baseline. During the low-rate insulin clamp, glycerol Rα and fat oxidation were higher in pubertal versus adult subjects (1.5 ± 0.2 vs. 0.9 ± 0.1 μmol · min−1 · kg FFM−1 P = 0.04, and 3.7 ± 0.4 vs. 2.2 ± 0.4 μmol · min−1 · kg FFM−1 P = 0.03, respectively). During the high-rate insulin clamp, fat oxidation was significantly higher in pubertal (1.7 ± 0.3) versus prepubertal (0.7 ± 0.2) versus adult subjects (0.4 ± 0.2 μmol · min−1 · kg FFM−1), and IGF-I levels correlated positively with total-body lipid oxidation (r = 0.72, P < 0.001). Insulin-stimulated total and nonoxidative Rd were significantly lower in pubertal subjects compared with prepubertal and adult subjects (total Rd, 57.7 ± 3.6 vs. 75.8 ± 2.8 vs. 70.0 ± 4.6 l μmol · min−1 · kg FFM−1; nonoxidative Rd, 34.9 ± 3.9 vs. 44.6 ± 1.4 vs. 48.9 ± 3.9 μmol · min−1 · kg FFM−1). Fat oxidation correlated inversely with glucose oxidation, with nonoxidative Rd, and with total Rd. Moreover, the percentage of decrease in lipid oxidation during the clamp correlated with the percentage of increase in carbohydrate oxidation (r = 0.55, P = 0.004). In summary, insulin action in suppressing lipid oxidation and stimulating glucose Rd is decreased during puberty. These data suggest that increased lipid oxidation during puberty may contribute to pubertal insulin resistance at high physiological levels of insulinemia. The mechanisms for these findings remain to be determined but could be influenced by elevated growth hormone and IGF-I levels in puberty.