To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13 C and 31 P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 Ϯ 0.02 mM [mean Ϯ SEM]; control) or high (1.93 Ϯ 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic ( ف 5.2 mM) hyperinsulinemic ( ف 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be ف 46% of control values after 6 h ( P Ͻ 0.00001). Augmented lipid oxidation was accompanied by a ف 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion ( P Ͻ 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to ف 50% of control values (4.0 Ϯ 1.0 vs. 9.3 Ϯ 1.6 mol/[kg и min], P Ͻ 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at ف 1.5 h (195 Ϯ 25 vs. control: 237 Ϯ 26 M; P Ͻ 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an ف 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation. ( J. Clin. Invest. 1996. 97:2859-2865.) Key words: free fatty acids • muscle glycogen • glucose transport • nuclear magnetic resonance spectroscopy • glucose-6-phosphate
Exercise increases insulin sensitivity in both normal subjects and the insulin-resistant offspring of diabetic parents because of a twofold increase in insulin-stimulated glycogen synthesis in muscle, due to an increase in insulin-stimulated glucose transport-phosphorylation.
The alpha-actinin 3 (ACTN3) gene encodes a protein of the Z disk of myofibers, and a polymorphism of ACTN3 results in complete loss of the protein. The ACTN3 genotype (R577X) has been found to be associated with performance in Australian elite athletes (Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, and North K. Am J Hum Genet 73: 627-631, 2003). We studied associations between ACTN3 genotype and muscle size [cross-sectional area of the biceps brachii via magnetic resonance imaging (MRI)] and elbow flexor isometric (MVC) and dynamic [1-repetition maximum (1-RM)] strength in a large group of men (N = 247) and women (N = 355) enrolled in a 12-wk standardized elbow flexor/extensor resistance training program of the nondominant arm at one of eight study centers. We found no association between ACTN3 R577X genotype and muscle phenotype in men. However, women homozygous for the ACTN3 577X allele (XX) had lower baseline MVC compared with heterozygotes (P < 0.05) when adjusted for body mass and age. Women homozygous for the mutant allele (577X) demonstrated greater absolute and relative 1-RM gains compared with the homozygous wild type (RR) after resistance training when adjusted for body mass and age (P < 0.05). There was a trend for a dose-response with genotype such that gains were greatest for XX and least for RR. Significant associations were validated in at least one ethnic subpopulation (Caucasians, Asians) and were independent of training volume. About 2% of baseline MVC and of 1-RM strength gain after training were attributable to ACTN3 genotype (likelihood-ratio test P value, P = 0.01), suggesting that ACTN3 is one of many genes contributing to genetic variation in muscle performance and adaptation to exercise.
In the present study, we tested the hypothesis that a carbohydrate-protein (CHO-Pro) supplement would be more effective in the replenishment of muscle glycogen after exercise compared with a carbohydrate supplement of equal carbohydrate content (LCHO) or caloric equivalency (HCHO). After 2.5 +/- 0.1 h of intense cycling to deplete the muscle glycogen stores, subjects (n = 7) received, using a rank-ordered design, a CHO-Pro (80 g CHO, 28 g Pro, 6 g fat), LCHO (80 g CHO, 6 g fat), or HCHO (108 g CHO, 6 g fat) supplement immediately after exercise (10 min) and 2 h postexercise. Before exercise and during 4 h of recovery, muscle glycogen of the vastus lateralis was determined periodically by nuclear magnetic resonance spectroscopy. Exercise significantly reduced the muscle glycogen stores (final concentrations: 40.9 +/- 5.9 mmol/l CHO-Pro, 41.9 +/- 5.7 mmol/l HCHO, 40.7 +/- 5.0 mmol/l LCHO). After 240 min of recovery, muscle glycogen was significantly greater for the CHO-Pro treatment (88.8 +/- 4.4 mmol/l) when compared with the LCHO (70.0 +/- 4.0 mmol/l; P = 0.004) and HCHO (75.5 +/- 2.8 mmol/l; P = 0.013) treatments. Glycogen storage did not differ significantly between the LCHO and HCHO treatments. There were no significant differences in the plasma insulin responses among treatments, although plasma glucose was significantly lower during the CHO-Pro treatment. These results suggest that a CHO-Pro supplement is more effective for the rapid replenishment of muscle glycogen after exercise than a CHO supplement of equal CHO or caloric content.
To study the effects of glycogen depletion and insulin concentration on glycogen synthesis, gastrocnemius glycogen was measured with 13C-nuclear magnetic resonance at 4.7 T after exercise. Subjects performed single-leg toe raises to deplete gastrocnemius glycogen to 75, 50, or 25% of resting concentration (protocol I). Insulin dependence of glycogen synthesis was assessed after depletion to 25% with (protocol II) and without (protocol III) infusion of somatostatin to inhibit insulin secretion. After depletion to 75 and 50%, glycogen resynthesis rates were similar (2.4 +/- 0.7 and 2.8 +/- 0.6 mM/h, respectively). When glycogen was depleted to 25% (< 30 mM), the resynthesis rate was significantly higher (P < 0.02) at 33 +/- 7 mM/h, and it declined to 3.5 +/- 0.9 mM/h at > 35 mM glycogen. At < 35 mM glycogen, synthesis was not affected by low insulin (24 +/- 4 mM/h, protocol vs. 19 +/- 3 mM/h, protocol III), whereas at > 35 mM glycogen, synthesis ceased without insulin (-0.07 +/- 0.19 mM/h, protocol II). After depletion to 25% (protocol III), plasma lactate transiently increased (0.81 mM at rest, 1.82 mM 0 h after exercise, and 0.76 mM 2 h after exercise), whereas other plasma constituents did not significantly change. We conclude that after depletion to < 30 mM initial glycogen resynthesis is insulin independent and glycogen dependent, which suggests local control.
Recent developments in I3C nuclear magnetic resonance ( NMR) spectroscopy have permitted noninvasive assessment of glycogen concentration in human skeletal muscle. Before these indirect measurements could be accepted as accurate, it was essential that validation should be carried out by comparing the widely used method of muscle biopsy and direct biochemical assay for glycogen concentration with measurement by NMR. Eight normal subjects underwent six NMR scans of gastrocnemius and three biopsies of the same muscle on the same day. The overall mean for muscle glycogen concentration was 87.4 mM by NMR and 88.3 m M by biopsy. There was a close correlation between the pairs of observations on each subject (R = 0.95; P < 0.0001 ). The mean coefficient of variation for NMR measurement was 4.3 f 2.1% and that for biopsy was 9.3 +-5.9%. The performance of the muscle biopsies was accompanied by a small but significant rise in plasma-free fatty acids (529 f 157 to 667 f 250; P < 0.01 ), epinephrine ( 17 2 6 to 25 t 8 pg/ml; P < 0.02), and norepinephrine (318 2 119 to 400 f 140 pg/ml; P < 0.02) but no change in plasma glucose, plasma insulin, nor muscle glycogen concentration assessed by NMR. The study demonstrates that in vivo I3C NMR measurement of human muscle glycogen can be regarded as accurate, and the technique is associated with a higher precision than biopsy with direct biochemical assessment. o
FAMuSS should help identify genetic factors associated with muscle performance and the response to exercise training. Such insight should contribute to our ability to predict the individual response to exercise training but may also contribute to understanding better muscle physiology, to identifying individuals who are susceptible to muscle loss with environmental challenge, and to developing pharmacologic agents capable of preserving muscle size and function.
To examine the impact of insulin resistance on the insulin-dependent and insulin-independent portions of muscle glycogen synthesis during recovery from exercise, we studied eight young, lean, normoglycemic insulin-resistant (IR) offspring of individuals with non-insulin-dependent diabetes mellitus and eight age-weight matched control (CON) subjects after plantar flexion exercise that lowered muscle glycogen to -25% of resting concentration. After '20 min of exercise, intramuscular glucose 6-phosphate and glycogen were simultaneously monitored with 31P and 13C NMR spectroscopies. The postexercise rate of glycogen resynthesis was nonlinear. Glycogen synthesis rates during the initial insulin independent portion (0-1 hr of recovery) were similar in the two groups (IR, 15.5 ± 1.3 mM/hr and CON, 15.8 + 1.7 mM/hr); however, over the next 4 hr, insulin-dependent glycogen synthesis was significantly reduced in the IR group [IR, 0.1 + 0.5 mM/hr and CON, 2.9 ± 0.2 mM/hr; (P ' 0.001)]. After exercise there was an initial rise in glucose 6-phosphate concentrations that returned to baseline after the first hour of recovery in both groups. In summary, we found that following muscle glycogen-depleting exercise, IR offspring of parents with non-insulin-dependent diabetes mellitus had (i) normal rates of muscle glycogen synthesis during the insulin-independent phase of recovery from exercise and (ii) severely diminished rates of muscle glycogen synthesis during the subsequent recovery period (2-5 hr), which has previously been shown to be insulin-dependent in normal CON subjects. These data provide evidence that exercise and insulin stimulate muscle glycogen synthesis in humans by different mechanisms and that in the IR subjects the early response to stimulation by exercise is normal.After intense exercise that depletes muscle glycogen concentrations to <35 mM glycogen, resynthesis proceeds in an approximately biphasic manner in both animal and human skeletal muscles (1-4). In normal healthy humans, there is an initial phase of rapid glycogen resynthesis (12-30 mM/hr) lasting -45 min that is insulin independent (1). The subsequent period of glycogen resynthesis (beyond -35 mM glycogen) is much slower (-3 mM/hr) and insulin dependent (5).Exercise and insulin are both known to stimulate muscle glucose uptake and subsequent glycogen synthesis in an independent and additive manner (6-10). Under resting conditions, the effect of insulin stimulation on glycogen synthesis has been compared in healthy control (CON) subjects and in subjects with non-insulin-dependent diabetes mellitus (NIDDM) by 13C NMR (11). In both CON subjects and NIDDM subjects placed under hyperglycemic-hyperinsulinemic conditions, the major pathway of insulin-dependent glucose metabolism was muscle glycogen synthesis (11). However, in the NIDDM subjects the rate of muscle glycogen synthesis was significantly impaired (11).31P NMR has been used to measure concentrations of glucose 6-phosphate (G6P), an intermediate of glycogen synthesis, under hyperglycemic-...
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