Glycemic index of a meal fed before exercise alters substrate use and glucose flux in exercising horses.

In a randomized, balanced, crossover study each of six fit, adult horses ran on a treadmill at 50% of maximal rate of oxygen consumption for 60 min after being denied access to food for 18 h and then 1) fed corn (51.4 kJ/kg digestible energy), or 2) fed an isocaloric amount of alfalfa 2-3 h before exercise, or 3) not fed before exercise. Feeding corn, compared with fasting, resulted in higher plasma glucose and serum insulin and lower serum nonesterified fatty acid concentrations before exercise (P < 0.05) and in lower plasma glucose, serum glycerol, and serum nonesterified fatty acid concentrations and higher skeletal muscle utilization of blood-borne glucose during exercise (P < 0.05). Feeding corn, compared with feeding alfalfa, resulted in higher carbohydrate oxidation and lower lipid oxidation during exercise (P < 0.05). Feeding a soluble carbohydrate-rich meal (corn) to horses before exercise results in increased muscle utilization of blood-borne glucose and carbohydrate oxidation and in decreased lipid oxidation compared with a meal of insoluble carbohydrate (alfalfa) or not feeding. Carbohydrate feedings did not produce a sparing of muscle glycogen compared with fasting.     

Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia

Derangements in skeletal muscle fatty acid (FA) metabolism associated with insulin resistance in obesity appear to involve decreased FA oxidation and increased accumulation of lipids such as ceramides and diacylglycerol (DAG). We investigated potential lipid-related mechanisms of metformin (Met) and/or exercise for blunting the progression of hyperglycemia/hyperinsulinemia and skeletal muscle insulin resistance in female Zucker diabetic fatty rats (ZDF), a high-fat (HF) diet-induced model of diabetes. Lean and ZDF rats consumed control or HF diet (48 kcal %fat) alone or with Met (500 mg/kg), with treadmill exercise, or with both exercise and Met interventions for 8 wk. HF-fed ZDF rats developed hyperglycemia (mean: 24.4 +/- 2.1 mM), impairments in muscle insulin-stimulated glucose transport, increases in the FA transporter FAT/CD36, and increases in total ceramide and DAG content. The development of hyperglycemia was significantly attenuated with all interventions, as was skeletal muscle FAT/CD36 abundance and ceramide and DAG content. Interestingly, improvements in insulin-stimulated glucose transport and increased GLUT4 transporter expression in isolated muscle were seen only in conditions that included exercise training. Reduced FA oxidation and increased triacylglycerol synthesis in isolated muscle were observed with all ZDF rats compared with lean rats (P < 0.01) and were unaltered by therapeutic intervention. However, exercise did induce modest increases in peroxisome proliferator-activated receptor-gamma coactivator-1alpha, citrate synthase, and beta-hydroxyacyl-CoA dehydrogenase activity. Thus reduction of skeletal muscle FAT/CD36 and content of ceramide and DAG may be important mechanisms by which exercise training blunts the progression of diet-induced insulin resistance in skeletal muscle.     

The influence of insulin on glucose and fatty acid metabolism in the isolated perfused rat hind quarter.

Glucose and fatty acid metabolism of resting skeletal muscle were studied by perfusion of the isolated rat hind leg with a hemoglobin-free medium. Tissue integrity was demonstrated by normal ATP, ADP and creatine phosphate levels, by a sufficient oxygen supply, and by a normal appearance of perfused muscle specimens under the electron microscope. The rates of glucose and fatty acid uptake, and of lactate, alanine, glycerol and fatty acid release were constant over a perfusion period of 60 min. Insulin (1 unit/l) caused a more than threefold increase in glucose uptake, a stimulation of lactate production, and a 20% increase in the muscular glycogen levels. Fatty acids and alanine release were significantly diminished by insulin, but glycerol release did not change. The uptake of oleate by the rat hind leg was dependent on the medium concentration in a range of 0.7-1.9mM oleate, and was stimulated by insulin. Glucose uptake was not influenced by oleate, whether sodium was present or not. When the leg was perfused with [1-14C]oleate, 75% of the incorporated fatty acids were found in muscle lipids, 10% were oxidized to CO2, and 5% were recovered in bone lipids. The absolute amount of oleate oxidation was not altered by insulin. In all experiments with and without glucose in the medium, 70-80% of the 14C label incorporated into muscle lipids was found in the triglyceride fraction. In the presence of glucose, insulin significantly increased the incorporation of [1-14C]oleate into muscle triglycerides, whereas no insulin effect, either on fatty acid uptake or on triglyceride formation, could be observed when glucose was omitted from the perfusate. The present results indicate that a "glucose-fatty acid cycle" as found in rat heart muscle does not operate in resting peripheral skeletal muscle tissue. They also demonstrate that the stimulating effect of insulin on muscular fatty acid uptake and triglyceride synthesis is dependent on glucose supply. This finding can be intrepreted as a stimulation of fatty acid esterification by sn-glycerol 3-phosphate derived from an increased glucose turnover, which is in turn due to insulin.     

Substrate usage during prolonged exercise following a preexercise meal

The effect of a high-carbohydrate meal 4 h before 105 min of exercise at 70% of maximal O2 uptake was determined in seven endurance-trained cyclists and compared with exercise following a 16-h fast. The preexercise meal produced a transient elevation of plasma insulin and blood glucose, which returned to fasting basal levels prior to the initiation of exercise. The meal also resulted in a 42% elevation (P less than 0.05) of glycogen within the vastus lateralis at the beginning of exercise. The 1st h of exercise when subjects were fed was characterized by a 13-25% decline (P less than 0.05) in blood glucose concentration, a suppression of the normal increase in plasma free fatty acids and blood glycerol, and a 45% (P less than 0.05) greater rate of carbohydrate oxidation compared with exercise when subjects were fasted. After 105 min of exercise, there were no significant differences when subjects were fed or fasted regarding blood glucose levels, rate of carbohydrate oxidation, or muscle glycogen concentration. The greater muscle glycogen utilization (97 +/- 18 vs. 64 +/- 8 mmol glucosyl units X kg-1; P less than 0.05) and carbohydrate oxidation when subjects were fed appeared to be derived from the glycogen synthesized following the meal. These results indicate that preexercise feedings alter substrate availability despite a return of plasma insulin to fasting levels prior to exercise and that these effects persist until the 2nd h of exercise.     

Impaired skeletal muscle substrate oxidation in glucose-intolerant men improves after weight loss

Objective: An impaired fatty acid handling in skeletal muscle may be involved in the development of insulin resistance and diabetes mellitus type 2 (DM2). We investigated muscle fatty acid metabolism in glucose‐intolerant men (impaired glucose tolerance (IGT)), a prediabetic state, relative to BMI‐matched control men (normal glucose tolerance (NGT)) during fasting and after a meal, because most people in the western society are in the fed state most of the day. Methods and Procedures: Skeletal muscle free fatty acid (FFA) uptake and oxidation were studied using the stable isotope tracer [2,2‐²H]‐palmitate and muscle indirect calorimetry in the forearm model during fasting and after a mixed meal (33 energy % (E%) carbohydrates, 61 E% fat). Intramyocellular triglycerides (IMTGs) were monitored with ¹H‐magnetic resonance spectroscopy. IGT men were re‐examined after weight loss (?15% of body weight (BW)). Results: The postprandial increase in forearm muscle respiratory quotient (RQ) was blunted in IGT compared to NGT, but improved after weight loss. Weight loss also improved fasting‐fat oxidation and tended to decrease IMTGs (P = 0.08). No differences were found in fasting and postprandial forearm muscle fatty acid uptake between NGT and IGT, or in IGT before and after weight loss. Discussion: The ability to switch from fat oxidation to carbohydrate oxidation after a meal is already impaired in the prediabetic state, suggesting this may be an early factor in the development toward DM2. This impaired ability to regulate fat oxidation during fasting and after a meal (impaired metabolic flexibility) can be (partly) reversed by weight loss.     

Metabolic effects of glucose, medium chain triglyceride and long chain triglyceride feeding before prolonged exercise in rats

The purpose of this study was to test the hypothesis that oral ingestion of lipids could increase endurance by slowing the rate of glycogen depletion. Trained rats were killed after a 2 h run on a rodent treadmill, following an intragastric infusion of water, glucose, medium chain triglycerides (MCT) or long chain triglycerides (LCT). Glucose and triglycerides were administered in equicaloric concentrations (50 kJ). The results show that oral ingestion of lipids (MCT or LCT) did not reduce glycogen depletion in liver, heart or skeletal muscle after exercise whereas the fat diet increased muscle and heart glycogen stores in resting conditions. In contrast, glucose feeding induced a significant sparing effect on endogenous carbohydrate utilization and reduced physical exercise lipolysis. These data indicated, firstly, that enhanced lipid availability induced by a single lipid meal before exercise was not able to modify the glycogen depletion occurring after exercise and, secondly, that the glucose/fatty acid cycle was not effective in these conditions. The comparison between lipids indicated that the effect on glycogen use of MCT did not differ from that of LCT, and did not seem to be of any particular importance during physical exercise.     

Genistein stimulates fatty acid oxidation in a leptin receptor-independent manner through the JAK2-mediated phosphorylation and activation of AMPK in skeletal muscle

Obesity is a public health problem that contributes to the development of insulin resistance, which is associated with an excessive accumulation of lipids in skeletal muscle tissue. There is evidence that soy protein can decrease the ectopic accumulation of lipids and improves insulin sensitivity; however, it is unknown whether soy isoflavones, particularly genistein, can stimulate fatty acid oxidation in the skeletal muscle. Thus, we studied the mechanism by which genistein stimulates fatty acid oxidation in the skeletal muscle. We showed that genistein induced the expression of genes of fatty acid oxidation in the skeletal muscle of Zucker fa/fa rats and in leptin receptor (ObR)-silenced C2C12 myotubes through AMPK phosphorylation. Furthermore, the genistein-mediated AMPK phosphorylation occurred via JAK2, which was possibly activated through a mechanism that involved cAMP. Additionally, the genistein-mediated induction of fatty acid oxidation genes involved PGC1α and PPARδ. As a result, we observed that genistein increased fatty acid oxidation in both the control and silenced C2C12 myotubes, as well as a decrease in the RER in mice, suggesting that genistein can be used in strategies to decrease lipid accumulation in the skeletal muscle.     

Splanchnic and muscle fructose metabolism during and after exercise

Regional substrate exchange was studied in 12 healthy males during 90 min of bicycle exercise at 30% of maximal O2 consumption with a 20-min recovery. Six subjects received an intravenous fructose infusion (8.5 mmol/min) from 40 min of exercise to the end of recovery. Splanchnic glucose output, muscle glucose uptake, arterial glucose, and insulin were uninfluenced by the infusion. The respiratory exchange ratio rose to 0.93 +/- 0.04, and arterial free fatty acids fell by 50% (P less than 0.05). Fructose was taken up by splanchnic tissues (45% of administered load), leg muscle (28%), and resting muscle (28%). During infusion, arterial lactate and pyruvate rose two- to threefold, and these substrates were released from splanchnic tissues and taken up by exercising and resting muscle. Splanchnic release of lactate, pyruvate, and glucose accounted for 78% of fructose uptake at 90 min of exercise. Uptake of fructose, lactate, and pyruvate accounted for 55% and together with glucose for 103% of the total oxidative metabolism by exercising muscle. The regional fructose uptakes and lactate exchanges persisted throughout recovery. The present results indicate that fructose infusion during leg exercise 1) results in increased carbohydrate oxidation from fructose, lactate, and pyruvate in exercising muscle, 2) exerts a glycogenic effect in resting muscle and liver during exercise and in liver and muscle recovering from exercise, and 3) does not interfere with glucose metabolism, and that fructose transport into muscle differs from that of glucose.     

Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle

During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast.     

Carbohydrate- and lipid-enriched meals acutely disrupt glycemic homeostasis by inducing transient insulin resistance in rats

Chronic intake of high-carbohydrate or high-lipid diets is a well-known insulin resistance inducer. This study investigates the immediate effect (1-6 h) of a carbohydrate- or lipid-enriched meal on insulin sensitivity. Fasted rats were refed with standard, carbohydrate-enriched (C), or lipid-enriched (L) meal. Plasma insulin, glucose, and non-esterified fatty acids (NEFA) were measured at 1, 2, 4, and 6 h of refeeding. The glucose-insulin index showed that either carbohydrates or lipids decreased insulin sensitivity at 2 h of refeeding. At this time point, insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) detected insulin resistance in C rats, while GTT confirmed it in L rats. Reduced glycogen and phosphorylated AKT and GSK3 content revealed hepatic insulin resistance in C rats. Reduced glucose uptake in skeletal muscle subjected to the fatty acid concentration that mimics the high NEFA level of L rats suggests insulin resistance in these animals is mainly in muscle. In conclusion, carbohydrate- or lipid-enriched meals acutely disrupt glycemic homeostasis, inducing a transient insulin resistance, which seems to involve liver and skeletal muscle, respectively. Thus, the insulin resistance observed when those types of diets are chronically consumed may be an evolution of repeated episodes of this transient insulin resistance.     

Alpha2-AMPK activity is not essential for an increase in fatty acid oxidation during low-intensity exercise

A single bout of exercise increases glucose uptake and fatty acid oxidation in skeletal muscle, with a corresponding activation of AMP-activated protein kinase (AMPK). While the exercise-induced increase in glucose uptake is partly due to activation of AMPK, it is unclear whether the increase of fatty acid oxidation is dependent on activation of AMPK. To examine this, transgenic mice were produced expressing a dominant-negative (DN) mutant of alpha(1)-AMPK (alpha(1)-AMPK-DN) in skeletal muscle and subjected to treadmill running. alpha(1)-AMPK-DN mice exhibited a 50% reduction in alpha(1)-AMPK activity and almost complete loss of alpha(2)-AMPK activity in skeletal muscle compared with wild-type littermates (WT). The fasting-induced decrease in respiratory quotient (RQ) ratio and reduced body weight were similar in both groups. In contrast with WT mice, alpha(1)-AMPK-DN mice could not perform high-intensity (30 m/min) treadmill exercise, although their response to low-intensity (10 m/min) treadmill exercise was not compromised. Changes in oxygen consumption and the RQ ratio during sedentary and low-intensity exercise were not different between alpha(1)-AMPK-DN and WT. Importantly, at low-intensity exercise, increased fatty acid oxidation in response to exercise in soleus (type I, slow twitch muscle) or extensor digitorum longus muscle (type II, fast twitch muscle) was not impaired in alpha(1)-AMPK-DN mice, indicating that alpha(1)-AMPK-DN mice utilize fatty acid in the same manner as WT mice during low-intensity exercise. These findings suggest that an increased alpha(2)-AMPK activity is not essential for increased skeletal muscle fatty acid oxidation during endurance exercise.     

Restoration of skeletal muscle leptin response does not precede the exercise-induced recovery of insulin-stimulated glucose uptake in high-fat-fed rats

Leptin administration increases fatty acid (FA) oxidation rates and decreases lipid storage in oxidative skeletal muscle, thereby improving insulin response. We have previously shown high-fat (HF) diets to rapidly induce skeletal muscle leptin resistance, prior to the disruption of normal muscle FA metabolism (increase in FA transport; accumulation of triacylglycerol, diacylglycerol, ceramide) that occurs in advance of impaired insulin signaling and glucose transport. All of this occurs within a 4-wk period. Conversely, exercise can rapidly improve insulin response, in as little as one exercise bout. Thus, if the early development of leptin resistance is a contributor to HF diet-induced insulin resistance (IR) in skeletal muscle, then it is logical to predict that the rapid restoration of insulin response by exercise training would be preceded by the recovery of leptin response. In the current study, we sought to determine 1) whether 1, 2, or 4 wk of exercise training was sufficient to restore leptin response in isolated soleus muscle of rats already consuming a HF diet (60% kcal), and 2) whether this preceded the training-induced corrections in FA metabolism and improved insulin-stimulated glucose transport. In the low-fat (LF)-fed control group, insulin increased glucose transport by 153% and leptin increased AMPK and ACC phosphorylation and the rate of palmitate oxidation (+73%). These responses to insulin and leptin were either severely blunted or absent following 4 wk of HF feeding. Exercise intervention decreased muscle ceramide content (-28%) and restored insulin-stimulated glucose transport to control levels within 1 wk; muscle leptin response (AMPK and ACC phosphorylation, FA oxidation) was also restored, but not until the 2-wk time point. In conclusion, endurance exercise training is able to restore leptin response, but this does not appear to be a necessary precursor for the restoration of insulin response.     

The insulin-sensitive GLUT4 storage compartment is a postendocytic and heterogeneous population recruited by acute exercise

Insulin and acute exercise stimulate glucose transport in skeletal muscle by translocating GLUT4 glucose transporters to the cell surface. GLUT4 is distributed in skeletal muscle in two intracellular membrane populations, an endosomal pool that remains unaltered after insulin treatment and an storage population that is markedly GLUT4 depleted in response to insulin. Here we have further characterized the storage GLUT4 compartment in regard to protein composition and sensitivity to acute exercise. This GLUT4 compartment contained IRAP (insulin-regulated aminopeptidase), transferrin receptors or mannose-6-phosphate/IGF-II receptors, indicating a postendocytic origin. Insulin administration caused a depletion of GLUT4 and IRAP but no changes in transferrin receptors, which suggests that this pool is heterogeneous. In addition, acute exercise caused a marked GLUT4 depletion in the storage compartment, whereas no changes were detected in the endosomal population. In all, our data indicate that the GLUT4 storage population represents a postendocytic and heterogeneous compartment; the storage compartment represents the recruitment site that triggers GLUT4 translocation to the cell surface in response to both insulin and acute exercise.     

Diacylglycerol kinase ε deficiency preserves glucose tolerance and modulates lipid metabolism in obese mice

Diacylglycerol kinases (DGKs) catalyze the phosphorylation and conversion of diacylglycerol (DAG) into phosphatidic acid. DGK isozymes have unique primary structures, expression patterns, subcellular localizations, regulatory mechanisms, and DAG preferences. DGKε has a hydrophobic segment that promotes its attachment to membranes and shows substrate specificity for DAG with an arachidonoyl acyl chain in the sn-2 position of the substrate. We determined the role of DGKε in the regulation of energy and glucose homeostasis in relation to diet-induced insulin resistance and obesity using DGKε-KO and wild-type mice. Lipidomic analysis revealed elevated unsaturated and saturated DAG species in skeletal muscle of DGKε KO mice, which was paradoxically associated with increased glucose tolerance. Although skeletal muscle insulin sensitivity was unaltered, whole-body respiratory exchange ratio was reduced, and abundance of mitochondrial markers was increased, indicating a greater reliance on fat oxidation and intracellular lipid metabolism in DGKε KO mice. Thus, the increased intracellular lipids in skeletal muscle from DGKε KO mice may undergo rapid turnover because of increased mitochondrial function and lipid oxidation, rather than storage, which in turn may preserve insulin sensitivity. In conclusion, DGKε plays a role in glucose and energy homeostasis by modulating lipid metabolism in skeletal muscle.     

Metabolic adaptations in skeletal muscle overexpressing GLUT4: effects on muscle and physical activity.

To understand the long-term metabolic and functional consequences of increased GLUT4 content, intracellular substrate utilization was investigated in isolated muscles of transgenic mice overexpressing GLUT4 selectively in fast-twitch skeletal muscles. Rates of glycolysis, glycogen synthesis, glucose oxidation, and free fatty acid (FFA) oxidation as well as glycogen content were assessed in isolated EDL (fast-twitch) and soleus (slow-twitch) muscles from female and male MLC-GLUT4 transgenic and control mice. In male MLC-GLUT4 EDL, increased glucose influx predominantly led to increased glycolysis. In contrast, in female MLC-GLUT4 EDL increased glycogen synthesis was observed. In both sexes, GLUT4 overexpression resulted in decreased exogenous FFA oxidation rates. The decreased rate of FFA oxidation in male MLC-GLUT4 EDL was associated with increased lipid content in liver, but not in muscle or at the whole body level. To determine how changes in substrate metabolism and insulin action may influence energy balance in an environment that encouraged physical activity, we measured voluntary training activity, body weight, and food consumption of MLC-GLUT4 and control mice in cages equipped with training wheels. We observed a small decrease in body weight of MLC-GLUT4 mice that was paradoxically accompanied by a 45% increase in food consumption. The results were explained by a marked fourfold increase in voluntary wheel exercise. The changes in substrate metabolism and physical activity in MLC-GLUT4 mice were not associated with dramatic changes in skeletal muscle morphology. Collectively, results of this study demonstrate the feasibility of altering muscle substrate utilization by overexpression of GLUT4. The results also suggest that as a potential treatment for type II diabetes mellitus, increased skeletal muscle GLUT4 expression may provide benefits in addition to improvement of insulin action.     

Regulation of plasma long-chain fatty acid oxidation in relation to uptake in human skeletal muscle during exercise

In the present study, we investigated possible sites of regulation of long-chain fatty acid (LCFA) oxidation in contracting human skeletal muscle. Leg plasma LCFA kinetics were determined in eight healthy men during bicycling (60 min, 65% peak oxygen uptake) with either high (H-FOX) or low (L-FOX) leg fat oxidation (H-FOX: 1,098 +/- 140; L-FOX: 494 +/- 84 micromol FA/min, P < 0.001), which was achieved by manipulating preexercise muscle glycogen (H-FOX: 197 +/- 21; L-FOX: 504 +/- 25 mmol/kg dry wt, P < 0.001). Several blood metabolites and hormones were kept nearly similar between trials by allocating a preexercise meal and infusing glucose intravenously during exercise. During exercise, leg plasma LCFA fractional extraction was identical between trials (H-FOX: 17.8 +/- 1.6; L-FOX: 18.2 +/- 1.8%, not significant), suggesting similar LCFA transport capacity in muscle. On the contrary, leg plasma LCFA oxidation was 99% higher in H-FOX than in L-FOX (421 +/- 47 vs. 212 +/- 37 micromol/min, P < 0.001). Probably due to the slightly higher (P < 0.01) plasma LCFA concentration in H-FOX than in L-FOX, leg plasma LCFA uptake was nonsignificantly (P = 0.17) higher (25%) in H-FOX than in L-FOX, yet the fraction of plasma LCFA uptake oxidized was 61% higher (P < 0.05) in H-FOX than in L-FOX. Accordingly, the muscle content of several lipid-binding proteins did not differ significantly between trials, although fatty acid translocase/CD36 and caveolin-1 were elevated (P < 0.05) by the high-intensity exercise and dietary manipulation allocated on the day before the experimental trial. The present data suggest that, in contracting human skeletal muscle with different fat oxidation rates achieved by manipulating preexercise glycogen content, transsarcolemmal transport is not limiting plasma LCFA oxidation. Rather, the latter seems to be limited by intracellular regulatory mechanisms.     

Peripheral glucose metabolism in patients with essential hypertension.

The present study was designed to determine the effect of essential hypertension on peripheral glucose metabolism during the postabsorptive state and after an oral glucose challenge. Ten normal subjects and nine patients with essential hypertension were studied after an overnight fast (12-14 h) and for 3 h after the ingestion of 75 g of glucose. Peripheral glucose metabolism was analyzed by the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. Decreased forearm glucose uptake was observed in hypertensive patients compared to normal subjects (4.9+/-0.6 vs. 8.6+/-0.5 mmol x 100 ml forearm(-1) x 3 h(-1)) with diminished nonoxidative glucose metabolism (2.7+/-0.5 vs. 6.9+/-0.6 mmol x 100 ml forearm(-1) x 3 h(-1)). Muscle glucose oxidation did not differ significantly between groups. Both serum free fatty acid levels and lipid oxidation rates were similar in the normal subjects and the hypertensive patients, and declined in a similar fashion after glucose ingestion. Basal serum insulin levels did not differ significantly between normal and hypertensive patients, whereas the insulinemic response to glucose load was greater among the patients with essential hypertension. These data show that insulin resistance occurring in patients with essential hypertension is accompanied by impaired muscle glucose uptake and nonoxidative metabolism.     

Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism

Acute exercise can reverse muscle insulin resistance, but the mechanism(s) of action are unknown. With the use of a hindlimb perfusion model, we have found that acute contraction restores insulin-stimulated glucose uptake in muscle of obese Zucker rats to levels witnessed in lean controls. Previous reports have suggested that obesity-related insulin resistance stems from lipid oversupply and tissue accumulation of toxic lipid intermediates that impair insulin signaling. We reasoned that contraction might activate hydrolysis and oxidation of intramuscular lipids, thus alleviating "lipotoxicity" and priming the muscle for enhanced insulin action. Indeed, analysis of mitochondrial-derived acyl-carnitine esters suggested that contraction caused robust increases in -oxidative flux and mitochondrial oxidation. As predicted, contraction decreased intramuscular triacylglycerol content; however, diacylglycerol and long chain acyl-CoAs, lipid intermediates presumed to trigger insulin resistance, were either unchanged or increased. In muscles from obese animals, insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 remained impaired after contraction, whereas phosphorylation of the downstream signaling protein, AS160, was partially restored. These results suggest that acute exercise enables diabetic muscle to circumvent upstream defects in insulin signal transduction via mechanisms that are more tightly coupled to increased mitochondrial energy metabolism than the lowering of diacylglycerol and long chain acyl-CoA. skeletal muscle; intramuscular lipids; signaling; exercise     

Effect of exercise on insulin action in human skeletal muscle

The effect of 1 h of dynamic one-legged exercise on insulin action in human muscle was studied in 6 healthy young men. Four hours after one-legged knee extensions, a three-step sequential euglycemic hyperinsulinemic clamp combined with arterial and bilateral femoral vein catheterization was performed. Increased insulin action on glucose uptake was found in the exercised compared with the rested thigh at mean plasma insulin concentrations of 23, 40, and 410 microU/ml. Furthermore, prior contractions directed glucose uptake toward glycogen synthesis and increased insulin effects on thigh O2 consumption and at some insulin concentrations on potassium exchange. In contrast, no change in insulin effects on limb exchange of free fatty acids, glycerol, alanine or tyrosine were found after exercise. Glycogen concentration in rested vastus lateralis muscle did not increase measurably during the clamp even though indirect estimates indicated net glycogen synthesis. In contrast, in exercised muscle estimated and biopsy-verified increases in muscle glycogen concentration agreed. Local contraction-induced increases in insulin sensitivity and responsiveness play an important role in postexercise recovery of human skeletal muscle.     

Glucose-fatty acid interaction in skeletal muscle and adipose tissue in insulin resistance

Insulin resistance (IR) is the result of long-lasting positive energy balance and the imbalance between the uptake of energy rich substrates (glucose, lipids) and energy output. The defects in the metabolism of glucose in IR and type 2 diabetes are closely associated with the disturbances in the metabolism of lipids. In this review, we have summarized the evidence indicating that one of the important mechanisms underlying the development of IR is the impaired ability of skeletal muscle to oxidize fatty acids as a consequence of elevated glucose oxidation in the situation of hyperglycemia and hyperinsulinemia and the impaired ability to switch easily between glucose and fat oxidation in response to homeostatic signals. The decreased fat oxidation results into the accumulation of intermediates of fatty acid metabolism that are supposed to interfere with the insulin signaling cascade and in consequence negatively influence the glucose utilization. Pathologically elevated fatty acid concentration in serum is now accepted as an important risk factor leading to IR. Adipose tissue plays a crucial role in the regulation of fatty acid homeostasis. The adipose tissue may be the primary site where the early metabolic disturbances leading to the development of IR take place and the development of IR in other tissues follows. In this review we present recent evidence of mutual interaction between skeletal muscle and adipose tissue in the establishment of IR and type 2 diabetes.