The effects of cortisol on insulin sensitivity in muscle

Holmäng , A. & Björntorp , P. 1992. The effects of cortisol on insulin sensitivity in muscle. Acta Physiol Scand 144 , 425–431. Received 12 September 1 991 , accepted 20 November 1991. ISSN 0001–6722. Department of Medicine I and The Wallenberg Laboratory, Sahlgren's Hospital, University of C., teborg, Sweden The effects of cortisol on insulin sensitivity were examined in rats with the euglycaemic, hyperinsulinaemic clamp technique. Uptake of 2–deoxyglucose and incorporation of glucose into glycogen was followed in the white gastrocnemius, extensor digitorum longus, red gastrocnemius and soleus muscles as well as the liver (only glycogen synthesis). Maximal velocity and fractional velocity of the insulin-sensitive part of glycogen synthase (FV %) was measured in the muscles, as well as muscle fibre composition and capillary density. After 24 h exposure to cortisol, insulin sensitivity was diminished in the clamp measurements. This was paralleled by a decrease in glycogen synthesis in the most insulin-sensitive red gastrocnemius and Soleus muscles, but not in the white gastrocnemius or extensor digitorum longus muscles or the liver, and no effect was seen on 2–deoxyglucose uptake in muscles. FV % was markedly inhibited in all muscles. After 48 h exposure to cortisol, glycogen synthesis was markedly inhibited in all muscles, and 2–deoxyglucose uptake in all except the least insulin-sensitive muscle, WG. No changes in muscle morphology were found. These results suggest that the insulin resistance caused by cortisol is elicited in a stepwise manner, starting with an inhibition in the glycogen synthesis system in insulin-sensitive muscles, later including all muscles as well as 2–deoxyglucose uptake. This occurs without changes in morphology.     

Effect of creatine supplementation on creatine and glycogen content in rat skeletal muscle

The effects of high dose creatine feeding (5 g kg(-1) BW day(-1), 5 days) on creatine content, glucose transport, and glycogen accumulation in white gastrocnemius, red gastrocnemius and soleus muscles of the rat was investigated. Isolated rat hindquarters of creatine fed and control rats were perfused with a standard medium containing either insulin alone (0, 100 or 20 000 microU mL(-1)) or in combination with creatine (2 or 10 mmol L(-1)). Furthermore, plasma insulin concentration was measured in normal rats during creatine feeding, as well as in anaesthetized rats during intravenous creatine infusion. Five days of creatine feeding increased (P < 0.05) total creatine content in soleus (+ 20%) but not in red gastrocnemius (+15%, n.s.) and white gastrocnemius (+ 10%, n.s.). In parallel, glycogen content was markedly elevated (P < 0.05) in soleus (+ 40%), less (P < 0.05) in red gastrocnemius (+ 15%), and not in white gastrocnemius (+ 10%, n.s.). Glucose transport rate, muscle GLUT-4 content, glycogen synthase activity in perfused muscles and glycogen synthesis rate were not significantly altered by creatine feeding in either muscle type. Furthermore, high dose creatine feeding raised (P < 0.05) plasma creatine concentration fivefold but did not alter circulating insulin level. It is concluded that short-term high dose creatine feeding enhances creatine disposal and glycogen storage in rat skeletal muscle. However, the creatine and glycogen response to creatine supplementation is markedly greater in oxidative than in glycolytic muscles.     

Improved insulin‐stimulated glucose uptake and glycogen synthase activation in rat skeletal muscles after adrenaline infusion: role of glycogen content and PKB phosphorylation

Aim: Effects of in vivo adrenaline infusion on subsequent insulin‐stimulated glucose uptake and glycogen synthase activation was investigated in slow‐twitch (soleus) and fast‐twitch (epitrochlearis) muscles. Furthermore, role of glycogen content and Protein kinase B (PKB) phosphorylation for modulation insulin sensitivity was investigated. Methods: Male Wistar rats received adrenaline from osmotic mini pumps (≈150 μg kg^?1 h^?1) for 1 or 12 days before muscles were removed for in vitro studies. Results: Glucose uptake at physiological insulin concentration was elevated in both muscles after 1 and 12 days of adrenaline infusion. Insulin‐stimulated glycogen synthase activation was also improved in both muscles. This elevated insulin sensitivity occurred despite the muscles were exposed to hyperglycaemia in vivo. After 1 day of adrenaline infusion, glycogen content was reduced in both muscles; insulin‐stimulated PKB ser⁴⁷³ phosphorylation was increased in both muscles only at the highest insulin concentration. After 12 days of adrenaline infusion, glycogen remained low in epitrochlearis, but returned to normal level in soleus; insulin‐stimulated PKB phosphorylation was normal in both muscles. Conclusion: Insulin‐stimulated glucose uptake and glycogen synthase activation were increased after adrenaline infusion. Increased insulin‐stimulated glucose uptake and glycogen synthase activation after adrenaline infusion cannot be explained by a reduction in glycogen content or an increase in PKB phosphorylation. The mechanisms for the improved insulin sensitivity after adrenaline treatment deserve particular attention as they occur in conjunction with hyperglycaemia.     

The effects of cortisol on insulin sensitivity in muscle.

The effects of cortisol on insulin sensitivity were examined in rats with the euglycaemic, hyperinsulinaemic clamp technique. Uptake of 2-deoxyglucose and incorporation of glucose into glycogen was followed in the white gastrocnemius, extensor digitorum longus, red gastrocnemius and soleus muscles as well as the liver (only glycogen synthesis). Maximal velocity and fractional velocity of the insulin-sensitive part of glycogen synthase (FV %) was measured in the muscles, as well as muscle fibre composition and capillary density. After 24 h exposure to cortisol, insulin sensitivity was diminished in the clamp measurements. This was paralleled by a decrease in glycogen synthesis in the most insulin-sensitive red gastrocnemius and Soleus muscles, but not in the white gastrocnemius or extensor digitorum longus muscles or the liver, and no effect was seen on 2-deoxyglucose uptake in muscles. FV % was markedly inhibited in all muscles. After 48 h exposure to cortisol, glycogen synthesis was markedly inhibited in all muscles, and 2-deoxyglucose uptake in all except the least insulin-sensitive muscle, WG. No changes in muscle morphology were found. These results suggest that the insulin resistance caused by cortisol is elicited in a stepwise manner, starting with an inhibition in the glycogen synthesis system in insulin-sensitive muscles, later including all muscles as well as 2-deoxyglucose uptake. This occurs without changes in morphology.     

The effects of long-term hyperinsulinaemia on insulin sensitivity in rats

The effects of long-term exposure (7 wk) to hyperinsulinaemia on insulin sensitivity were studied in female rats. The rats were made hyperinsulinaemic by implantation of osmotic minipumps that were changed once a week. Elevated adrenergic activity and secretion of glucocorticoids were controlled by another minipump with propranolol and adrenalectomy with corticosterone substitution, respectively. This resulted in hyperinsulinaemia and moderate hypoglycaemia, the latter probably counteracted by overeating and increased glucagon secretion, as indicated by increased body weight and lower liver glycogen contents, respectively. Euglycaemic, hyperinsulinaemic clamp measurements showed a significantly higher glucose disposal rate (P < 0.05) in the hyperinsulinaemic rats 18.8± 1.1 mg kg^-1 min^-1 compared with the control groups 14.6±0.4 and 15.4±0.9 mg kg^-1 min^-1. Insulin stimulation of 2-deoxyglucose as well as glycogen synthesis was measured in the extensor digitorum longus muscle, the red and white part of the gastrocnemius, the soleus muscle, the liver and in parametrial, retroperitoneal, and inguinal adipose tissue. No differences were found between the groups in the insulin response of the 2-deoxyglucose uptake. Glycogen synthesis was significantly elevated in all muscles in the insulin treated compared with the control rats but no differences were found in the liver. Capillary density was significantly elevated per unit muscle surface area in the soleus and extensor digitorum longus muscles of the insulin-exposed rats. These results suggest that long-term exposure to insulin is followed by increased insulin sensitivity, apparently localized to the insulin regulation of glycogen synthesis in muscles. Muscle capillary density is elevated in parallel.     

The effect of acute exercise on glycogen synthesis rate in obese subjects studied by 13C MRS

In obesity, insulin-stimulated glucose uptake in skeletal muscle is decreased. We investigated whether the stimulatory effect of acute exercise on glucose uptake and subsequent glycogen synthesis was normal. The study was performed on 18 healthy volunteers, 9 obese (BMI?=?32.6?±?1.2?kg/m², mean?±?SEM) and 9 lean (BMI?=?22.0?±?0.9?kg/m²), matched for age and gender. All participants underwent a euglycemic hyperinsulinemic clamp, showing reduced glucose uptake in the obese group (P?=?0.01), during which they performed a short intense local exercise (single-legged toe lifting). Dynamic glucose incorporation into glycogen in the gastrocnemius muscle before and after exercise was assessed by ¹³C magnetic resonance spectroscopy combined with infusion of [1-¹³C]glucose. Blood flow was measured to investigate its potential contribution to glucose uptake. Before exercise, glycogen synthesis rate tended to be lower in obese subjects compared with lean (78?±?14 vs. 132?±?24???mol/kg muscle/min; P?=?0.07). Exercise induced highly significant rises in glycogen synthesis rates in both groups, but the increase in obese subjects was reduced compared with lean (112?±?15 vs. 186?±?27???mol/kg muscle/min; P?=?0.03), although the relative increase was similar (184?±?35 vs. 202?±?51%; P?=?0.78). After exercise, blood flow increased equally in both groups, without a temporal relationship with the rate of glycogen synthesis. In conclusion, this study shows a stimulatory effect of a short bout of acute exercise on insulin-induced glycogen synthesis rate that is reduced in absolute values but similar in percentages in obese subjects. These results suggest a shared pathway between insulin- and exercise-induced glucose uptake and subsequent glycogen synthesis.     

Glycogen content regulates insulin‐ but not contraction‐mediated glycogen synthase activation in the rat slow‐twitch soleus muscles

Aim: The aim of this study was to investigate the effect of glycogen content on glycogen synthase (GS) activation and phosphorylation in the slow‐twitch soleus muscles after contraction, during insulin stimulation and when these two stimuli were combined. Methods: Glycogen content was manipulated in vivo with 24 h fasting and fasting followed by 24 h refeeding. Soleus strips were electrically stimulated for 30 min in vitro, and GS activation and phosphorylation were investigated after an additional 30 min incubation with or without insulin. Results: Fasting reduced glycogen content in soleus muscle by 40% and refeeding enhanced by 40%, compared to rats with free access to chow. Insulin‐stimulated GS fractional activity was inversely correlated with glycogen content (R = ?0.95, P < 0.001, n = 24) and rate of glycogen synthesis was also inversely correlated with glycogen content (R = ?0.70, P < 0.001, n = 36). After contraction, GS fractional activity was increased to similar levels in muscles with low, normal and high glycogen content; rate of glycogen synthesis after contraction was also similar. After contraction, insulin additively increased GS activation at all glycogen contents. Group means of GS fractional activity was inversely correlated with GS Ser⁶⁴¹ (R = ?0.93, P < 0.001) and Ser^{645,649,653,657} (R = ?0.85, P < 0.001) phosphorylation, but not with Ser⁷ phosphorylation. Conclusion: Glycogen content regulates insulin‐ but not contraction‐stimulated GS activation and glycogen synthesis in soleus muscles. Furthermore, phosphorylation of GS Ser⁶⁴¹ and Ser^{645,649,653,657} seems to regulate GS activity in soleus.     

Dynamic multivoxel‐localized 31P MRS during plantar flexion exercise with variable knee angle

Exercise studies investigating the metabolic response of calf muscles using ³¹P MRS are usually performed with a single knee angle. However, during natural movement, the distribution of workload between the main contributors to force, gastrocnemius and soleus is influenced by the knee angle. Hence, it is of interest to measure the respective metabolic response of these muscles to exercise as a function of knee angle using localized spectroscopy. Time‐resolved multivoxel ³¹P MRS at 7 T was performed simultaneously in gastrocnemius medialis and soleus during rest, plantar flexion exercise and recovery in 12 healthy volunteers. This experiment was conducted with four different knee angles. PCr depletions correlated negatively with knee angle in gastrocnemius medialis, decreasing from 79±14 % (extended leg) to 35±23 %(～40°), and positively in soleus, increasing from 20±21 % to 36±25 %; differences were significant. Linear correlations were found between knee angle and end‐exercise PCr depletions in gastrocnemius medialis (R²=0.8) and soleus (R²=0.53). PCr recovery times and end‐exercise pH changes that correlated with PCr depletion were consistent with the literature in gastrocnemius medialis and differences between knee angles were significant. These effects were less pronounced in soleus and not significant for comparable PCr depletions. Maximum oxidative capacity calculated for all knee angles was in excellent agreement with the literature and showed no significant changes between different knee angles. In conclusion, these findings confirm that plantar flexion exercise with a straight leg is a suitable paradigm, when data are acquired from gastrocnemius only (using either localized MRS or small surface coils), and that activation of soleus requires the knee to be flexed. The present study comprises a systematic investigation of the effects of the knee angle on metabolic parameters, measured with dynamic multivoxel ³¹P MRS during muscle exercise and recovery, and the findings should be used in future study design.     

Acute and chronic effects of strenuous exercise on glucose metabolism in isolated, incubated soleus muscle of exercise-trained rats

Male and female Wistar rats were exercise-trained for 6 or 11 weeks respectively, to examine the effects of acute exercise or exercise training per se on insulin-stimulated glucose utilization in soleus muscles isolated and incubated in vitro. The maximal activities of hexokinase and 2-oxoglutarate dehydrogenase were significantly elevated (by greater than 50%) in gastrocnemius muscle of exercise-trained male and female rats, indicating an adaptation to the training regime. No significant differences in any of the variables studied were observed between appropriately matched male and female rats. There were no significant differences in the sensitivity or responsiveness of the rates of lactate formation or glycogen synthesis in soleus muscles isolated from exercise-trained and sedentary animals at rest (exercise-trained animals were studied 40 h after the last exercise bout). On the other hand, acute exercise caused significant changes in soleus muscle glucose metabolism. Basal and insulin-stimulated rates of glycogen synthesis were significantly elevated in soleus muscles incubated from both sedentary and exercise-trained rats immediately after an exercise bout. In addition, the responsiveness of glucose utilization to insulin in soleus muscles from exercise-trained rats was significantly increased after acute exercise. The results indicate that significant changes in the control of glucose metabolism by insulin in soleus muscle occur as a result of an acute exercise bout, while no adaptive changes in insulin sensitivity occur in soleus muscle after exercise training.     

The effects of testosterone on insulin sensitivity in male rats

In order to examine the effects of testosterone (T) on insulin sensitivity, male rats were castrated or sham-operated, and exposed to low or high doses of T to substitute normal or to produce high serum T concentrations. Insulin sensitivity was followed by euglycaemic, hyperinsulinaemic glucose clamp measurements. An index of insulin-stimulated glucose transport was obtained in the white gastrocnemius (WG), extensor digitorum longus (EDL), red gastrocnemius (RG) and soleus (SOL) muscles after a bolus dose of [2-³H]deoxyglucose (2-DOG) when steady state was obtained in the clamp measurements. Glycogen synthesis was followed similarly with [U-14C]glucose as a labelled precursor after isolation of glycogen in the muscles mentioned, and in the liver. Castration and high T were followed by a marked insulin resistance in the clamp measurements. This was paralleled by a diminished insulin stimulation of glucose incorporation into glycogen down to about 50% of control values, apparently equally pronounced in all muscles but not found in liver glycogen synthesis. 2-DOG uptake was diminished by castration in the WG and RG muscles but was unaffected by high doses of T. Substitution of castrated rats with a low dose of T, restoring their serum T concentrations to the normal range, completely abolished these perturbations of insulin sensitivity. It is concluded that T is an important regulator of muscular insulin sensitivity, which seems to be highest in a ‘window’ of normal serum T concentrations.     

Brain cooling in diving seals

A previous study reported elevations of insulin-mediated muscle protein synthesis following four days of resistance exercise in rats (Fluckey et al. 1996. Am J Physiol 270, E313–E319). The purpose of this study was to determine if insulin-stimulated muscle glucose uptake (a–v diff.) and 2-deoxyglucose (2-DG) transport were altered under similar conditions. The protocol consisted of squat-like exercises during four sessions with progressively increased weight (70–190 g). Each session consisted of 50 repetitions and sessions were separated by 48 h. Sixteen hours after the last exercise session, basal glucose uptake in perfused hindlimbs was not different (P > 0.05) between exercised (n=6) and non-exercised controls (n=6). However, there was a significant (P < 0.05) attenuation of insulin-stimulated (20 000 μU mL^–1) glucose uptake in exercised vs. non-exercised rats (491 ± 31 vs. 664 ± 58 μmol glucose^–1 g^–1 [15-min insulin period]^–1, respectively). Following resistance exercise, insulin-stimulated 2-DG transport, measured during the last 10 min of the perfusion period, was significantly reduced (P < 0.05) in the soleus, white gastrocnemius and extensor digitorum longus muscles. Additionally, GLUT-4 glucose transporter protein content was significantly reduced (P < 0.05) in white gastrocnemius and extensor digitorum longus muscles. These results demonstrate that insulin-stimulated glucose uptake and transport are reduced after resistance exercise. Furthermore, the applied resistance exercise protocol causes directionally opposite changes of insulin action in two major metabolic pathways, i.e. glucose transport and protein synthesis.     

Insulin action on rates of muscle protein synthesis following eccentric,muscle‐damaging contractions

The purpose of this study was to determine whether eccentric, muscle‐damaging contractions affect insulin action on muscle protein synthesis. Male Wistar rats (n=28) were anaesthetized either once or twice separated by 7 days’ rest, and one limb was electrically stimulated to contract eccentrically, while the contralateral limb served as a non‐stimulated control. Twenty‐four and 48 h after contractions, rates of protein synthesis were assessed in soleus and red or white gastrocnemius muscles during a hindlimb perfusion with or without insulin (20 000 μU mL^–1). Rates of protein synthesis were not different in non‐stimulated muscle, with or without insulin (P > 0.05). In red or white gastrocnemius without insulin, rates of protein synthesis were significantly reduced (P < 0.05) 24 and 48 h after a single session and 48 h after a double session of muscle contractions. However, protein synthesis was normalized with insulin 24 and 48 h after contractions in red, and 48 h after contractions in white gastrocnemius. In soleus muscle, protein synthesis was impaired only 48 h after the second session, but partially restored by insulin (P < 0.05). These results indicate that muscle becomes more sensitive to insulin action on rates of protein synthesis after muscle‐damaging contractions.     

Training decreases muscle glycogen turnover during exercise

The present study was undertaken to determine the effects of endurance training on glycogen kinetics during exercise. A new model describing glycogen kinetics was applied to quantitate the rates of synthesis and degradation of glycogen. Trained and untrained rats were infused with a 25% glucose solution with 6-³H-glucose and U-¹⁴C-lactate at 1.5 and 0.5?μCi?·?min^?1 (where 1 Ci?=?3.7?×?10¹⁰ Bq), respectively, during rest (30?min) and exercise (60?min). Blood samples were taken at 10-min intervals starting just prior to isotopic infusion, until the cessation of exercise. Tissues harvested after the cessation of exercise were muscle (soleus, deep, and superficial vastus lateralis, gastrocnemius), liver, and heart. Tissue glycogen was quantitated and analyzed for incorporation of ³H and ¹⁴C via liquid scintillation counting. There were no net decreases in muscle glycogen concentration from trained rats, whereas muscle glycogen concentration decreased to as much as 64% (P?P?相似文献   

Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes

Creatine supplementation may exert beneficial effects on muscle performance and facilitate peripheral glucose disposal in both rats and human subjects. The present study was undertaken to explore the effects of creatine supplementation on the ATP, creatine, phosphocreatine and glycogen content of white and red gastrocnemius and soleus muscles and on blood D-glucose and plasma insulin concentrations before and during an intravenous glucose tolerance test in Goto-Kakizaki rats, a current animal model of inherited type 2 diabetes mellitus. Creatine supplementation increased muscle creatine content, especially in the soleus muscle of young rats (+35.5-/+15.8%; d.f.=10; p<0.05), and lowered the insulinogenic index, i.e. the paired ratio between plasma insulin and blood D-glucose concentrations. The latter change was mainly attributable to a lowering of plasma insulin concentration. It is proposed, therefore, that creatine supplementation may improve the sensitivity to insulin in extrapancreatic sites in the present animal model of type 2 diabetes.     

Elevated free fatty acid levels inhibit glucose phosphorylation in slow-twitch rat skeletal muscle

The effect of increased free fatty acid concentrations on glucose metabolism in rat skeletal muscle was investigated at several different steps in glucose metabolism including glucose transport, glucose phosphorylation, glucose oxidation and glycogen synthesis. In isolated soleus (slow-twitch) muscles, insulin-stimulated (100 μml^-1) glucose phosphorylation, but not glucose transport, was inhibited by 26 and 22% in the presence of 1.0 and 2.0 mM oleate, respectively (P< 0.01). Regardless of oleate concentration (0.3 or 2.0 mM), insulin-stimulated glucose 6-phosphate levels were elevated to the same extent over the non-insulin-stimulated levels in soleus muscles {P < 0.01). Insulin-stimulated glucose oxidation was inhibited by 44% in soleus muscles exposed to 2.0 mM oleate (P < 0.05), whereas the rate of glucose incorporation into glycogen was not altered. In insulin-stimulated epitrochlearis (fast-twitch) muscles, elevated concentrations of oleate had no effect on the rates of glucose transport or glucose phosphorylation, or on the level of glucose 6-phosphate. These data suggest that increased free fatty acid availability decreases glucose utilization by selectively inhibiting glucose phosphorylation and oxidation in slow-twitch, but not fast-twitch skeletal muscle.     

A pilot validation of multi‐echo based echo‐planar correlated spectroscopic imaging in human calf muscles

A current limitation of MR spectroscopic imaging of multiple skeletal muscles is prolonged scan duration. A significant reduction in the total scan duration using the echo‐planar correlated spectroscopic imaging (EP‐COSI) sequence was accomplished using two bipolar readout trains with different phase‐encoded echoes for one of two spatial dimensions within a single repetition time (TR). The second bipolar readout was used for spatially encoding the outer k‐space, whereas the first readout was used for the central k‐space only. The performance of this novel sequence, called multi‐echo based echo‐planar correlated spectroscopic imaging (ME‐EPCOSI), was demonstrated by localizing specific key features in calf muscles and bone marrow of 11 healthy volunteers and five subjects with type 2 diabetes (T2D). A 3 T MRI–MRS scanner equipped with a transmit–receive extremity coil was used. Localization of the ME‐EPCOSI sequence was in good agreement with the earlier single‐readout based EP‐COSI sequence and the required scan time was reduced by a factor of two. In agreement with an earlier report using single‐voxel based 2D MRS, significantly increased unsaturated pools of intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) and decreased IMCL and EMCL unsaturation indices (UIs) were observed in the soleus and tibialis anterior muscle regions of subjects with T2D compared with healthy controls. In addition, significantly decreased choline content was observed in the soleus of T2D subjects compared with healthy controls. Multi‐voxel characterization of IMCL and EMCL ratios and UI in the calf muscle may be useful for the non‐invasive assessment of altered lipid metabolism in the pathophysiology of T2D. Copyright © 2014 John Wiley & Sons, Ltd.     

Regional differences in in vivo skeletal muscle responsiveness to insulin after burn injury

To investigate postburn insulin resistance, rats were subjected to a 3-sec single-hindlimb scald. This injury increases the temperature of calf muscles briefly to the level (46–55°C) at which human tissues show signs of thermal damage. Three days later burned rats and controls were injected with trace amounts of 2-deoxy-d-[1-¹⁴C]glucose, a nonmetabolizable glucose analog, with or without 0.5 units of insulin/kg body weight iv. In both burned and control animals, insulin produced a hyperinsulinemia not exceeding 25 min. Soleus muscles from the burned and unburned hindlimbs of burned rats as well as from controls were excised at 25 min postinjection and the intracellular accumulation of 2-deoxyglucose/g dry muscle was determined. Under basal conditions, cellular uptake of 2-deoxyglucose by soleus muscles from the unburned limb of burned rats did not differ from that in controls, but uptake by soleus muscle from the burned limb was increased 125% (P < 0.03). The induced hyperinsulinemia elevated 2-deoxyglucose uptake by both groups of uninjured muscles seven-fold (P < 0.001). In contrast, insulin did not significantly increase cellular accumulation of 2-deoxyglucose in soleus muscle from the burned limb. It is concluded that burn injury limited to a small area of body surface results in regional differences in skeletal-muscle metabolism and its responsiveness to insulin. Muscles underlying the wound develop a chronic elevation in glucose uptake and loss of responsiveness to insulin, while muscles remote from the burned region maintain normal glucose utilization and sensitivity to the hormone.     

Measuring the acute effect of insulin infusion on ATP turnover rate in human skeletal muscle using phosphorus‐31 magnetic resonance saturation transfer spectroscopy

Mitochondrial dysfunction has been proposed to underlie the insulin resistance of type 2 diabetes. However, the relative time course of insulin action in stimulating ATP turnover rate and glucose uptake in skeletal muscle has not been examined. These two parameters were measured in young healthy subjects using the ³¹P MRS saturation transfer method in conjunction with the euglycaemic hyperinsulinaemic clamp technique respectively. Glucose infusion rate rose rapidly from 0 to 2.90 ± 0.11 mg/kg_ffm/min during the first 10 min of insulin infusion and further to 6.17 ± 0.57 mg/kg_ffm/min between 15 and 45 min. In contrast, baseline ATP turnover rate was 9.0 ± 0.4 µmol/g/min of muscle and did not change during the first 45 min of insulin infusion. Between 50 and 80 minutes ATP turnover rate increased by 8% and remained steady to 150 minutes (9.7 ± 0.5 µmol/g/min of muscle, p = 0.03 vs baseline). The in vivo time course of insulin stimulation of skeletal muscle ATP turnover rate is not consistent with a rate limiting effect upon the initiation of insulin‐stimulated glycogen synthesis. Copyright © 2010 John Wiley & Sons, Ltd.     

Muscle glycogen repletion and pre-exercise glycogen content: effect of carbohydrate loading in rats previously fed a high fat diet

We have recently reported that rates of muscle glycogen repletion during the early period of recovery were increased by carbohydrate (CHO) loading in rats previously fed a high fat diet. However, the reason for this remained unanswered. The purpose of this study was to examine whether an increase of glycogen utilization due to an elevated pre-exercise glycogen store would enhance rates of glycogen repletion in muscle. Despite an equal degree of glycogen depletion, the rates of glycogen repletion of soleus, red and white gastrocnemius muscles by postexercise administration of glucose (3.0 g · kg^–1 body mass) and citrate (0.5 g · kg^–1 body mass) were faster in the CHO loaded (3 days) rats than in the nonloaded rats, as a result of elevated pre-exercise glycogen content and consequently the greater glycogen utilization. The higher rate of muscle glycogen repletion may in part be explained by increased postexercise glycogen synthase activity.     

Caffeine and theophylline block insulin-stimulated glucose uptake and PKB phosphorylation in rat skeletal muscles

Aim: Caffeine and theophylline inhibit phosphatidylinositol 3-kinase (PI3-kinase) activity and insulin-stimulated protein kinase B (PKB) phosphorylation. Insulin-stimulated glucose uptake involves PI3-kinase/PKB, and the aim of the present study was to test the hypothesis that caffeine and theophylline inhibit insulin-stimulated glucose uptake in skeletal muscles. Methods: Rat epitrochlearis muscles and soleus strips were incubated with insulin and different concentrations of caffeine and theophylline for measurement of glucose uptake, force development and PKB phosphorylation. The effect of caffeine was also investigated in muscles stimulated electrically. Results: Caffeine and theophylline completely blocked insulin-stimulated glucose uptake in both soleus and epitrochlearis muscles at 10 mm . Furthermore, insulin-stimulated PKB Ser⁴⁷³ and Thr³⁰⁸ and GSK-3β Ser⁹ phosphorylation were blocked by caffeine and theophylline. Caffeine reduced and theophylline blocked insulin-stimulated glycogen synthase activation. Caffeine stimulates Ca²⁺ release and force development increased rapidly to 10–20% of maximal tetanic contraction. Dantrolene (25 μm ), a well-known inhibitor of Ca²⁺-release, prevented caffeine-induced force development, but caffeine inhibited insulin-stimulated glucose uptake in the presence of dantrolene. Contraction, like insulin, stimulates glucose uptake via translocation of glucose transporter-4 (GLUT4). Caffeine and theophylline reduced contraction-stimulated glucose uptake by about 50%, whereas contraction-stimulated glycogen breakdown was normal. Conclusion: Caffeine and theophylline block insulin-stimulated glucose uptake independently of Ca²⁺ release, and the likely mechanism is via blockade of insulin-stimulated PI3-kinase/PKB activation. Caffeine and theophylline also reduced contraction-stimulated glucose uptake, which occurs independently of PI3-kinase/PKB, and we hypothesize that caffeine and theophylline also inhibit glucose uptake in skeletal muscles via an additional and hitherto unknown molecule involved in GLUT4 translocation.