Increased Muscle GLUT4 Research Articles

Effect of Capsinoids Supplementation on Fat Oxidation and Muscle Glycogen Restoration During Post-exercise Recovery in Humans.

Capsinoids (CSN), the novel non-pungent capsaicin analogs have been reported to promote metabolic health and exercise tolerance. However, the effect of CSN on fat oxidation and changes in skeletal muscle glycogen levels during post-exercise recovery has not been investigated in humans. We examined the effect of CSN supplementation on energy reliance, glycogen resynthesis and molecular proteins in the skeletal muscle of young adults during post-exercise recovery. In this crossover-designed study, nine healthy adult male volunteers (aged 21.4±0.2 years, BMI 21.9±1.3 kg/m2) completed a 60-min cycling exercise at 70% VO2max. Participants consumed either CSN (12 mg, single dosage) or placebo capsules with a high-carbohydrate meal (2 g carb/kg bodyweight) immediately after exercise. Biopsied muscle samples (vastus lateralis), blood, and gaseous samples were obtained during 3h postexercise recovery period. We found that oral CSN supplementation right after exercise significantly altered the energy reliance on fat oxidation during recovery. This was evidenced by lower respiratory exchange ratio (RER) and higher fat oxidation rate in CSN trial. Despite this, acute CSN dosage does not contribute in enhancing the glycogen replenishment in skeletal muscle during 3h recovery. We identified no significant differences in postprandial glucose and insulin area under the curve in both trials. Western blot data showed an increased muscle GLUT4 expression, but no significant response of p-Akt/Akt ratio with CSN during post-exercise recovery. Our findings conclude that acute CSN intake could change energy reliance on fat oxidation but is unable to enhance muscle glycogen resynthesis during post-exercise recovery. Thus, ergogenic properties of CSN in relevance to muscle glycogen restoration following exercise needs to be further investigated in young adults.

726-P: Impaired Glucose Tolerance Blunts Exercise-Training Induced Improvements in Aerobic Exercise Capacity

Background: Low aerobic exercise capacity independently and strongly predicts metabolic disease and mortality. While aerobic exercise training can increase exercise capacity and reduce health risks, people with impaired glucose tolerance (IGT; i.e., prediabetes, T1D and T2D) have lower exercise capacity than glucose-tolerant subjects, even when exercise training “dose” is matched. We tested the hypothesis that low exercise capacity in IGT is caused by blunted exercise training-induced improvements in exercise capacity. Methods: IGT was induced in CD-1 mice by a) diet-induced insulin resistance (Western Diet, WD; 40% kcal from fat), or b) streptozotocin injection (STZ; 2x 40 mg/kg) to reduce circulating insulin. Control and STZ mice consumed standard chow (10% fat). Eight weeks following treatment, mice were partitioned into sedentary or exercise-trained (voluntary wheel running) groups. Exercise capacity (meters, m) was measured before and after a 3-week training intervention, and the change (Δ) in exercise capacity was calculated. Body composition was measured (DEXA) and tissues were harvested to measure metabolic health outcomes. Results: Baseline exercise capacity and total running distance were similar among Control, WD and STZ groups. Mice from all treatment groups displayed metabolic benefits from training, including increased muscle GLUT4 and mitochondrial content, and reduced adiposity. In contrast, exercise capacity only improved with training in Control mice (Δ124.82±40.25 m), whereas WD-trained (Δ29.69±24.11 m) and STZ-trained (Δ37.10±25.76 m) animals had no significant increase in exercise capacity. These data demonstrate that IGT can prevent improvements in exercise capacity with exercise training, despite the induction of other beneficial metabolic health outcomes. Conclusions: Our data identify IGT as a negative regulator of improved exercise capacity with training and a novel mechanism underlying low exercise capacity in diabetes. Disclosure T. MacDonald: None. P. Pathak: None. S. Lessard: None. Funding American Heart Association (1-19-PDF-168)

Reduced delta-6 desaturase activity partially protects against high-fat diet-induced impairment in whole-body glucose tolerance

Delta-6 desaturase (D6D), which is encoded by the fatty acid desaturase (Fads2) gene, is the rate-limiting enzyme for the endogenous production of n-3 long-chain polyunsaturated fatty acids. The absence of D6D activity in Fads2−/− knockout mice results in the inability to produce eicosapentaenoic acid and docosahexaenoic acid, and has previously been associated with altered glucose and lipid metabolism. Skeletal muscle is a major site for insulin-stimulated glucose disposal; however, the consequences of reduced D6D activity on skeletal muscle metabolism are unknown. The objective of this study was to examine the role of a partial reduction in D6D activity on whole-body glucose tolerance, skeletal muscle fatty acid profiles and protein content of key markers of carbohydrate and fat signaling pathways in the context of both low- and high-fat diets. Male C57BL/6J heterozygous (Fads2+/−) and wild-type (WT) mice were fed either a low-fat (16% kcal from fat) or high-fat (HFD; 45% kcal from fat) diet for 21 weeks. Fads2+/− mice were protected from the HFD-induced impairment in glucose tolerance. Unexpectedly, HFD-fed Fads2+/− mice had reduced GLUT4 skeletal muscle protein content compared to their WT counterparts. No changes were detected in total protein content of key markers of fatty acid uptake, glycogen formation or substrate oxidation. This study shows that reduced D6D activity is partially protective against HFD-induced impairments in whole-body glucose tolerance but does not appear to be due to increased muscle GLUT4 content or total content of proteins regulating substrate utilization.

Flaxseed lignan secoisolariciresinol diglucoside improves insulin sensitivity through upregulating GLUT4 expression in diet‐induced obese mice (829.25)

Flaxseed Lignan Secoisolariciresinol Diglucoside Improves Insulin Sensitivity through Upregulating GLUT4 Expression in Diet‐Induced Obese Mice Yanwen Wang1, Bourlaye Fofana2, Moumita Roy1, and Kaushik Ghose 2 1 Aquatic and Crop Resource Development, National Research Council of Canada, Charlottetown, PE, Canada C1A 4P3 2 Agriculture and Agri‐Food Canada, Charlottetown, PE, Canada C1A 4P3 The objective of this study was to determine the anti‐diabetic effect and underlying mechanisms of flaxseed lignans in diet‐induced obese and insulin resistant mice. Male C57BL/6J mice, at the age of 8 wk, were provided with a high‐fat diet to induce insulin resistance. The age‐matched male C57BL/6J mice fed in parallel with a low‐fat diet were used as the normal control. After 12 wk, the high‐fat diet‐fed mice were randomized into 4 groups and treated by gavage feeding once a day with 0 (high‐fat/insulin resistant control), 10, 100, and 1,000 mg/kg/d of secoisolariciresinol diglucoside (SDG, 60% pure) lignan dissolved in water, respectively, for 6 weeks. The high‐fat and low‐fat control groups were gavaged with the vehicle. It was demonstrated that oral administration of SDG lowered body weight, serum insulin, total cholesterol and free fatty acid levels. SDG also improved oral glucose tolerance and insulin tolerance. Further molecular experiments showed that SDG increased muscle GLUT4 protein expression. The results suggest that flaxseed SDG lignan protects from insulin resistance in diet‐induced obese mice and has potential to be used as a natural product for the prevention and treatment of obesity‐related insulin resistance or diabetes.Grant Funding Source: TUFGEN 604381

Improvements of insulin resistance in ovariectomized rats by a novel phytoestrogen from Curcuma comosa Roxb

BackgroundCurcuma comosa Roxb. (C. comosa) is an indigenous medicinal herb that has been used in Thailand as a dietary supplement to relieve postmenopausal symptoms. Recently, a novel phytoestrogen, (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol or compound 049, has been isolated and no study thus far has investigated the role of C. comosa in preventing metabolic alterations occurring in estrogen-deprived state. The present study investigated the long-term effects (12 weeks) of C. comosa hexane extract and compound 049 on insulin resistance in prolonged estrogen-deprived rats.MethodsFemale Sprague-Dawley rats were ovariectomized (OVX) and treated with C. comosa hexane extract (125 mg, 250 mg, or 500 mg/kg body weight (BW)) and compound 049 (50 mg/kg BW) intraperitoneally three times per week for 12 weeks. Body weight, food intake, visceral fat weight, uterine weight, serum lipid profile, glucose tolerance, insulin action on skeletal muscle glucose transport activity, and GLUT-4 protein expression were determined.ResultsProlonged ovariectomy resulted in dyslipidemia, impaired glucose tolerance and insulin-stimulated skeletal muscle glucose transport, as compared to SHAM. Treatment with C. comosa hexane extract and compound 049, three times per week for 12 weeks, markedly reduced serum total cholesterol and low-density lipoprotein levels, improved insulin sensitivity and partially restored uterine weights in ovariectomized rats. In addition, compound 049 or high doses of C. comosa hexane extract enhanced insulin-mediated glucose uptake in skeletal muscle and increased muscle GLUT-4 protein levels.ConclusionsTreatment with C. comosa and its diarylheptanoid derivative improved glucose and lipid metabolism in estrogen-deprived rats, supporting the traditional use of this natural phytoestrogen as a strategy for relieving insulin resistance and its related metabolic defects in postmenopausal women.

High-intensity Interval Training Increases Muscle GLUT4 and Mitochondrial Capacity in Prediabetes and Type 2 Diabetes

High-intensity Interval Training Increases Muscle GLUT4 and Mitochondrial Capacity in Prediabetes and Type 2 Diabetes

A grape polyphenol extract modulates muscle membrane fatty acid composition and lipid metabolism in high-fat–high-sucrose diet-fed rats

Accumulation of muscle TAG content and modification of muscle phospholipid fatty acid pattern may have an impact on lipid metabolism, increasing the risk of developing diabetes. Some polyphenols have been reported to modulate lipid metabolism, in particular those issued from red grapes. The present study was designed to determine whether a grape polyphenol extract (PPE) modulates skeletal muscle TAG content and phospholipid fatty acid composition in high-fat-high-sucrose (HFHS) diet-fed rats. Muscle plasmalemmal and mitochondrial fatty acid transporters, GLUT4 and lipid metabolism pathways were also explored. The PPE decreased muscle TAG content in HFHS/PPE diet-fed rats compared with HFHS diet-fed rats and induced higher proportions of n-3 PUFA in phospholipids. The PPE significantly up-regulated GLUT4 mRNA expression. Gene and protein expression of muscle fatty acid transporter cluster of differentiation 36 (CD36) was increased in HFHS diet-fed rats but returned to control values in HFHS/PPE diet-fed rats. Carnitine palmitoyltransferase 1 protein expression was decreased with the PPE. Mitochondrial β-hydroxyacyl CoA dehydrogenase was increased in HFHS diet-fed rats and returned to control values with PPE supplementation. Lipogenesis, mitochondrial biogenesis and mitochondrial activity were not affected by the PPE. In conclusion, the PPE modulated membrane phospholipid fatty acid composition and decreased muscle TAG content in HFHS diet-fed rats. The PPE lowered CD36 gene and protein expression, probably decreasing fatty acid transport and lipid accumulation within skeletal muscle, and increased muscle GLUT4 expression. These effects of the PPE are in favour of a better insulin sensibility.

The In Vivo Antidiabetic Activity of Nigella sativa Is Mediated through Activation of the AMPK Pathway and Increased Muscle Glut4 Content.

The antidiabetic effect of N. sativa seed ethanol extract (NSE) was assessed in Meriones shawi after development of diabetes. Meriones shawi were divided randomly into four groups: normal control, diabetic control, diabetic treated with NSE (2 g eq plant/kg) or with metformin (300 mg/kg) positive control, both administered by daily intragastric gavage for 4 weeks. Glycaemia and body weight were evaluated weekly. At study's end, an Oral Glucose Tolerance Test (OGTT) was performed to estimate insulin sensitivity. Upon sacrifice, plasma lipid profile, insulin, leptin, and adiponectin levels were assessed. ACC phosphorylation and Glut4 protein content were determined in liver and skeletal muscle. NSE animals showed a progressive normalization of glycaemia, albeit slower than that of metformin controls. Moreover, NSE increased insulinemia and HDL-cholesterol, compared to diabetic controls. Leptin and adiponectin were unchanged. NSE treatment decreased OGTT and tended to decrease liver and muscle triglyceride content. NSE stimulated muscle and liver ACC phosphorylation and increased muscle Glut4. These results confirm NSE's previously reported hypoglycaemic and hypolipidemic activity. More significantly, our data demonstrate that in vivo treatment with NSE exerts an insulin-sensitizing action by enhancing ACC phosphorylation, a major component of the insulin-independent AMPK signaling pathway, and by enhancing muscle Glut4 expression.

Decreasing intramuscular phosphagen content simultaneously increases plasma membrane FAT/CD36 and GLUT4 transporter abundance

Decreasing muscle phosphagen content through dietary administration of the creatine analog beta-guanidinopropionic acid (beta-GPA) improves skeletal muscle oxidative capacity and resistance to fatigue during aerobic exercise in rodents, similar to that observed with endurance training. Surprisingly, the effect of beta-GPA on muscle substrate metabolism has been relatively unexamined, with only a few reports of increased muscle GLUT4 content and insulin-stimulated glucose uptake/clearance in rodent muscle. The effect of chronically decreasing muscle phophagen content on muscle fatty acid (FA) metabolism (transport, oxidation, esterification) is virtually unknown. The purpose of the present study was to examine changes in muscle substrate metabolism in response to 8 wk feeding of beta-GPA. Consistent with other reports, beta-GPA feeding decreased muscle ATP and total creatine content by approximately 50 and 90%, respectively. This decline in energy charge was associated with simultaneous increases in both glucose (GLUT4; +33 to 45%, P < 0.01) and FA (FAT/CD36; +28 to 33%, P < 0.05) transporters in the sarcolemma of red and white muscle. Accordingly, we also observed significant increases in insulin-stimulated glucose transport (+47%, P < 0.05) and AICAR-stimulated palmitate oxidation (+77%, P < 0.01) in the soleus muscle of beta-GPA-fed animals. Phosphorylation of AMPK (+20%, P < 0.05), but not total protein, was significantly increased in both fiber types in response to muscle phosphagen reduction. Thus the content of sarcolemmal transporters for both of the major energy substrates for muscle increased in response to a reduced energy charge. Increased phosphorylation of AMPK may be one of the triggers for this response.

AMP kinase is not required for the GLUT4 response to exercise and denervation in skeletal muscle.

An acute bout of exercise increases muscle GLUT4 mRNA in mice, and denervation decreases GLUT4 mRNA. AMP-activated protein kinase (AMPK) activity in skeletal muscle is also increased by exercise, and GLUT4 mRNA is increased in mouse skeletal muscle after treatment with AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside(AICAR). These findings suggest that AMPK activation might be responsible for the increase in GLUT4 mRNA expression in response to exercise. To investigate the role of AMPK in GLUT4 regulation in response to exercise and denervation, transgenic mice with a mutated AMPK alpha-subunit (dominant negative; AMPK-DN) were studied. GLUT4 did not increase in AMPK-DN mice that were treated with AICAR, demonstrating that muscle AMPK is inactive. Exercise (two 3-h bouts of treadmill running separated by 1 h of rest) increased GLUT4 mRNA in both wild-type and AMPK-DN mice. Likewise, denervation decreased GLUT4 mRNA in both wild-type and AMPK-DN mice. GLUT4 mRNA was also increased by AICAR treatment in both the innervated and denervated muscles. These data demonstrate that AMPK is not required for the response of GLUT4 mRNA to exercise and denervation.

Creatine increases muscle GLUT4 protein content

Creatine increases muscle GLUT4 protein content

Sarcolemmal glucose transport and GLUT-4 translocation during exercise are diminished by endurance training.

Glucose utilization during exercise of a given submaximal power output is decreased after endurance training. The aim of the present study was to elucidate the mechanisms behind this phenomenon by utilizing the sarcolemmal giant vesicle technique. Eight healthy young untrained men endurance trained one thigh for 3 wk. They then exercised both thighs simultaneously at the same work load (77% of peak O2 uptake of the untrained thigh) for 40 min. Training increased muscle GLUT-4 protein by 70% (P < 0.05). Glucose uptake during exercise was 38% lower (P < 0.05) in the trained (T) thigh than in the untrained (UT) thigh because of both a lower (P < 0.05) glucose extraction and blood flow in T. During exercise, sarcolemmal GLUT-4 protein content and glucose transport capacity increased significantly less in T than in UT muscle, and muscle glucose concentration was lower in T compared with UT (P < 0.05) at the end of exercise. It is concluded that, despite a large increase in muscle GLUT-4 with endurance training, exercise of a given submaximal power output increases muscle glucose uptake less in T than in UT muscle. It is suggested that the mechanism behind this phenomenon is blunted exercise-induced translocation of GLUT-4 to the sarcolemma, resulting in a blunted increase in sarcolemmal glucose transport in T muscle.

This Month in the Journal

This Month in the Journal

Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats

Alpha lipoic acid (lipoate [LA]), a cofactor of α-ketodehydrogenase, exhibits unique antioxidant properties. Recent studies suggest a direct effect of LA on glucose metabolism in both human and experimental diabetes. This study examines the possbility that LA positively affects glucose homeostasis in streptozotocin (STZ)-induced diabetic rats by altering skeletal muscle glucose utilization. Blood glucose concentration in STZ-diabetic rats following 10 days of intraperitoneal (IP) injection of LA 30 mg/kg was reduced compared with that in vehicle-treated diabetic rats [495 ± 131 v 641 ± 125 mg/dL in fed state, P = .003, and 189 ± 48 v 341 ± 36 mg/dL after 12-hour fast, P = .001). No effect of LA on plasma insulin was observed. gastroenemius muscle crude membrane GLUT4 protein was elevated both in control and in diabetic rats treated with LA by 1.5- and 2.8-fold, respectively, without significant changes in GLUT4 mRNA levels. Gastroenemius lactic acid was increased in diabetic rats (19.9 ± 5.5 v 10.4 ± 2.8 μmol/g muscle, P < .05 v nondiabetic rats), and was normal in LA-treated diabetic rats (9.1 ± 5.0 μmol/g muscle). Insulin-stimulated 2-deoxyglucose (2 DG) uptake into isolated soleus muscle was reduced in treatment prevented this reduction, resulting in insulin-stimulated glucose uptake comparable to that of nondiabetic animals. These results suggest that daily LA treatment may reduce blood glucose concentrations in STZ-diabetic rats by enhancing muscle GLUT4 protein content and by increasing muscle glucose utilization.

THE EFFECTS OF IMMOBILIZATION AND SUBSEQUENT EXERCISE ON HUMAN MUSCLE GLUT4 mRNA LEVELS 1311

Muscle glucose transporter GLUT4 plays an important role in maintaining glucose homeostasis. Previous studies have shown that exercise increases muscle GLUT4 gene expression and protein level in animal models. The purpose of this study was to investigate the human skeletal muscle GLUT4 mRNA levels before and after immobilization and subsequent exercise. Four human subjects were immobilized with a full cast on the left leg for 3 weeks followed by 12 weeks of resistance exercise training. Total RNA was isolated from biopsy samples of the vastus lateralis muscle of the immobilized leg. Ribonuclease protection assay was used to measure the mRNA levels of GLUT4 transporter. Immobilization decreased GLUT4 mRNA levels to 60% of control(p<0.05). Subsequent resistance exercise training on the immobilized leg induced a 2.0-fold increase in GLUT4 mRNA levels vs immobilization(p<0.05). The results of this study suggest that human skeletal muscle glucose transporter GLUT4 can be regulated at the pre-translational level by immobilization and exercise.

Physical training increases muscle GLUT4 protein and mRNA in patients with NIDDM

Physical training increases muscle GLUT4 protein and mRNA in patients with NIDDM

Exercise increases muscle GLUT-4 levels and insulin action in subjects with impaired glucose tolerance

A decline in insulin sensitivity is associated with aging, inactivity, and obesity. The effects of exercise training on glucose homeostasis independent of weight loss in older glucose-intolerant individuals are not well established. We examined the effects of exercise training on oral glucose tolerance, insulin action, and concentration of the GLUT-4 glucose transporters in skeletal muscle. Exercise training at 50 and 75% of heart rate reserve was performed for 12 wk in 18 individuals (age = 64 +/- 2, body fat = 37.0 +/- 1.5%). Peripheral insulin action was determined 96 h after the last exercise bout using a two-step hyperinsulinemic-euglycemic glucose clamp (insulin = 192 and 708 pmol/l). Percent body fat and fat-free mass (FFM) were unchanged with training. Diet composition, assessed by diet record, did not change over the 12 wk. Improved oral glucose tolerance was observed, as exhibited by lower plasma glucose concentrations after training (P < 0.05), whereas plasma insulin response remained unchanged. The rate of glucose disposal was unchanged during the low insulin concentration but increased 11.0% at the high insulin concentration (P < 0.05) after training (54.4 +/- 4.4 vs. 60.4 +/- 5.5 mumol.kg FFM-1.min-1). Skeletal muscle glycogen and GLUT-4 concentration increased 24 and 60%, respectively, with training. There was no direct relationship between the change in GLUT-4 protein and the change in glucose disposal rate. These findings demonstrate that chronic exercise training without changes in body composition improves peripheral insulin action in subjects with impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycemia and exercise training alter glucose transport and GLUT4 in the Zucker rat

The purpose of this study was to determine the effects of chronic hyperglycemia and/or exercise training on the muscle concentration of the insulin-responsive glucose transporter protein, GLUT4, and on maximally insulin-stimulated hindlimb muscle glucose transport. Five-wk-old lean and obese Zucker rats were randomly assigned to sham-operated control (CTL) or 90% pancreatectomized (PX) groups. Obese-PX animals were further randomized into sedentary or exercise trained groups (15-wk treadmill running for 2 h.d-1, 5 d.wk-1, 15% grade, at 15-18 m.min-1). Muscle GLUT4 protein content and maximally insulin-stimulated glucose transport were determined in gastrocnemius, plantaris, and soleus muscles. At 20 wk, lean-PX displayed mild fasting hyperglycemia but normal insulin levels. Obese-PX rats had insulin levels similar to lean-CTL rats but had severe hyperglycemia. Hyperglycemia in lean-PX was associated with a 28% decrease in maximal glucose transport and a 65% decrease in muscle GLUT4 (P < 0.05) compared with lean-CTL. In obese-PX, maximal glucose transport was not affected, but muscle GLUT4 was reduced by 62% (P < 0.05) compared to obese-CTL. Exercise training obese-PX reduced hyperglycemia, increased maximal glucose transport by 45%, and increased muscle GLUT4 by > 2-fold (P < 0.05) compared with obese-CTL. Thus, hyperglycemia associated with PX may be an important factor in the reduction of muscle GLUT4 levels in lean and obese rats. The reduced GLUT4 was accompanied by reduced maximal glucose transport in lean but not obese rats. Exercise training reduced hyperglycemia, normalized glucose transport, and increased muscle GLUT4 in obese-PX.(ABSTRACT TRUNCATED AT 250 WORDS)