Skeletal Muscle Glycogen Research Articles

Gαi -coupled GPR41 activation increases Ca2+ influx in C2C12 cells and shows a therapeutic effect in diabetic animals.

This study aimed to investigate the possible mechanisms by which orphan G protein-coupled receptor GPR41 activation enhances glucose uptake into C2C12 myotubes using a GPR41-selective agonist, AR420626, and to examine the ability of this agent to improve insulin sensitivity and glucose homeostasis in vivo. Basal and insulin-stimulated glucose uptake and glucose transporter 4 translocations were measured in C2C12 myotubes. Ca2+ influx into cells was measured and GPR41-mediated signaling by AR420626 was examined. An oral glucose tolerance test was performed, and plasma insulin levels were measured in streptozotocin-treated or high-fat diet-fed diabetic mice. The glycogen content was measured in skeletal muscle tissue. AR420626 increased basal and insulin-stimulated glucose uptake, which was reduced by pertussis toxin, an inhibitor of Gαi -mediated signaling, and treatment with small interfering RNA for GPR41 (siGPR41). AR420626 increased intracellular Ca2+ influx and phosphorylated Ca2+ /calmodulin-dependent protein kinase type II, cyclic AMP-responsive element-binding protein, and mitogen-activated protein kinase (p38) in C2C12 myotubes, which were inhibited by treating with pertussis toxin, amlodipine (Ca2+ channel blocker), and siGPR41. AR420626 increased plasma insulin levels and skeletal muscle glycogen content and improved glucose tolerance in streptozotocin- and high-fat diet-induced diabetic mouse models. GPR41 activation with AR420626 increased glucose uptake mediated by Ca2+ signaling via GPR41, improving diabetes mellitus.

Development of Continuum of Care for McArdle disease: A practical tool for clinicians and patients

McArdle disease (glycogen storage disease type V; GSDV) is a rare genetic disease caused by the inability to break down glycogen in skeletal muscle due to a deficiency in myophosphorylase. Glycolysis is only partially blocked in GSDV, as muscle fibres can take up circulating glucose and convert it to glucose-6-phosphate downstream of the metabolic block. Because skeletal muscle predominantly relies on anaerobic energy during the first few minutes of transition from rest to activity, and throughout more intense activities, individuals with GSDV experience muscle fatigue/pain, tachypnea, and tachycardia during these activities. If warning signs are not heeded, a muscle contracture may rapidly occur, and if significant, may lead to acute rhabdomyolysis. Without a cure or treatment, individuals with GSDV must be consistent in employing proper management techniques; however, this can be challenging due to the nuances inherent in this metabolic myopathy. The International Association for Muscle Glycogen Storage Disease collaborated with an international team of five expert clinicians to identify areas of learning to achieve an optimal state. A Continuum of Care model was developed that outlines five pivotal steps (diagnosis; understanding; acceptance; learning and exercise) to streamline assessments and more succinctly assist clinicians in determining patient-specific learning needs. This model serves as a translational tool to help optimize care for this patient population.

Intestinal Glucose Absorption Is Lower in Obese than in Lean Zucker Rats

Obese Zucker (fa/fa) rats had lower intestinal glucose absorption following an intragastric [U-14C]glucose load than lean (+/?) Zucker rats. In the fa/fa animals, the rate of oxidation of the tracer to 14CO2 was similar to that observed in their lean counterparts. Although there were no differences in the incorporation of the tracer in liver and skeletal muscle glycogen, the conversion and incorporation of [U-14C]glucose into tissue [14C]lipid was higher in the obese animals. Isolated enterocytes from lean and obese Zucker rats showed a similar capacity for [U-14C]glucose utilization. Reconstituted brush border membrane vesicles from obese Zucker rats showed a higher Vmax for glucose transport than those from their lean counterparts. The lower glucose absorption found in the fa/fa rats in vivo may contribute to the maintenance of normoglycemia in these animals.

Acute PDE4 Inhibition Induces a Transient Increase in Blood Glucose in Mice.

cAMP-phosphodiesterase 4 (PDE4) inhibitors are currently approved for the treatment of inflammatory diseases. There is interest in expanding the therapeutic application of PDE4 inhibitors to metabolic disorders, as their chronic application induces weight loss in patients and animals and improves glucose handling in mouse models of obesity and diabetes. Unexpectedly, we have found that acute PDE4 inhibitor treatment induces a temporary increase, rather than a decrease, in blood glucose levels in mice. Blood glucose levels in postprandial mice increase rapidly upon drug injection, reaching a maximum after ~45 min, and returning to baseline within ~4 h. This transient blood glucose spike is replicated by several structurally distinct PDE4 inhibitors, suggesting that it is a class effect of PDE4 inhibitors. PDE4 inhibitor treatment does not reduce serum insulin levels, and the subsequent injection of insulin potently reduces PDE4 inhibitor-induced blood glucose levels, suggesting that the glycemic effects of PDE4 inhibition are independent of changes in insulin secretion and/or sensitivity. Conversely, PDE4 inhibitors induce a rapid reduction in skeletal muscle glycogen levels and potently inhibit the uptake of 2-deoxyglucose into muscle tissues. This suggests that reduced glucose uptake into muscle tissue is a significant contributor to the transient glycemic effects of PDE4 inhibitors in mice.

THE ROLE OF ADRENERGIC RECEPTORS IN THE ACTION OF ADRENALINE ON PLASMA LACTATE, GLUCOSE, LIVER, AND SKELETAL MUSCLE GLYCOGEN IN THE COMMON AFRICAN TOAD BUFO REGULARIS

In mammals, the roles of liver and skeletal muscle glycogen in adrenaline-induced hyperglycaemia are well known. However, in amphibians, there is limited information on the relative contribution of liver and skeletal muscle glycogen in adrenaline-induced hyperglycaemia. This study investigated the effects of adrenaline on blood glucose, plasma lactate, liverand skeletal muscle glycogen and the role of adrenergic receptors in the common African toad, bufo regularis. One hundred and twenty-five adult common African toads (70-100g) of both sexes were randomly collected and used in the study.Blood samples were collected from truncus arteriosus to estimate glucose and lactate levels. Blood glucose was determined immediately by modified glucose oxidase method. Plasma lactate was determined by modification of the Barker-Summerson method. Liver and gastrocnemius muscle glycogen were determined using anthrone reagents method. Adrenaline caused significant increase in blood glucose, lactate levels and significant reduction in liver and muscle glycogen. When toads were pre-treated with propranolol or prazosin, adrenalines reduction in liver and muscle glycogen was significantly reduced while the increase in blood glucose and lactate levels was prevented. Combination of both blockers abolished the increase in blood glucose, lactate levels and blocked reduction in liver and muscle glycogen produced by adrenaline. The results of this study showed that adrenalinecaused liver and skeletal muscle glycogen breakdown, increase in plasma lactate levels which resulted in hyperglycaemia in the common African toad bufo regularis. The study also showed that both alpha- and beta-adrenergic receptors are involved in mediating the effects of adrenaline on blood glucose, plasma lactate, liver, and muscle glycogenolysis and gluconeogenesis.

Hepatalin: the missing link in prediabetes, obesity, and type 2 diabetes.

Hepatalin is a hormone secreted by the liver in response to pulses of insulin after a mixed nutrient meal, but only if the liver receives two permissive synergistic feeding signals from the stomach. Hepatalin stimulates glucose uptake and storage as glycogen in skeletal muscle, heart, and kidney but not liver, intestines, or adipocytes. Insulin acts primarily on liver and fat. Reduced hepatalin action results in postprandial hyperglycemia, compensatory elevation of insulin secretion, and a resultant shift in partitioning of nutrient energy storage from glycogen in muscle, to fat. Chronic hepatalin suppression leads to a predictable chronology of dysfunctions, first diagnosable as Absence of Meal-induced Insulin Sensitization (AMIS) which progresses to prediabetes, adiposity, and type 2 diabetes. The focus on nutrient partitioning and the role of hepatalin allows AMIS to be diagnosed, prevented, and treated, including through the use of lifestyle interventions.

Polysaccharides from apple pomace exhibit anti-fatigue activity through increasing glycogen content.

The polysaccharides were isolated from apple pomace by hot-water extraction, and their anti-fatigue activity was evaluated in C2C12 muscle myoblasts and male Kunming mice. The purified polysaccharides from apple pomace (PAP) have a molecular weight of 1.74 × 105Da and were composed of mannose, rhamnose, glucose, galactose and arabinose. In C2C12 myoblasts, PAP showed no cytotoxicity in the concentrations of 0-300μg/ml. PAP treatment increased the glycogen content, while the ATP content was not affected in C2C12 myoblasts. Further investigation found that the activity and gene expression of glycogen synthase, rather than glycogen phosphorylase, were upregulated by PAP treatment. The studies in vivo showed that PAP treatment did not affect the food intake and weight again in mice. Importantly, PAP prolonged the exhaustive swimming time, increased hepatic and skeletal muscle glycogen levels, and effectively inhibited the accumulation of blood lactic and blood urea nitrogen in mice. Taken together, the results suggested that PAP exhibit anti-fatigue activity in vitro and in vivo through increasing glycogen content.

Effect of Pulicaria mauritanica on Glucose Metabolism and Glycogen Content in Streptozotocin-Induced Diabetic Rats.

The study aimed to assess the antihyperglycemic activity of Pulicaria mauritanica. Pulicaria mauritanica is a medicinal and aromatic plant used for the treatment of many diseases such as inflammation, diabetes, and intestinal disorders. The main goals of this present paper were to confirm the antihyperglycemic capacity of aqueous extract from Pulicaria mauritanica in normoglycemic and diabetic rats over a period of time (7 days of treatment). The effect of the aqueous extract of Pulicaria mauritanica from aerial parts (AEPM) on glucose and lipid metabolism was tested using an acute test (single dose during 6 hours) and subchronic assay (repeated oral administration for seven days) at a dose of 60 mg/kg and the serum glucose levels were measured in normoglycemic and streptozotocin(STZ)-induced diabetic rats. In addition, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus was evaluated. The antioxidant activity, phytochemical screening, and quantification of some secondary metabolites of this extract were also performed. AEPM at a dose of 60 mg/kg reduced the plasma glucose concentrations significantly in STZ-induced diabetic rats after a single oral administration (p<0.05). This lowering effect became more significant during the repeated oral administration in hyperglycemic rats (p<0.0001). Also, the findings showed that this plant exhibited a significant increase in liver and skeletal soleus muscle glycogen content in diabetic rats. AEPM revealed a remarkable antioxidant activity in addition to the presence of polyphenol compounds such as flavonoids, tannins, saponins, sterols, glucides, terpenoids, quinones, anthraquinones, and mucilage. The study shows that AEPM exhibits antihyperglycemic activity in diabetic rats, and it increases liver and muscle glycogen content.

Effect of Intermittent Fasting on Muscle Glycogen Stores in Rats with High-Calorie Diet

Insulin resistance in skeletal muscle is important since it is normally responsible for most of the insulin-mediated glucose disposal and contains the largest glycogen storage regulated by insulin sensitivity. A high-calorie diet is known to be a risk factor for insulin resistance. Lifestyle modification by regulating caloric intake through intermittent fasting (IF) is recommended to prevent insulin resistance. This study aims to analyze the effect of eight weeks of intermittent fasting on skeletal muscle glycogen stores in rats with a four-week high-calorie diet. A total 24 healthy male Wistar rats were divided into four groups, Ad-libitum with a standard diet (AL-SD) Ad-libitum with a high-calorie diet (AL-HCD) IF with a standard diet (IF-SD) IF with a high-calorie diet (IF-HCD). Muscles were obtained and stained with PAS stain to evaluate glycogen expression based on color intensity. The results of the glycogen expression score were obtained as follows, AL-SD=2.113±0.589 AL-HCD=1.827±0.375 IF-SD=2.109±0.499 IF-HCD=1.979±0.334. Although there was no significant difference between groups (p> 0.05), IF can prevent excessive reduction of glycogen stores in subjects with a HCD compared to the AL-HCD group. In conclusion, this study suggests that IF might improve the reduction of glycogen stores in muscles due to a high-calorie diet.

Insulin Sensitization Following a Single Exercise Bout Is Uncoupled to Glycogen in Human Skeletal Muscle: A Meta-analysis of 13 Single-Center Human Studies.

Exercise profoundly influences glycemic control by enhancing muscle insulin sensitivity, thus promoting glucometabolic health. While prior glycogen breakdown so far has been deemed integral for muscle insulin sensitivity to be potentiated by exercise, the mechanisms underlying this phenomenon remain enigmatic. We have combined original data from 13 of our studies that investigated insulin action in skeletal muscle either under rested conditions or following a bout of one-legged knee extensor exercise in healthy young male individuals (n = 106). Insulin-stimulated glucose uptake was potentiated and occurred substantially faster in the prior contracted muscles. In this otherwise homogenous group of individuals, a remarkable biological diversity in the glucometabolic responses to insulin is apparent both in skeletal muscle and at the whole-body level. In contrast to the prevailing concept, our analyses reveal that insulin-stimulated muscle glucose uptake and the potentiation thereof by exercise are not associated with muscle glycogen synthase activity, muscle glycogen content, or degree of glycogen utilization during the preceding exercise bout. Our data further suggest that the phenomenon of improved insulin sensitivity in prior contracted muscle is not regulated in a homeostatic feedback manner from glycogen. Instead, we put forward the idea that this phenomenon is regulated by cellular allostatic mechanisms that elevate the muscle glycogen storage set point and enhance insulin sensitivity to promote the uptake of glucose toward faster glycogen resynthesis without development of glucose overload/toxicity or feedback inhibition.

The Effects of Exercise Training on Glucose Homeostasis and Muscle Metabolism in Type 1 Diabetic Female Mice.

Although exercise training is an important recommendation for the management of type 1 diabetes (T1D), most of the available research studies predominantly focus on male subjects. Given the importance of sex as a biological variable, additional studies are required to improve the knowledge gap regarding sex differences in T1D research. Therefore, the purpose of this study was to examine the role of exercise training in mediating changes in glucose homeostasis and skeletal muscle metabolism in T1D female mice. Female mice were injected with streptozotocin (STZ) to induce T1D. Two weeks after STZ injection, control (CON) and STZ mice were exercise trained on a treadmill for 4 weeks. Aerobic exercise training failed to improve glucose tolerance, prevent the decrease in body weight and adipose tissue mass, or attenuate muscle atrophy in T1D female mice. However, insulin sensitivity was improved in T1D female mice after exercise training. Aerobic exercise training maintained skeletal muscle triglyceride content but did not prevent depletion of skeletal muscle or liver glycogen in T1D mice. Gene expression analysis suggested that T1D resulted in decreased glucose transport, decreased ketone body oxidation, and increased fatty acid metabolism in the skeletal muscle, which was not altered by exercise training. These data demonstrate that 4 weeks of aerobic exercise training of a moderate intensity is insufficient to counteract the negative effects of T1D in female mice, but does lead to an improvement in insulin sensitivity.

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism

The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.

High-refined carbohydrate diet alters different metabolic functions in female rats

A diet containing refined carbohydrate (HCD) caused obesity and white adipose tissue (WAT) abnormalities, but it is unclear if HCD is linked with other metabolic dysfunctions in female models. Thus, we assessed whether HCD results in WAT, pancreas, liver, skeletal muscle (SM) and thyroid (TH) abnormalities in female rats. Female rats were fed with HCD for 15 days and metabolic morphophysiology, inflammation, oxidative stress (OS), and fibrosis markers were assessed. HCD rats presented large adipocytes, hyperleptinemia, and WAT OS. HCD caused irregular glucose metabolism, low insulin levels, and large pancreatic isle. Granulomas, reduced glycogen, and OS were observed in HCD livers. HCD caused hypertrophy and increased in glycogen in SM. HCD caused irregular TH morphophysiology, reduced colloid area and high T3 levels. In all selected tissues, inflammation and fibrosis were observed in HCD rats. Collectively, these data suggest that the HCD impairs metabolic function linked with irregularities in WAT, pancreas, liver, SM and TH in female rats.

Skeletal Muscle Glycogen Concentrations And Glut4 Concentrations 72 H Following Eccentric Exercise

Muscle glycogen concentrations are significantly reduced 24-72 h after eccentric exercise that produces indices of skeletal muscle damage. It is suggested that the muscle damage produced by eccentric exercise contributes to the decrease in skeletal muscle glycogen concentrations after eccentric exercise. Decreased skeletal muscle glycogen concentrations are associated with lower GLUT4 protein concentrations 48 h after eccentric exercise. PURPOSE: To determine muscle glycogen concentrations and GLUT4 concentrations 72 h after eccentric exercise. METHODS: A total of 12 individuals performed concentric knee extensions (CON) with one leg, while the contralateral leg performed eccentric knee extensions (ECC). Subjects then cycled for 1 h at 65% of VO2peak. Muscle biopsies were obtained from the vastus lateralis of CON and ECC legs 72 h after exercise. Muscle biopsies were analyzed for muscle glycogen concentrations. Muscle damage was assessed by electron microscopy. Muscle soreness ratings were determined using a 10 point scale. Muscle biopsies were pooled and analyzed for total GLUT4 protein concentrations. RESULTS: Compared to the CON leg, muscle glycogen concentrations in the ECC leg were 25% lower 72 h after exercise (120.7 ± 8.28 vs. 157.3 ± 7.7 μmol.g wet wt-1, p < 0.05). Muscle damage such as myofibrillar disruptions and necrotic fibers were apparent in the ECC leg 72 h after exercise. Indices of muscle damage were not apparent in the CON leg. Ratings of muscle soreness in the ECC leg were higher than for the CON leg (4.43 ± 0.57 vs. 1.36 ± 0.50, p < 0.05). Total pooled GLUT4 protein concentrations were similar 72 h after exercise. CONCLUSIONS: Muscle glycogen concentrations were reduced and muscle damage was produced in the ECC leg 72 h after exercise. Pooled muscle GLUT4 protein concentrations were not altered 72 h after exercise.

Trilobatin, a Naturally Occurring Food Additive, Ameliorates Exhaustive Exercise-Induced Fatigue in Mice: Involvement of Nrf2/ARE/Ferroptosis Signaling Pathway.

Nrf2-mediated oxidative stress is a promising target of exhaustive exercise-induced fatigue (EEIF). Trilobatin (TLB) is a naturally occurring food additive with antioxidant effect and Nrf2 activation potency. The present study aimed to investigate the effect of TLB on EEIF and elucidate its underlying mechanism. Our results showed that TLB exerted potent anti-EEIF effect, as reflected by the rope climbing test and exhaustive swimming test. Moreover, TLB also effectively reduced the levels of lactate, creatine kinase, and blood urea nitrogen, and increased liver glycogen and skeletal muscle glycogen in mice after EEIF insult. Additionally, TLB also balanced the redox status as evidenced by decreasing the generation of reactive oxygen species and improving the antioxidant enzyme activities including superoxide dismutase, catalase, and glutathione peroxidase, as well as the level of glutathione both in the tissue of muscle and myocardium. Furthermore, TLB promoted nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, and upregulated its downstream antioxidant response element (ARE) including quinone oxidoreductase-1 and heme oxygenase-1. Intriguingly, TLB also upregulated the GPx4 protein expression and reduced iron overload in mice after EEIF insult. Encouragingly, the beneficial effect of TLB on EEIF-induced oxidative stress and ferroptosis were substantially abolished in Nrf2-deficient mice. In conclusion, our findings demonstrate, for the first time, that TLB alleviates EEIF-induced oxidative stress through mediating Nrf2/ARE/ferroptosis axis.

Clamping Skeletal Muscle PO2 Eliminates Hyperinsulinemic Microvascular Blood Flow Response

ObjectiveTo determine if insulin mediated hyperemia is partially dependent on local muscle oxygen concentration.HypothesisThe blood flow responses to insulin are partially mediated by the local metabolic demand reflecting the increased oxygen consumption required to uptake and convert glucose into glycogen in skeletal muscle.Methods16 male Sprague Dawley rats (161g ‐ 204g) were anesthetized with sodium pentobarbital, the carotid artery and jugular vein were then cannulated for blood pressure monitoring and fluid resuscitation. Following cannulation, the extensor digitorum longus (EDL) was isolated and reflected onto an inverted microscope. Intravital video microscopy sequences of the EDL microcirculation were recorded during baseline and following hyperinsulinemic euglycemia or sham in all experiments. The muscle was reflected over a glass stage insert during Experiment 1a and 1b which allowed for direct observation of microvascular blood flow response to systemic insulin infusion in Experiment 1a. Experiment 1b consisted of a sham hyperinsulinemic euglycemic clamp which involved infusing saline at similar rates as insulin and glucose in standard clamp procedures. In Experiment 2, the EDL was reflected over a gas exchange chamber and microvascular capillary blood flow was recorded during sequential changes (7%‐12%‐2%‐7%) of oxygen concentration [O2] within the chamber during baseline and euglycemic conditions. The gas exchange chamber is fitted into the stage of an inverted microscope that interfaces directly with the EDL via a gas permeable polydimethylsiloxane membrane. By adjusting the concentration of gases flowing through the gas exchange chamber we have direct control of the [O2] within the overlying muscle. Hemodynamic measurements including capillary red blood cell (RBC) velocity, supply rate (SR), hematocrit, and oxygen saturation (SO2) were taken from in focus capillaries in the EDL during each experiment and analyzed offline using custom MATLAB software. All animal protocols were approved by Memorial University’s Institutional Animal Care Committee.ResultsIn Experiment 1a, the hyperinsulinemic euglycemic clamp caused a significant increase in SR from 8.9 ± 3.1 to 14.2 ± 4.9 cells/s at baseline to euglycemia (p = 0.01; N = 6, 677 capillaries at baseline and 552 at clamp), while no significant SR variation was detected after performing a sham clamp in Experiment 1b (11.0 ± 1.6 cells/sec at baseline and 11.4 ± 3.7 cells/sec at sham clamp; N = 6, 837 capillaries at baseline and 724 at sham clamp). In Experiment 2 using the gas exchange chamber, SR significantly decreased at 12% O2 (p = 0.01, p &lt; 0.03) and significantly increased at 2% O2 (p = 0.01, p &lt; 0.04), compared to baseline 7% O2, under both baseline and euglycemic conditions respectively (N = 6, 313 capillaries at baseline and 195 at clamp). SR responses to oxygen oscillations during euglycemia were not different to those at baseline for each O2 concentration (p &gt; 0.9). SO2 significantly increased at 12% O2 and significantly decreased at 2% O2 under both baseline and euglycemic conditions (p &lt; 0.05).ConclusionsOur saturation measurements demonstrate the effectiveness of using a gas exchange device to manipulate local oxygen concentrations in the muscle. Our SR results suggest the increase in blood flow observed in response to insulin is eliminated if the tissue oxygen microenvironment is fixed at a given [O2].

Effects of a Very High-Carbohydrate Diet and Endurance Exercise Training on Pancreatic Amylase Activity and Intestinal Glucose Transporter Content in Rats.

We previously reported that the combination of a very high-carbohydrate diet and endurance training increased glucose transporter 4 and glycogen concentration in skeletal muscle. However, it remains unclear whether they also affect the digestive and absorptive capacity in the pancreas and small intestine, which are suggested to be rate-limiting steps in the delivery of exogenous carbohydrates to skeletal muscle and muscle glycogen synthesis. Thus, we aimed to evaluate the effects of a very high-carbohydrate diet and endurance training on pancreatic amylase activity and intestinal glucose transporters in rats and to examine the relationship between these adaptations and their influence on muscle glycogen concentration. Male Sprague-Dawley rats (n=29) were fed a high-carbohydrate diet (59% carbohydrate) or a very high-carbohydrate diet (76% carbohydrate) for 4 wk. Half of the rats in each dietary group were subjected to 6-h swimming exercise training (two 3-h sessions separated by 45 min of rest) for 4 wk. Although there was no significant effect of diet or endurance training on sodium-dependent glucose transporter 1 and glucose transporter 2 contents in the intestine, the rats fed a very high-carbohydrate diet in combination with endurance training had substantially higher pancreatic amylase activity and muscle glycogen concentration. Furthermore, there was a positive correlation between pancreatic amylase activity and muscle glycogen concentration (r=0.599, p=0.001). In conclusion, intake of a very high-carbohydrate diet and endurance training synergistically elevated carbohydrate digestive capacity, which partially accounted for the higher muscle glycogen accumulation.

Skeletal muscle cell-specific differences in type 2 diabetes

Major stores of glucose are found as glycogen in skeletal muscle and liver. Skeletal muscle is a heterogenous tissue, with cellular metabolic and contractile distinctions dependent on whether the cell (fibre) is slow-twitch (Type I) or fast-twitch (Type II). We hypothesised that proteins important for glycogen metabolism would be differentially abundant between these diverse fibres. We further hypothesised that the cellular location of these proteins would be different in muscle samples between control (CON) and individuals with type 2 diabetes (T2D). We dissected individual muscle fibre segments from vastus lateralis skeletal muscle biopsy samples from CON and T2D and used cell-type-specific approaches to address muscle heterogeneity. We measured glycogen and glycogen-related proteins by immunoblotting techniques. A lower proportion of Type I fibres was found in muscle in T2D compared with CON. AMPK-β2, glycogen branching enzyme (GBE), glycogen debranching enzyme (GDE), and glycogen phosphorylase (GP) were differentially localized between fibre types and in fibres from CON and T2D individuals. A key novel finding was that the majority of glycogen is loosely bound or cytosolic in location in human skeletal muscle. The proportion of this diffusible pool of glycogen was significantly lower in Type I fibres in T2D compared to CON. A hyperinsulinaemic, euglycaemic clamp in people with type 2 diabetes had no effect on the proportion of diffusible glycogen. We identify cell-type as an important consideration when assessing glycogen metabolism in muscle. Our findings demonstrate varying glucose handling abilities in specific muscle fibre types in type 2 diabetes. A model is presented to provide an overview of the cell-specific differences in glycogen metabolism in type 2 diabetes.

Disrupting AMPK-Glycogen Binding in Mice Increases Carbohydrate Utilization and Reduces Exercise Capacity.

The AMP-activated protein kinase (AMPK) is a central regulator of cellular energy balance and metabolism and binds glycogen, the primary storage form of glucose in liver and skeletal muscle. The effects of disrupting whole-body AMPK-glycogen interactions on exercise capacity and substrate utilization during exercise in vivo remain unknown. We used male whole-body AMPK double knock-in (DKI) mice with chronic disruption of AMPK-glycogen binding to determine the effects of DKI mutation on exercise capacity, patterns of whole-body substrate utilization, and tissue metabolism during exercise. Maximal treadmill running speed and whole-body energy utilization during submaximal running were determined in wild type (WT) and DKI mice. Liver and skeletal muscle glycogen and skeletal muscle AMPK α and β2 subunit content and signaling were assessed in rested and maximally exercised WT and DKI mice. Despite a reduced maximal running speed and exercise time, DKI mice utilized similar absolute amounts of liver and skeletal muscle glycogen compared to WT. DKI skeletal muscle displayed reduced AMPK α and β2 content versus WT, but intact relative AMPK phosphorylation and downstream signaling at rest and following exercise. During submaximal running, DKI mice displayed an increased respiratory exchange ratio, indicative of greater reliance on carbohydrate-based fuels. In summary, whole-body disruption of AMPK-glycogen interactions reduces maximal running capacity and skeletal muscle AMPK α and β2 content and is associated with increased skeletal muscle glycogen utilization. These findings highlight potential unappreciated roles for AMPK in regulating tissue glycogen dynamics and expand AMPK’s known roles in exercise and metabolism.

Anti-diabetic potential of Psidium guajava leaf in streptozotocin induced diabetic rats

BackgroundPsidium guajava is a medicinal plant with antidiabetic properties and can be found growing in tropical and sub-tropical countries around the world. PurposeThe aim of the present study was to investigate the anti-diabetic potential of Psidium guajava leaf in streptozotocin-induced diabetic rats, with particular focus on key enzymes of glycogen metabolism in skeletal muscle. Study designThe study design involved preparation of an aqueous Psidium guajava leaf extract; investigation of its effect on muscle glycogen synthase and phosphorylase activities and possible protective effect on pancreas in streptozotocin induced diabetic male Sprague-Dawley rats and phytochemical study of the extract to identify further compounds with anti-diabetic potential. MethodDiabetes was induced in male Sprague-Dawley rats with a single intraperitoneal injection of 40 mg/kg streptozotocin. Normal and diabetic animals were treated with 400 mg/kg body weight of Psidium guajava leaves aqueous extract for a period of 14 days. ResultsThe treatment of diabetic animals with the Psidium guajava extract ameliorated damage to the pancreatic islets and enhanced lowering of blood glucose following a glucose load. Diabetes significantly decreased (P < 0.05) glycogen synthase activity by 31% compared to normal animals this being associated with a decrease in enzyme expression. Psidium guajava treatment returned the enzyme activity to near normal levels. In diabetic animals, glycogen phosphorylase activity was elevated but not significantly (P > 0.5) and treatment of both diabetic and normal animals with the extract reduced activity of the enzyme. The Psidium guajava extract also reduced glycogen phosphorylase expression in diabetic animals. Skeletal muscle glycogen content reduced by diabetes was increased as a result of treatment of diabetic animals with the Psidium guajava extract. Phytochemical analysis of the aqueous extract of Psidium guajava using Gas Chromatography-Mass Spectroscopy indicated the presence of triterpenes and phenolic compounds and we also report what we believe are three new compounds. ConclusionThe results from this study suggest that the antidiabetic effects of Psidium guajava may be due to modulation of glycogen metabolism mediated by phenolic compounds and triterpenes present in the extract.