Enhanced Muscle Glucose Uptake Research Articles

Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as a prevalent health concern, encompassing a wide spectrum of liver-related disorders. Insulin resistance, a key pathophysiological feature of MASLD, can be effectively ameliorated through dietary interventions. The Mediterranean diet, rich in whole grains, fruits, vegetables, legumes, and healthy fats, has shown promising results in improving insulin sensitivity. Several components of the Mediterranean diet, such as monounsaturated fats and polyphenols, exert anti-inflammatory and antioxidant effects, thereby reducing hepatic steatosis and inflammation. Furthermore, this dietary pattern has been associated with a higher likelihood of achieving MASLD remission. In addition to dietary modifications, physical exercise, particularly resistance exercise, plays a crucial role in enhancing metabolic flexibility. Resistance exercise training promotes the utilization of fatty acids as an energy source. It enhances muscle glucose uptake and glycogen storage, thus reducing the burden on the liver to uptake excess blood glucose. Furthermore, resistance exercise stimulates muscle protein synthesis, contributing to an improved muscle-to-fat ratio and overall metabolic health. When implemented synergistically, the Mediterranean diet and resistance exercise can elicit complementary effects in combating MASLD. Combined interventions have demonstrated additive benefits, including greater improvements in insulin resistance, increased metabolic flexibility, and enhanced potential for MASLD remission. This underscores the importance of adopting a multifaceted approach encompassing dietary modifications and regular physical exercise to effectively manage MASLD. This narrative review explores the biological mechanisms of diet and physical exercise in addressing MASLD by targeting insulin resistance and decreased metabolic flexibility.

Fractions from Annona muricata attenuate oxidative stress in pancreatic tissues, inhibits key carbohydrate digesting enzymes and intestinal glucose absorption but enhances muscle glucose uptake.

The ameliorating effect of different fractions of Anonna muricata ethanol leaves extract in oxidative pancreatic injury as well as their antihyperglycemic effectwere investigated in vitro and ex vivo. Oxidative pancreatic injury was induced by incubating pancreatic tissuewith ferroussulphate (FeSO4 ). The antioxidative potentials of the fractions together with its ability to inhibit carbohydrate digesting enzymes, intestinalglucose absorption, and its ability to modulate muscleglucose uptake were determined. All the fractions significantly scavenge free radicals in dose-dependent manner and increase significantly increase the catalase and superoxide dimutase level thereby ameliorating lipid peroxidation. All the fractions also inihibited glucose digesting enzymes and absorption in dose-dependent manner. Glucose uptake was enhanced by the fractions in isolatedpsoas muscleof rats. The ethyl acetate fractionshowed more potent amelioration and anti-hyperglycemic potentials among all the fractions. This could be further exploited as therapeutic strategy for the management of postprandial hyperglycemia as well asT2D. PRACTICAL APPLICATIONS: Annona muricata is among the edible fruits in the world with reported nutritional as well as medicinal values. The anticancer activity of the leaves and the fruits have been reported. Its ability to inhibitcarbohydrate digesting enzymes and absorption andenhancing muscleglucose uptake as well as protection of pancreatic β-cell from oxidative damage further support its reported antidiabetic properties. A. muricata provided a cheap and alternative source of nutraceuticals, which could be further exploited as therapeutic strategy for the treatment of postprandial hyperglycemia in T2D.

229-OR: GLP-1 Infusions during Postprandial Insulin Clamps Enhance Muscle Microvascular Flow, Glucose Uptake, and Protein Anabolism in Older Men

Introduction: Ageing skeletal muscle becomes insulin resistant and atrophic. This is largely due to a failure in sequestering of amino acids and glucose from dietary intake into muscle protein and glycogen. GLP-1 possesses pleiotropic multi-organ properties and its receptor is expressed and exert effects in muscle tissue(s) e.g., endothelium. We hypothesized GLP-1 infusion would enhance muscle glucose uptake and bolster the trophic effects of an anabolic stimulus i.e., feeding. Methods: Eight men (71±1y) were studied in a cross-over trial. Basal measures were taken (first 3 h) prior to insulin (i.e., postprandial (fed-state)) and glucose (euglycaemic) clamps. Participants received I.V co-infusions of octreotide, Vamin 14-EF ±GLP-1. Four muscle biopsies were taken at 90-120 min intervals. Muscle protein turnover was quantified via A-V balance and direct incorporation of 13C6 phenylalanine via mass spectrometric techniques. GLP-1 and insulin were measured using Milliplex Map, ELISA kits. Muscle microvascular blood flow (MBF) was assessed via contrast enhanced ultrasound. Glucose handling was assayed by infusion rates and leg A-V balance. Results: GLP-1 (vs. -GLP-1 condition) augmented muscle protein synthesis (basal: 0.058±0.004%.h-1 vs. fed: 0.102±0.005%.h-1, p<0.01), net protein balance (p<0.0001 and p=0.03 vs. basal at 1.5h and 3h postprandial, respectively) and MBF (5±2 vs. 1.9±0.7 fold-change from basal respectively, p<0.01) - while increasing whole-body glucose uptake (AUC 17.0±1.7 vs. 11.4±1.8 mg.kg-1.180 min-1, p=0.02 with and without GLP, respectively). Muscle protein breakdown was equally suppressed with and without GLP-1. Leg glucose uptake was unchanged by GLP-1. Conclusions: The beneficial effects of GLP-1 upon whole-body glycaemic control are seemingly independent of muscle under fed-conditions. The pro-anabolic effect of GLP-1 in ageing is striking and requires further clinical and mechanistic research. Disclosure H. Abdulla: None. B.E. Phillips: None. M.C. Limb: None. D.J. Wilkinson: None. T. Jandova: None. J. Cegielski: None. J.J. Bass: None. D. Rankin: None. J.S. Lewis: None. J. Williams: None. K. Smith: None. I.R. Idris: None. P.J. Atherton: None. Funding Medical Research Council UK; Arthritis Research UK

Crassocephalum rubens, a leafy vegetable, suppresses oxidative pancreatic and hepatic injury and inhibits key enzymes linked to type 2 diabetes: An ex vivo and in silico study.

Crassocephalum rubens falls under the wild edible, under-cultivated traditional leafy vegetables (TLV) in Africa; it is used by locals in managing diabetes mellitus among other diseases. This study investigated the in vitro, ex vivo antioxidant and antidiabetic potentials of different extracts of C. rubens. The ameliorative effects of the extracts on Fe2+ -induced oxidative injury was investigated ex vivo together with the effects of the aqueous extract on intestinal glucose absorption and muscle glucose uptake in freshly harvested tissues from normal rats. The aqueous extract was subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) analysis to identify possible bioactive compounds which were then docked with the tested enzymes through in silico modeling. The extracts exhibited antioxidant activity, inhibited α-glucosidase and lipase enzyme activities, intestinal glucose absorption and enhanced muscle glucose uptake compared to controls. Sanguisorbic acid dilactone identified through LC-MS analysis showed a high binding affinity for catalase and lipase enzymes. PRACTICAL APPLICATIONS: The results of this study suggest that the aqueous extract of C. rubens possesses better antioxidant and possible antidiabetic potentials compared to other extracts which could be associated to the synergistic action of its identified bioactive compounds.

TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet-Induced Insulin Resistance in Skeletal Muscle.

Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that muscle-specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)-induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher β-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α and PPARβ, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.

Histochemistry, phenolic content, antioxidant, and anti-diabetic activities of Vernonia amygdalina leaf extract.

Vernonia amygdalina leaves were investigated for their histochemical properties and antidiabetic activities. Histochemical analysis of the leaf revealed distributions of acidic lipid, mucilage, and pectin, lipids, polyphenols, and alkaloids at the mid rib, glandular trichome, and epidermis. HPLC analysis of the leaves hot water infusion revealed the presence of quercetin and (-)-epi-catechin. The infusion had significant (p<0.05) 2,2'-diphenyl-1-picrylhydrazyl scavenging activity and ferric reducing antioxidant power. Ex vivo antioxidative analysis revealed the ability of the infusion to increase glutathione level, superoxide dismutase, and catalase activities, while concomitantly depleting malondialdehyde level and DNA fragmentation in Fe2+ -induced hepatic injury. The infusion showed significant (p<0.05) inhibitory activity against α-glucosidase and pancreatic lipase. It also inhibited intestinal glucose absorption and enhanced muscle glucose uptake, respectively. The ability of the infusion to abate oxidative stress, DNA fragmentation and stimulate muscle glucose uptake may suggest the antioxidative, anti-apoptotic, and insulin-sensitizing activity of V. amygdalina. PRACTICAL APPLICATIONS: Vernonia amygdalina (bitter leaf) is among the common leafy vegetables in West Africa reported for its various medicinal and nutritional properties. It is utilized as a food ingredient as well as supplement for the treatment and management of type 2 diabetes (T2D). Its ability to inhibit intestinal glucose absorption, enhance muscle glucose uptake, and protect against hepatic oxidative stress gives more credence to its reported antidiabetic properties. Being a common leafy vegetable, V. amygdalina can be a cheap source of nutraceutical for the treatment and management of T2D and its complications.

IL-15 improves skeletal muscle oxidative metabolism and glucose uptake in association with increased respiratory chain supercomplex formation and AMPK pathway activation

BackgroundIL-15 is believed to play a role in the beneficial impact of exercise on muscle energy metabolism. However, previous studies have generally used supraphysiological levels of IL-15 that do not represent contraction-induced IL-15 secretion. MethodsL6 myotubes were treated acutely (3 h) and chronically (48 h) with concentrations of IL-15 mimicking circulating (1–10 pg/ml) and muscle interstitial (100 pg/ml −20 ng/ml) IL-15 levels with the aim to better understand its autocrine/paracrine role on muscle glucose uptake and mitochondrial function. ResultsAcute exposure to IL-15 levels representing muscle interstitial IL-15 increased basal glucose uptake without affecting insulin sensitivity. This was accompanied by increased mitochondrial oxidative functions in association with increased AMPK pathway and formation of complex III-containing supercomplexes. Conversely, chronic IL-15 exposure resulted in a biphasic effect on mitochondrial oxidative functions and ETC supercomplex formation was increased with low IL-15 levels but decreased with higher IL-15 concentrations. The AMPK pathway was activated only by high levels of chronic IL-15 treatment. Similar results were obtained in skeletal muscle from muscle-specific IL-15 overexpressing mice that show very high circulating IL-15 levels. ConclusionsAcute IL-15 treatment that mimics local IL-15 concentrations enhances muscle glucose uptake and mitochondrial oxidative functions. That mitochondria respond differently to different levels of IL-15 during chronic treatments indicates that IL-15 might activate two different pathways in muscle depending on IL-15 concentrations. General significanceOur results suggest that IL-15 may act in an autocrine/paracrine fashion and be, at least in part, involved in the positive effect of exercise on muscle energy metabolism.

Azadirachta indica inhibits key enzyme linked to type 2 diabetes in vitro, abates oxidative hepatic injury and enhances muscle glucose uptake ex vivo

The progression of secondary complications in type 2 diabetes (T2D) has been linked to oxidative stress caused by hyperglycemia. Therefore, the control of hyperglycemia is the main target in the treatment of diabetes. The present study investigated the scavenging and ameliorative potentials of different fractions of Azadirachta indica (A. indica) ethanol stem bark extract in Fe2+-induced oxidative injury in hepatic tissue as well as their ability to inhibit enzymes linked to diabetes and in enhancing muscle glucose uptake via some in vitro and ex vivo experimental models. The results revealed that the butanol fraction of the extract showed a significantly (p < 0.05) higher DPPH scavenging activity than the other fractions (IC50 0.0154 μg/mL), while the aqueous fraction showed the highest FRAP activity (IC50 25.32 μg/mL). Although all the fractions ameliorated Fe2+-induced oxidative injury in hepatic tissue by significantly reducing malondialdehyde (MDA) concentration in a dose dependent manner, the butanol fraction showed the highest activity in this regard. In addition, the activities of catalase and superoxide dismutase (SOD) were significantly improved by the butanol and dichloromethane fractions. Butanol and ethyl acetate fractions showed the highest inhibitory effect on α-glucosidase (IC50 0.23 μg/mL) and α-amylase (IC50 14.79 μg/mL) activities, respectively. Although all the fractions significantly improved glucose uptake in psoas muscle with or without insulin, the butanol fraction showed the highest activity (GU50 6.22 μg/mL) in this regard. Gas chromatography–mass spectroscopy (GC–MS) analysis of the fractions revealed the presence of sistosterol, stigmasterol, campestrol, squalene, nimbiol among others. Molecular docking of some of these compounds with AMP-activated protein kinase (α-AMPK), α-amylase and α-glucosidase showed a positive interaction. These results suggest that the butanol and ethyl acetate fractions of A. indica may have bioactive compounds with antidiabetic potentials.

Concentrated hot water-infusion of phragmanthera incana improves muscle glucose uptake, inhibits carbohydrate digesting enzymes and abates Fe2+-induced oxidative stress in hepatic tissues.

Chronic hyperglycemia has been implicated in the development of oxidative stress and as a major factor in etiology of secondary complication in diabetes. In the present study, the antidiabetic potential of Phragamenthra incana (P. incana) hot infusion and its possible inhibitory effects on carbohydrate digesting enzymes, promotion of muscle glucose uptake, and the antioxidative potentials in Fe2+-induced oxidative stress in hepatic tissue were investigated. The infusion significantly (p < 0.05) scavenged free radicals (DPPH) and displayed favourable ferric reducing antioxidant power (FRAP) with increasing concentrations. It also significantly ameliorated Fe2+-induced oxidative stress in hepatic tissues by increasing superoxide dismutase (SOD) and catalase activities and depleting malondialdehyde (MDA) level. The results further showed that the infusion significantly (p < 0.05) inhibited α-amylase and α-glucosidase activity, and enhanced muscle glucose uptake, with and without insulin. Liquid Chromatography-Mass Spectroscopy (LCMS) analysis of the infusion revealed the presence of 2-methoxythiazole; l-cysteine; nicotinic acid; S-methyl-l-cysteine; isoquinoline, 1-methyl-; and 1H-indole-2,3-dione,5-methyl. The results of this study suggest that the observed antidiabetic and antioxidative potentials of P. incana could be attributed to its identified phytochemical constituents, however, this supports folkloric medicinal use of this plant.

Uncarboxylated Osteocalcin Enhances Glucose Uptake Ex Vivo in Insulin-Stimulated Mouse Oxidative But Not Glycolytic Muscle.

Uncarboxylated osteocalcin (ucOC) stimulates muscle glucose uptake in mice EDL and soleus muscles. However, whether ucOC also exerts a similar effect in insulin-stimulated muscles in a muscle type-specific manner is currently unclear. We aimed to test the hypothesis that, with insulin stimulation, ucOC per se has a greater effect on oxidative muscle compared with glycolytic muscle, and to explore the underlying mechanisms. Mouse (C57BL6, male 9-12weeks) extensor digitorum longus (EDL) and soleus muscles were isolated and longitudinally split into halves. Muscle samples were treated with varying doses of recombinant ucOC (0, 0.3, 1, 3, 30ng/ml), followed by insulin addition. Muscle glucose uptake, protein phosphorylation and total expression of protein kinase B (Akt), Akt substrate of 160kDa (AS160), extracellular signal-regulated kinase isoform 2 (ERK2), and adenosine monophosphate-activated protein kinase subunit α (AMPKα) were assessed. ucOC treatment at 30ng/ml enhanced muscle glucose uptake in insulin-stimulated soleus, a mainly oxidative muscle (17.5%, p < 0.05), but not in EDL-a mostly glycolytic muscle. In insulin-stimulated soleus only, ucOC treatment (3 and 30ng/ml) increased phosphorylation of AS160 and ERK2, but not Akt or AMPKα. The ucOC-induced increase in ERK2 phosphorylation in soleus was not associated with the increase in glucose uptake or AS160 phosphorylation. ucOC enhances glucose uptake and AS160 phosphorylation in insulin-stimulated oxidative but not glycolytic muscle, via upstream mechanisms which appear to be independent of ERK or AMPK.

Phenolic compounds isolated from fermented blueberry juice decrease hepatocellular glucose output and enhance muscle glucose uptake in cultured murine and human cells

BackgroundWe recently reported that blueberry juice fermented (FJ) with Serratia vaccinii bacterium has antidiabetic activities both in vivo and in vitro. The purpose of this project was to elucidate the effect of FJ on glucose homeostasis in liver and skeletal muscle cells and to identify active fractions/compounds responsible for this effect.MethodsFJ was fractionated using standard chromatography procedures. Hepatic (H4IIE, HepG2) and skeletal muscle cells (C2C12) were treated with maximum non-toxic concentrations of FJ, fractions and isolated compounds thereof. Glucose-6-phosphatase (G6Pase) activity was measured using glucose oxidase method. To measure glucose uptake and glycogen synthase (GS) activity, radioactive assays were used.ResultsFractionation of FJ yielded seven fractions. FJ and its phenolic fractions F2, F3-1 and F3-2 respectively inhibited G-6Pase by 31, 45, 51 and 26%; activated GS by 2.3-, 2.3-, 2.2- and 2-fold; and stimulated glucose uptake by 19, 25, 18 and 15%, as compared to DMSO vehicle control. Subfractionation of the active fractions yielded 4 compounds (catechol, chlorogenic, gallic and protocatechuic acid). Catechol, yielding the greatest bioactivity in G6Pase and glucose uptake assays, decreased G6Pase activity by 54%, increased GS by 2-fold and stimulated glucose uptake by 44% at 45.5 μM.ConclusionsThis study identifies novel potential antidiabetic compounds that can help standardize FJ.

A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.

The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex.

Enhancement of muscle glucose uptake by the vasopeptidase inhibitor, omapatrilat, is independent of insulin signaling and the AMP kinase pathway

Omapatrilat (OMA), a vasopeptidase inhibitor (VPI), presently being tested in clinical trials for its antihypertensive properties, inhibits both angiotensin-converting enzyme and neutral endopeptidase, and raises tissue bradykinin levels. Recent studies from our laboratory and those of others have demonstrated that VPIs enhance muscle glucose uptake in animal models, and this effect is mediated by the bradykinin-nitric oxide pathway. The mechanism of the effect of OMA on muscle glucose uptake, however, is presently unknown. To investigate the effect of OMA on insulin signaling, soleus muscle was isolated 2 or 5 min after an i.v. bolus of insulin or saline from male Zucker fatty rats (8-10 weeks of age), following a 5-day treatment period of oral OMA (15 mg/kg per day) or drug vehicle (placebo). OMA resulted in significantly lower systolic blood pressure compared with the placebo-treated group (84.4+/- 7.52 mmHg in OMA vs 112+/-2.18 mmHg in controls, P<0.01). Immunoprecipitation and Western blot analysis of insulin receptor substrate 1 (IRS-1) revealed no changes in protein mass with OMA treatment. OMA did not enhance basal or insulin-stimulated IRS-1 tyrosine phosphorylation or its subsequent association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. Under basal and insulin-stimulated conditions, OMA treatment did not alter the protein mass or the phosphorylation of Akt/protein kinase B, p42/44 extracellular signal-regulated kinase or adenosine monophosphate-activated protein kinase, or GLUT4 protein expression. We conclude that the ability of OMA to enhance whole body and specifically muscle glucose uptake in Zucker fatty rats is not mediated by enhancing insulin or AMPK signaling. Future studies should examine whether hemodynamic effects of the drug, independent of insulin signaling, enhance glucose uptake in insulin-resistant skeletal muscle.

INTERACTION OF PHYSIOLOGICAL MECHANISMS IN CONTROL OF MUSCLE GLUCOSE UPTAKE

1. Control of glucose uptake is distributed between three steps. These are the rate that glucose is delivered to cells, the rate of transport into cells, and the rate that glucose is phosphorylated within these same cells. The functional limitations to each one of these individual steps has been difficult to assess because they are so closely coupled to each other. Studies have been performed in recent years using complex isotopic techniques or transgenic mouse models to shed new light on the role that each step plays in overall control of muscle glucose uptake. 2. Membrane glucose transport is a major barrier and glucose delivery and glucose phosphorylation are minor barriers to muscle glucose uptake in the fasted, sedentary state. GLUT-4 is translocated to the muscle membrane during exercise and insulin-stimulation. The result of this is that it can become so permeable to glucose that it is only a minor barrier to glucose uptake. 3. In addition to increasing glucose transport, exercise and insulin-stimulation also increase muscle blood flow and capillary recruitment. This effectively increases muscle glucose delivery and by doing so, works to enhance muscle glucose uptake. 4. There is a growing body of data that suggests that insulin resistance to muscle glucose uptake can be because of impairments in any one or more of the three steps that comprise the process.

AMP-activated protein kinase and muscle glucose uptake.

The AMP-activated protein kinase (AMPK) is an enzyme that is activated in situations where there are changes in the cellular energy status such as muscle contraction and hypoxia. AMPK can also be pharmacologically activated by the compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and the antidiabetic agent metformin. Several studies support the hypothesis that AMPK plays an important role in the stimulation of muscle glucose uptake by these physiological and pharmacological stimuli. In isolated rat muscles, activation of AMPK is associated with increases in glucose uptake through an insulin-independent mechanism. Studies done in rodents have shown that the activation of AMPK by AICAR is accompanied by decreases in blood glucose concentrations, in part due to enhanced muscle glucose uptake. Similar to exercise, AICAR not only directly stimulates glucose uptake into the skeletal muscle, but also enhances insulin sensitivity. The activation of AMPK and associated increases in muscle glucose uptake are affected by factors such as glycogen content, exercise training and fibre type. The effects of AMPK on muscle glucose uptake makes this protein a promising pharmacological target for the treatment of type 2 diabetes.

Effect of misoprostol (PGE1) on glucose metabolism in type‐2‐diabetic and control subjects

In vitro and in vivo studies have demonstrated that prostaglandins of the E series enhance muscle glucose uptake. We examined the effect of acute misoprostol (PGE1) administration on whole body insulin-mediated glucose disposal, as well as the major intracellular pathways of glucose metabolism in type 2 diabetic (n = 10) and non-diabetic (n = 4) subjects. Each subject received two 240-min euglycaemic insulin (40 mU/m2/min) clamp studies with tritiated glucose and indirect calorimetry. During one of the insulin clamp studies, 200 microg of misoprostol was ingested at 90 and 150 min after the start of the insulin infusion. Insulin-mediated total body glucose disposal, glycolysis, glycogenesis and glucose oxidation were similar during the insulin clamp studies performed without and with misoprostol in both the diabetic and non-diabetic groups. These results demonstrate that the acute administration of misoprostol does not enhance insulin-mediated glucose disposal in either type-2-diabetic or non-diabetic subjects.

Resistance to exercise-induced increase in glucose uptake during hyperinsulinemia in insulin-resistant skeletal muscle of patients with type 1 diabetes.

Insulin and exercise have been shown to activate glucose transport at least in part via different signaling pathways. However, it is unknown whether insulin resistance is associated with a defect in the ability of an acute bout of exercise to enhance muscle glucose uptake in vivo. We compared the abilities of insulin and isometric exercise to stimulate muscle blood flow and glucose uptake in 12 men with type 1 diabetes (age 24 +/- 1 years, BMI 23.0 +/- 0.4 kg/m(2)) and in 11 age- and weight-matched nondiabetic men (age 25 +/- 1 years, BMI 22.3 +/- 0.6 kg/m(2)) during euglycemic hyperinsulinemia (1 mU. kg(-1). min(-1) insulin infusion for 150 min). One-legged exercise was performed at an intensity of 10% of maximal isometric force for 105 min (range 45-150). Rates of muscle blood flow, oxygen consumption, and glucose uptake were quantitated simultaneously in both legs using [(15)O]water, [(15)O]oxygen, [(18)F]-2-fluoro-2-deoxy-D-glucose, and positron emission tomography. Resting rates of oxygen consumption were similar during hyperinsulinemia between the groups (2.4 +/- 0.3 vs. 2.0 +/- 0.5 ml. kg(-1) muscle. min(-1); normal subjects versus patients with type 1 diabetes, NS), and exercise increased oxygen consumption similarly in both groups (25.3 +/- 4.3 vs. 20.1 +/- 3.0 ml. kg(-1) muscle. min(-1), respectively, NS). Rates of insulin-stimulated muscle blood flow and the increments in muscle blood flow induced by exercise were also similar in normal subjects (129 +/- 14 ml. kg(-1). min(-1)) and in patients with type 1 diabetes (115 +/- 12 ml. kg(-1). min(-1)). The patients with type 1 diabetes exhibited resistance to both insulin stimulation of glucose uptake (34 +/- 6 vs. 76 +/- 9 micromol. kg(-1) muscle. min(-1), P < 0.001) and also to the exercise-induced increment in glucose uptake (82 +/- 15 vs. 162 +/- 29 micromol. kg(-1) muscle. min(-1), P < 0.05). We conclude that the ability of exercise to increase insulin-stimulated glucose uptake in vivo is blunted in patients with insulin-resistant type 1 diabetes compared with normal subjects. This could be caused by either separate or common defects in exercise- and insulin-stimulated pathways.

Enhanced muscle glucose uptake facilitates nitrogen efflux from exercised muscle.

The hypothesis that glucose ingestion in the postexercise state enhances the synthesis of glutamine and alanine in the skeletal muscle was tested. Glucose was infused intraduodenally for 150 min (44.5 micromol . kg-1 . min-1) beginning 30 min after a 150-min period of exercise (n = 7) or an equivalent duration sedentary period (n = 10) in 18-h-fasted dogs. Prior exercise caused a twofold greater increase in limb glucose uptake during the intraduodenal glucose infusion compared with uptake in sedentary dogs. Arterial glutamine levels fell gradually with the glucose load in both groups. Net hindlimb glutamine efflux increased in response to intraduodenal glucose in exercised but not sedentary dogs (P < 0. 05-0.01). Arterial alanine levels, depleted by 50% with exercise, rose with intraduodenal glucose in exercised but not sedentary dogs (P < 0.05-0.01). Net hindlimb alanine efflux also rose in exercised dogs in response to intraduodenal glucose (P < 0.05-0.01), whereas it was not different from baseline in sedentary controls for the first 90 min of glucose infusion. Beyond this point, it, too, rose significantly. We conclude that oral glucose may facilitate recovery of muscle from prolonged exercise by enhancing the removal of nitrogen in the form of glutamine and alanine.