The AMP-activated protein kinase (AMPK) is a metabolite sensing serine/threonine kinase that has been termed the master regulator of cellular energy metabolism due to its numerous roles in the regulation of glucose, lipid, and protein metabolism. In this review, we first summarize the current literature on a number of important aspects of AMPK in skeletal muscle. These include the following: (1) the structural components of the three AMPK subunits (i.e. AMPKalpha, beta, and gamma), and their differential localization in response to stimulation in muscle; (2) the biochemical regulation of AMPK by AMP, protein phosphatases, and its three known upstream kinases, LKB1, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor-beta-activated kinase 1 (TAK1); (3) the pharmacological agents that are currently available for the activation and inhibition of AMPK; (4) the physiological stimuli that activate AMPK in muscle; and (5) the metabolic processes that AMPK regulates in skeletal muscle.

Results from the Diabetes Prevention Program highlight the effectiveness of metformin or regular physical activity in the prevention of type 2 diabetes. Independently, metformin and exercise increase insulin sensitivity, but they have not been studied in combination. To assess the combined effects, insulin-resistant subjects ( n = 9) matched for weight, body fat, and aerobic fitness were studied before any treatment (B), after 2–3 wk of 2,000 mg/day metformin (MET), and after metformin plus 40 min of exercise at 65% V̇o2peak (MET + Ex). A second group ( n = 7) was studied at baseline and after an identical bout of exercise with no metformin (Ex). Biopsies of the vastus lateralis were taken at B, after MET, immediately after MET + Ex ( group 1), or immediately after Ex ( group 2). Insulin sensitivity was assessed 4 h postexercise with a euglycemic hyperinsulinemic (40 mU·m2·min−1) clamp enriched with [6,6-2H]glucose. Insulin sensitivity was 54% higher after Ex ( P < 0.01), but there was no change with Met + Ex. Skeletal muscle AMPKα2 activity was elevated threefold ( P < 0.01) after Ex, but there was no increase with MET + Ex. These findings suggest that the combination of short-term metformin treatment and an acute bout of exercise does not enhance insulin sensitivity, and the addition of metformin may attenuate the well-documented effects of exercise alone.

-When previously sedentary men and women follow exercise training programs with ad libitum feeding, men lose body fat, but women do not. The purpose of this study was to evaluate whether this observation could be related to sex differences in the way energy-regulating hormones and appetite perception respond to exercise. Eighteen (9 men, 9 women) overweight/ obese individuals completed four bouts of exercise with energy added to the baseline diet to maintain energy balance (BAL), and four bouts without energy added to induce energy deficit (DEF). Concentrations of acylated ghrelin, insulin, and leptin, as well as appetite ratings were measured in response to a meal after a no-exercise baseline and both exercise conditions. In men, acylated ghrelin area under the curve (AUC) was not different between conditions. In women, acylated ghrelin AUC was higher after DEF (ϩ32%) and BAL (ϩ25%), and the change from baseline was higher than men (P Ͻ 0.05). In men, insulin AUC was reduced (Ϫ17%) after DEF (P Ͻ 0.05), but not BAL. In women, insulin AUC was lower (P Ͻ 0.05) after DEF (Ϫ28%) and BAL (Ϫ15%). Leptin concentrations were not different across conditions in either sex. In men, but not in women, appetite was inhibited after BAL relative to DEF. The results indicate that, in women, exercise altered energy-regulating hormones in a direction expected to stimulate energy intake, regardless of energy status. In men, the response to exercise was abolished when energy balance was maintained. The data are consistent with the paradigm that mechanisms to maintain body fat are more effective in women. acylated ghrelin; leptin; insulin; physical activity; body fat; food intake EVIDENCE FROM THE NATIONAL WEIGHT CONTROL REGISTRY shows the critical importance of regular aerobic exercise in maintaining lost body weight and body fat (25). On the basis of a strong body of data, the Institute of Medicine indicated that preventing body fat gain over time probably requires 60 min of physical activity per day (4). When previously sedentary individuals begin exercise training programs, however, fat loss is neither inevitable nor consistent across the sexes (11, 36). In general, men lose body fat when they undertake structured exercise training programs with ad libitum eating (9,22,36). In contrast, women do not lose body fat in identical protocols (9,22,36). For example, Donnelly et al. (11) reported that supervised aerobic exercise 5 days/wk for 16 mo lowered body fat and body weight in men who ate ad libitum. In contrast, there were no changes in body fat and body mass in women. These data are corroborated by similar studies showing sex differences in body fat loss or fat oxidation (19,20,36). Taken together, these data suggest that during exercise training, men do not sufficiently increase energy intake to balance their new higher energy expenditure. In contrast, women more precisely match intake with expenditure and therefore maintain body weight and body fat.Sex differences in body fat loss in response to aerobic exercise may result, a...

To assess the roles of endogenous estrogen (E2) and progesterone (P4) in regulating exercise carbohydrate use, we used pharmacological suppression and replacement to create three distinct hormonal environments: baseline (B), with E2 and P4 low; estrogen only (E), with E2 high and P4 low; and estrogen/progesterone (E + P), with E2 and P4 high. Blood glucose uptake (R(d)), total carbohydrate oxidation (CHO(ox)), and estimated muscle glycogen utilization (EMGU) were assessed during 60 min of submaximal exercise by use of stable isotope dilution and indirect calorimetry in eight eumenorrheic women. Compared with B (1.26 +/- 0.04 g/min) and E + P (1.27 +/- 0.04 g/min), CHO(ox) was lower with E (1.05 +/- 0.02 g/min). Glucose R(d) tended to be lower with E and E + P relative to B. EMGU was 25% lower with E than with B or E + P. Plasma free fatty acids (FFA) were inversely related to EMGU (r(2) = 0.49). The data suggest that estrogen lowers CHO(ox) by reducing EMGU and glucose R(d). Progesterone increases EMGU but not glucose R(d). The opposing actions of E(2) and P(4) on EMGU may be mediated by their impact on FFA availability or vice versa.

During exercise, obese individuals oxidize less glycogen and more fat than their lean counterparts, but the shift in substrate use may be mediated by insulin resistance rather than body fat per se. In addition, individuals with Type 2 diabetes are not resistant to contraction-mediated glucose uptake during exercise, but in vivo studies uncomplicated by hyperglycemia are lacking. The purpose of this study was to compare blood glucose uptake and the balance between carbohydrate and fat utilization during exercise in insulin-resistant (IR) and insulin-sensitive (IS) women of equivalent body fatness and maximal oxygen consumption (VO2 max). Twelve overweight sedentary women were divided into two groups with similar body mass index (IR = 28.5 +/- 1.6, IS = 27.5 +/- 1.9), lean mass (IR = 42.4 +/- 1.8 kg, IS = 41.5 +/- 1.9 kg), and VO2 max (IR = 29.7 +/- 3.5 ml.kg(-1).min(-1), IS = 30.7 +/- 3.9 ml.kg(-1).min(-1)) but a markedly different composite insulin sensitivity index (IR = 3.0 +/- 0.7, IS = 7.7 +/- 0.9). Blood glucose kinetics and substrate oxidation were assessed by stable isotope dilution and indirect calorimetry during 50 min of treadmill walking at 45% VO2 max. Total carbohydrate oxidation and estimated muscle glycogen use were significantly lower in the IR group. Blood glucose uptake was the same in the IR and IS groups. These data suggest that insulin resistance, independent of body fat, spares muscle glycogen and shifts substrate oxidation toward less carbohydrate use during exercise. Insulin-resistant individuals with normoglycemia appear to have no defect in blood glucose uptake during exercise.

Individually, exercise and the drug metformin have been shown to prevent or delay type 2 diabetes. Metformin mildly inhibits complex I of the electron transport system and may impact aerobic capacity in people exercising while tak ing metformin. The purpose of the study was to evaluate the effects of metformin on maximal aerobic capacity in healthy individuals without mitochondrial dysfunction. Seventeen healthy, normal-weight men (n = 11) and women (n = 6) partici pated in a double-blind, placebo-controlled, cross-over design. Peak aerobic capacity was measured twice using a continu ous, incrementally graded protocol; once after 7-9 d of metformin (final dose = 2000 mg/d) and once with placebo, with 1 week between tests. The order of the conditions was counterbalanced. Peak oxygen uptake (VO2 peak), heart rate (HR), ventilation (VE), respiratory exchange ratio (RER), rating of perceived exertion (RPE), and test duration were compared across conditions using paired t tests with the R statistical program. VO2 peak (-2.7%), peak heart rate (-2.0%), peak ven tilation (-6.2%), peak RER (-3.0%), and exercise duration (-4.1%) were all reduced slightly, but significantly, with metformin (all p < 0.05). There was no effect of metformin on RPE or ventilatory breakpoint. Correlations between the decrement in VO2 peak and any of the other outcome variables were weak (r 2 < 0.20) and not significant. Shortterm treatment with metformin has statistically significant, but physiologically subtle, effects that reduce key outcomes related to maximal exercise capacity. Whether this small but consistent effect is manifested in people with insulin re sistance or diabetes who already have some degree of mitochondrial dysfunction remains to be determined.Key words: pre-diabetes, type 2 diabetes, exercise, biguanide.Résumé : Isolément, l'exercice physique et un médicament, la metformine, préviennent ou retardent l'apparition du dia bète de type 2. La metformine inhibe légèrement le complexe I de la chaîne respiratoire et peut avoir un effet sur la capa cité aérobie des individus qui font de l'exercice physique. Le but de cette étude est d'évaluer l'effet de la metformine sur la puissance aérobie maximale d'individus en bonne santé et sans troubles mitochondriaux. Six femmes et 11 hommes en bonne santé et de poids normal participent à une étude expérimentale à double insu avec groupe témoin et inversion des groupes. On mesure deux fois la puissance aérobie de pointe au moyen d'un test d'effort continu d'intensité croissante, une fois après 7 à 9 jours de consommation de metformine (dose terminale, 2 000 mg par jour) et l'autre fois, à sept jours d'écart, après avoir pris un placebo. L'ordre des séances d'évaluation est contrebalancé. Au moyen du programme d'analyse statistique R, on compare par des tests t pour mesures appariées les variables suivantes observées dans les deux conditions : la consommation d'oxygène (VO 2 ) de pointe, la fréquence cardiaque (HR), le débit ventilatoire (VE), le ratio d'échanges gazeux (RER), la p...

Purpose Exercise training alters protein abundance in muscle of healthy individuals, but the effect of exercise on these proteins in patients with type 2 diabetes (T2D) is unknown. The aim of this study was to determine how exercise training alters the skeletal muscle proteome in patients with T2D. Methods Biopsies of the vastus lateralis were obtained before and after 4 weeks of exercise training in six patients with T2D (54 ± 4 yrs, BMI 29± 2) and six age- and BMI- matched control subjects (48 ± 2, BMI 28 ± 3) studied at baseline. Proteins were identified and quantified using normalized spectral abundance factors (NSAF) by multidimensional high-resolution mass spectrometry. Results Of 1,329 proteins assigned at baseline, 438 were present in at least half of all muscle samples; of these, 15 proteins differed significantly between patients with T2D and control subjects (p<0.05). In the diabetic patients, exercise training altered the abundance of 17 proteins (p<0.05). Key training adaptations included an increase in proteins of the malate–aspartate shuttle and citric acid cycle, reduced abundance of glycolytic proteins, and altered abundance of cytoskeleton proteins. Conclusion The data from this study support the ability of exercise training to alter the abundance of proteins that regulate metabolism and cytoskeletal structure in patients with T2D. These findings open new avenues for future research.

Energy surplus raises circulating concentrations of leptin and insulin while lowering plasma ghrelin. Exercise has the opposite effects. The purpose of this study was to determine whether exercise counters the hormonal effects of energy surplus independent of changes in energy balance. To do that, we assessed plasma concentrations of leptin, insulin, and ghrelin at baseline, after overfeeding, and after overfeeding plus exercise. Baseline (B) leptin and insulin concentrations and ghrelin area under the curve were measured during an oral glucose challenge in 9 healthy, active subjects (6 male, 3 female) after 2 days in energy balance without exercise. Measurements were repeated after subjects were overfed by +3213 ± 849 kJ/d for 3 more sedentary days (OF). In the third condition, the same net energy surplus (+3125 ± 933 kJ/d) was generated for 24 hours by doubling the overfeeding (+6284 ± 1669 kJ/d) and countering it with a bout of exercise (expenditure = 3063 ± 803 kJ); and measurements were made the next day (OF + EX). Compared with B, leptin went up (5.8 ± 8.2 to 7.6 ± 10.6 ng/mL) after OF, but was not significantly higher after OF + EX (7.1 ± 10.2 ng/mL). Compared with B, insulin was +36% and +43% higher after OF and OF + EX, respectively. In contrast, ghrelin area under the curve did not change after OF but was significantly lower (−14%) than B or OF after OF + EX (indicating greater suppression). These data suggest that the effect of short-term exercise on fasting leptin and insulin depends on energy balance but the ghrelin response may be partially mediated by effects of exercise independent of energy balance..