Adrenaline increases skeletal muscle glycogenolysis, pyruvate dehydrogenase activation and carbohydrate oxidation during moderate exercise in humans

# 1.
To evaluate the role of adrenaline in regulating carbohydrate metabolism during moderate exercise, 10 moderately trained men completed two 20 min exercise bouts at 58 ± 2 % peak pulmonary oxygen uptake (̇V_o2,peak). On one occasion saline was infused (CON), and on the other adrenaline was infused intravenously for 5 min prior to and throughout exercise (ADR). Glucose kinetics were measured by a primed, continuous infusion of 6,6-[2H]glucose and muscle samples were obtained prior to and at 1 and 20 min of exercise.

# 2.
The infusion of adrenaline elevated (P < 0.01) plasma adrenaline concentrations at rest (pre-infusion, 0.28 ± 0.09; post-infusion, 1.70 ± 0.45 nmol l−1; means ±s.e.m.) and this effect was maintained throughout exercise. Total carbohydrate oxidation increased by 18 % and this effect was due to greater skeletal muscle glycogenolysis (P < 0.05) and pyruvate dehydrogenase (PDH) activation (P < 0.05, treatment effect). Glucose rate of appearance was not different between trials, but the infusion of adrenaline decreased (P < 0.05, treatment effect) skeletal muscle glucose uptake in ADR.

# 3.
During exercise muscle glucose 6-phosphate (G-6-P) (P = 0.055, treatment effect) and lactate (P < 0.05) were elevated in ADR compared with CON and no changes were observed for pyruvate, creatine, phosphocreatine, ATP and the calculated free concentrations of ADP and AMP.

# 4.
The data demonstrate that elevated plasma adrenaline levels during moderate exercise in untrained men increase skeletal muscle glycogen breakdown and PDH activation, which results in greater carbohydrate oxidation. The greater muscle glycogenolysis appears to be due to increased glycogen phosphorylase transformation whilst the increased PDH activity cannot be readily explained. Finally, the decreased glucose uptake observed during exercise in ADR is likely to be due to the increased intracellular G-6-P and a subsequent decrease in glucose phosphorylation.

Carbohydrate metabolism during exercise in females : effect of reduced fat availability

This study examined the effect of reduced plasma free fatty acid (FFA) availability on carbohydrate metabolism during exercise. Six untrained women cycled for 60 minutes at approximately 58% of maximum oxygen uptake after ingestion of a placebo (CON) or nicotinic acid (NA), 30 minutes before exercise (7.4 ± 0.5 mg·kg⁻¹ body weight), and at 0 minutes (3.7 ± 0.3 mg·kg⁻¹) and 30 minutes (3.7 ± 0.3 mg·kg⁻¹) of exercise. Glucose kinetics were measured using a primed, continuous infusion of [6,6-²H] glucose. Plasma FFA (CON, 0.86 ± 0.12; NA, 0.21 ± 0.11 mmol·L⁻¹ at 60 minutes, P < .05) and glycerol (CON, 0.34 ± 0.05; NA, 0.10 ± 0.04 mmol·L⁻¹ at 60 minutes, P < .05) were suppressed throughout exercise. Mean respiratory exchange ratio (RER) during exercise was higher (P < .05) in NA (0.89 ± 0.02) than CON (0.83 ± 0.02). Plasma glucose and glucose production were similar between trials. Total glucose uptake during exercise was greater (P < .05) in NA (1,876 ± 161 μmol·kg⁻¹) than in CON (1,525 ± 107 μmol·kg⁻¹). Total fat oxidation was reduced (P < .05) by approximately 32% during exercise in NA. Total carbohydrate oxidized was approximately 42% greater (P < .05) in NA (412 ± 40 mmol) than CON (290 ± 37 mmol), of which, approximately 16% (20 ± 10 mmol) could be attributed to glucose. Plasma insulin and glucagon were similar between trials. Catecholamines were higher (P < .05) during exercise in NA. In summary, during prolonged moderate exercise in untrained women, reduced FFA availability results in a compensatory increase in carbohydrate oxidation, which appears to be due predominantly to an increase in glycogen utilization, although there was a small, but significant, increase in whole body glucose uptake.

Regulation of glucose kinetics during intense exercise in humans: effects of α- and β-adrenergic blockade

This study examined the effect of combined α- and β-adrenergic blockade on glucose kinetics during intense exercise. Six endurance-trained men exercised for 20 minutes at approximately 78% of their peak oxygen consumption (V_O 2) following ingestion of a placebo (CON) or combined α- (prazosin hydrochloride) and β- (timolol maleate) adrenoceptor antagonists (BLK). Plasma glucose increased during exercise in CON (0 minutes: 5.5 ± 0.1; 20 minutes: 6.5 ± 0.3 mmol · L⁻¹, P < .05). In BLK, the exercise-induced increase in plasma glucose was abolished (0 minutes: 5.7 ± 0.3; 20 minutes: 5.7 ± 0.1 mmol · L⁻¹). Glucose kinetics were measured using a primed, continuous infusion of [6,6-²H] glucose. Glucose production was not different between trials; on average these values were 25.3 ± 3.9 and 30.9 ± 4.4 μmol · kg⁻¹ · min⁻¹ in CON and BLK, respectively. Glucose uptake during exercise was greater (P < .05) in BLK (30.6 ± 4.6 μmol · kg⁻¹ · min⁻¹) compared with CON (18.4 ± 2.5 μmol · kg⁻¹ · min⁻¹). In BLK, plasma insulin and catecholamines were higher (P < .05), while plasma glucagon was unchanged from CON. Free fatty acids (FFA) and glycerol were lower (P < .05) in BLK. These findings demonstrate that adrenergic blockade during intense exercise results in a blunted plasma glucose response that is due to enhanced glucose uptake, with no significant change in glucose production.

Effect of carbohydrate ingestion on glucose kinetics during exercise in the heat

Six endurance-trained men [peak oxygen uptake (VO₂) = 4.58 ± 0.50 (SE) l/min] completed 60 min of exercise at a workload requiring 68 ± 2% peak VO₂ in an environmental chamber maintained at 35°C (<50% relative humidity) on two occasions, separated by at least 1 wk. Subjects ingested either a 6% glucose solution containing 1 µCi [3-³H]glucose/g glucose (CHO trial) or a sweet placebo (Con trial) during the trials. Rates of hepatic glucose production [HGP = glucose rate of appearance (R_a) in Con trial] and glucose disappearance (R_d), were measured using a primed, continuous infusion of [6,6-^₂H]glucose, corrected for gut-derived glucose (gut R_a) in the CHO trial. No differences in heart rate, VO₂, respiratory exchange ratio, or rectal temperature were observed between trials. Plasma glucose concentrations were similar at rest but increased (P < 0.05) to a greater extent in the CHO trial compared with the Con trial. This was due to the absorption of ingested glucose in the CHO trial, because gut R_a after 30 and 50 min (16 ± 5 µmol · kg^-1 · min^-1) was higher (P < 0.05) compared with rest, whereas HGP during exercise was not different between trials. Glucose R_d was higher (P < 0.05) in the CHO trial after 30 and 50 min (48.0 ± 6.3 vs 34.6 ± 3.8 µmol · kg^-1 · min^-1, CHO vs. Con, respectively). These results indicate that ingestion of carbohydrate, at a rate of ~1.0 g/min, increases glucose Rd but does not blunt the rise in HGP during exercise in the heat.

Plasma glucose kinetics during prolonged exercise in trained humans when fed carbohydrate

Nine endurance-trained men exercised on a cycle ergometer at ~68% peak O₂ uptake to the point of volitional fatigue [232 ± 14 (SE) min] while ingesting an 8% carbohydrate solution to determine how high glucose disposal could increase under physiological conditions. Plasma glucose kinetics were measured using a primed, continuous infusion of [6,6-²H]glucose and the appearance of ingested glucose, assessed from [3-³H]glucose that had been added to the carbohydrate drink. Plasma glucose was increased (P < 0.05) after 30 min of exercise but thereafter remained at the preexercise level. Glucose appearance rate (Ra) increased throughout exercise, reaching its peak value of 118 ± 7 µmol · kg^-1 · min^-1 at fatigue, whereas gut R_a increased continuously during exercise, peaking at 105 ± 10 µmol · kg^-1 · min^-1 at the point of fatigue. In contrast, liver glucose output never rose above resting levels at any time during exercise. Glucose disposal (R_d) increased throughout exercise, reaching a peak value of 118 ± 7 µmol · kg^-1 · min^-1 at fatigue. If we assume 95% oxidation of glucose R_d, estimated exogenous glucose oxidation at fatigue was 1.36 ± 0.08 g/min. The results of this study demonstrate that glucose uptake increases continuously during prolonged, strenuous exercise when carbohydrate is ingested and does not appear to limit exercise performance.

Glucose production during strenuous exercise in humans : role of epinephrine

The increase in hepatic glucose production (HGP) that occurs during intense exercise is accompanied by a simultaneous increase in epinephrine, which suggests that epinephrine may be important in regulating HGP. To further investigate this, six trained men were studied twice. The first trial [control (Con)] consisted of 20 min of cycling at 40 ± 1% peak oxygen uptake (V˙o 2 peak) followed by 20 min at 80 ± 2%V˙o 2 peak. During the second trial [epinephrine (Epi)], subjects exercised for 40 min at 41 ± 2%V˙o 2 peak. Epinephrine was infused during the latter 20 min of exercise and resulted in plasma levels similar to those measured during intense exercise in Con. Glucose kinetics were measured using a primed, continuous infusion of [3-3H]glucose. HGP was similar at rest (Con, 11.0 ± 0.5 and Epi, 11.1 ± 0.5 μmol ⋅ kg−1 ⋅ min−1). In Con, HGP increased (P < 0.05) during exercise to 41.0 ± 5.2 μmol ⋅ kg−1 ⋅ min−1at 40 min. In Epi, HGP was similar to Con during the first 20 min of exercise. Epinephrine infusion increased (P < 0.05) HGP to 24.0 ± 2.5 μmol ⋅ kg−1 ⋅ min−1at 40 min, although this was less (P< 0.05) than the value in Con. The results suggest that epinephrine can increase HGP during exercise in trained men; however, epinephrine during intense exercise cannot fully account for the rise in HGP. Other glucoregulatory factors must contribute to the increase in HGP during intense exercise.

Effect of increased blood glucose availability on glucose kinetics during exercise

This study examined the effect of increased blood glucose availability on glucose kinetics during exercise. Five trained men cycled for 40 min at 77 ± 1% peak oxygen uptake on two occasions. During the second trial (Glu), glucose was infused at a rate equal to the average hepatic glucose production (HGP) measured during exercise in the control trial (Con). Glucose kinetics were measured by a primed continuous infusion ofd-[3-3H]glucose. Plasma glucose increased during exercise in both trials and was significantly higher in Glu. HGP was similar at rest (Con, 11.4 ± 1.2; Glu, 10.6 ± 0.6 μmol ⋅ kg−1 ⋅ min−1). After 40 min of exercise, HGP reached a peak of 40.2 ± 5.5 μmol ⋅ kg−1 ⋅ min−1in Con; however, in Glu, there was complete inhibition of the increase in HGP during exercise that never rose above the preexercise level. The rate of glucose disappearance was greater (P < 0.05) during the last 15 min of exercise in Glu. These results indicate that an increase in glucose availability inhibits the rise in HGP during exercise, suggesting that metabolic feedback signals can override feed-forward activation of HGP during strenuous exercise.

Effect of heat stress on glucose kinetics during exercise

To identify the mechanism underlying the exaggerated hyperglycemia during exercise in the heat, six trained men were studied during 40 min of cycling exercise at a workload requiring 65% peak pulmonary oxygen uptake (V˙o 2 peak) on two occasions at least 1 wk apart. On one occasion, the ambient temperature was 20°C [control (Con)], whereas on the other, it was 40°C [high temperature (HT)]. Rates of glucose appearance and disappearance were measured by using a primed continuous infusion of [6,6-2H]glucose. No differences in oxygen uptake during exercise were observed between trials. After 40 min of exercise, heart rate, rectal temperature, respiratory exchange ratio, and plasma lactate were all higher in HT compared with Con (P < 0.05). Plasma glucose levels were similar at rest (Con, 4.54 ± 0.19 mmol/l; HT, 4.81 ± 0.19 mmol/l) but increased to a greater extent during exercise in HT (6.96 ± 0.16) compared with Con (5.45 ± 0.18;P < 0.05). This was the result of a higher glucose rate of appearance in HT during the last 30 min of exercise. In contrast, the glucose rate of disappearance and metabolic clearance rate were not different at any time point during exercise. Plasma catecholamines were higher after 10 and 40 min of exercise in HT compared with Con (P < 0.05), whereas plasma glucagon, cortisol, and growth hormone were higher in HT after 40 min. These results indicate that the hyperglycemia observed during exercise in the heat is caused by an increase in liver glucose output without any change in whole body glucose utilization.

Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a multicenter 2 × 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and continuous with conventional glucose self-monitoring (HypoCOMPaSS)

To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin infusion [CSII]) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG).

Introducing personal liability under the continuous disclosure regime : The essentials and non-essentials

Under the Federal Government's CLERP 9 legislation, expected at the time of writing to come into force in July 2004, personal liability will be introduced for the first time under the continuous disclosure regime. Individuals who are 'involved' in a failure to immediately disclose materially price sensitive information to the market will be subject to a civil penalty, in addition to the company being liable. According to the author, the introduction of personal liability per se is not contentious and indeed is a favourable change; what is questionable, however, is whether 'involvement' in a contravention is the appropriate test for imposing personal liability in relation to breaches of the continuous disclosure provisions. Based on the case law to date on the meaning of 'involved', there is particular uncertainty as to whether an individual would need to have actual knowledge that non-disclosed information is 'materially price sensitive' in order to satisfy the test of 'involved' in the context of continuous disclosure, or whether mere knowledge that the information has not been disclosed would be sufficient. This uncertainty arises due to the vague concept of 'essential matters' which the courts have developed as a test for what degree of knowledge a person needs to have in order to be 'involved'. The author argues that all the confusion as to what 'involved' means could be addressed by removing the word 'essential' from the dialogue, so that the test of 'involvement' would simply be based on whether the particular person had actual knowledge of each of the factual elements constituting the offence.

Conductive wool yarns by continuous vapour phase polymerization of pyrrole

Conducting polypyrrole (PPy) coated wool yarns were prepared by a continuous vapour polymerization technique, using a speed of 1 m/min with different iron(III) chloride (FeCl₃) as the oxidant at different concentrations. The resistivities, tensile properties, longitudinal and cross-sectional views of PPy-coated wool yarns were investigated. Optimum specific electrical resistances of 2.96 Ω g/cm² at 80 g/L FeCl₃ and 1.69 Ω g/cm² at 70 g/L FeCl₃ were obtained for 500 and 400 twist per meter (TPM) yarns, respectively. PPy-coated wool yarns exhibited higher elongation than uncoated yarns. Longitudinal and cross-sectional views of the yarns indicate that PPy coating penetrated deep into the yarn cross-section and a uniform coating was obtained on the surface of the yarn surface.

Challenges of continuous global optimization in molecular structure prediction

The molecular geometry, the three dimensional arrangement of atoms in space, is a major factor determining the properties and reactivity of molecules, biomolecules and macromolecules. Computation of stable molecular conformations can be done by locating minima on the potential energy surface (PES). This is a very challenging global optimization problem because of extremely large numbers of shallow local minima and complicated landscape of PES. This paper illustrates the mathematical and computational challenges on one important instance of the problem, computation of molecular geometry of oligopeptides, and proposes the use of the Extended Cutting Angle Method (ECAM) to solve this problem.

ECAM is a deterministic global optimization technique, which computes tight lower bounds on the values of the objective function and fathoms those part of the domain where the global minimum cannot reside. As with any domain partitioning scheme, its challenge is an extremely large partition of the domain required for accurate lower bounds. We address this challenge by providing an efficient combinatorial algorithm for calculating the lower bounds, and by combining ECAM with a local optimization method, while preserving the deterministic character of ECAM.