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The present study aimed to investigate the actions of fibroblast growth factor 21 ( FGF21) on energy balance in a natural model of relative fatness, the Siberian hamster. Hamsters were studied under long days ( LD) to promote weight gain, or short days to induce weight loss, and treated with rh FGF21 (3 mg/kg/day) via s.c. minipumps for 14 days. On days 7-9, detailed assessments of ingestive behaviour, metabolic gas exchange and locomotor activity were made. FGF21 caused substantial (P < 0.0001) weight loss in the fat LD state but not in the lean SD state: at the end of the study, FGF21-treated hamsters in LD lost 18% of body weight compared to vehicle controls, which is comparable to the natural body weight loss observed in SD. Epididymal fat pads, a correlate of total carcass fat content, were reduced by 19% in FGF21 treated hamsters in LD, whereas no difference was found in SD. Body weight loss in LD was associated with a reduction in food intake (P < 0.001) and a decreased respiratory exchange ratio (P < 0.001), indicating increased fat oxidation. Treatment with FGF21 maintained the normal nocturnal increase in oxygen consumption and carbon dioxide production into the early light phase in hamsters in LD, indicating increased energy expenditure, although locomotor activity was unaffected. These data suggest a greater efficacy of FGF21 in hamsters in LD compared to those in SD, which is consistent with both the peripheral and possibly central actions of FGF21 with respect to promoting a lean phenotype. The observed differences in FGF21 sensitivity may relate to day length-induced changes in adipose tissue mass. [ABSTRACT FROM AUTHOR]

The role of pyruvate dehydrogenase complex (PDC) in insulin-stimulated glycogen replenishment the day after exercise, and its molecular control, has not been examined. This study investigated the effect of acute exercise on basal and insulin-stimulated PDC activity (the rate-limiting step in glucose oxidation), glycogen synthesis and the expression of metabolic genes and transcription factors associated with changes in PDC activation and glucose metabolism. Eight healthy men (age 24 ± 2 years, body mass 79 ± 4 kg) underwent a euglycaemic, hyperinsulinaemic clamp 22 h after 90 min of one-legged cycling at 60% maximal oxygen consumption. Skeletal muscle glycogen content was similar in the exercised (EX) and non-exercised leg (CON) preclamp (471 ± 30 versus 463 ± 50 mmol (kg dry matter)−1, respectively) but increased during the clamp in EX to 527 ± 20 mmol (kg dry matter)−1, such that it was 17% greater than in CON (449 ± 35 mmol (kg dry matter)−1, P < 0.05). This increase in insulin-mediated glycogen storage was independent of insulin-stimulated Akt serine473 phosphorylation and activation of PDC. Prior exercise did not modulate the mRNA expression and protein content of pyruvate dehydrogenase kinase 4 (PDK4) in skeletal muscle, but was associated with increased hexokinase II mRNA expression and protein content and upregulation of peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1α (PGC1α) and PPARδ gene expression. Collectively, these findings suggest that prior exercise does not alter basal and insulin-stimulated PDC activation and the protein content of PDK4 the following day, but is associated with increased capacity (through upregulation of hexokinase II content) of muscle to phosphorylate and divert glucose towards glycogen storage. [ABSTRACT FROM AUTHOR]

Exenatide, a glucagon like peptide-1 agonist, is a treatment for type 2 diabetes mellitus that stimulates insulin and suppresses glucagon secretion in a glucose-dependent manner. By contrast, during aerobic exercise, the serum insulin concentration normally falls, with a rise in plasma glucagon. We therefore assessed whether exenatide might predispose to hypoglycaemia during exercise. We studied eight non-diabetic men, who were 35.3 ± 6.3 years of age with BMI of 24.7 ± 1.7 kg/m2 (mean ± SD), using a randomised, crossover, double-blind design investigation. After an overnight fast, participants received 5 μg of subcutaneous exenatide or placebo and rested for 105 min before cycling at 60% of their maximal oxygen uptake ( $$ \dot V{{\text{O}}_{\text{2max}}} $$) for 75 min and then recovering for a further 60 min. The insulin/glucagon molar ratio rose with exenatide at rest ( p < 0.01), then fell during exercise with placebo and with exenatide. At rest, fasting blood glucose fell by approximately 1 mmol/l with exenatide to a nadir of 3.4 ± 0.1 mmol/l ( p < 0.01). During exercise, blood glucose fell with placebo but, unexpectedly, rose with exenatide. Plasma adrenaline (epinephrine) and noradrenaline (norepinephrine), but not cortisol concentrations increased to a greater extent during exercise after exenatide. No participant developed symptomatic hypoglycaemia and the lowest individual blood glucose recorded was 2.8 mmol/l with exenatide at 50 min in the pre-exercise period. In non-diabetic participants given exenatide, blood glucose concentrations rise rather than fall during aerobic exercise with an associated greater catecholamine response. [ABSTRACT FROM AUTHOR]

We compared in vivo changes in liver glycogen concentration during exercise between patients with type 1 diabetes and healthy volunteers. We studied seven men with type 1 diabetes (mean ± SEM diabetes duration 10 ± 2 years, age 33 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 8.1 ± 0.2% and VO2 peak 43 ± 2 ml [kg lean body mass]−1 min−1) and five non-diabetic controls (mean ± SEM age 30 ± 3 years, BMI 22 ± 1 kg/m2, HbA1c 5.4 ± 0.1% and VO2 peak 52 ± 4 ml [kg lean body mass]−1 min−1, before and after a standardised breakfast and after three bouts (EX1, EX2, EX3) of 40 min of cycling at 60% VO2 peak. 13C Magnetic resonance spectroscopy of liver glycogen was acquired in a 3.0 T magnet using a surface coil. Whole-body substrate oxidation was determined using indirect calorimetry. Blood glucose and serum insulin concentrations were significantly higher ( p < 0.05) in the fasting state, during the postprandial period and during EX1 and EX2 in subjects with type 1 diabetes compared with controls. Serum insulin concentration was still different between groups during EX3 ( p < 0.05), but blood glucose concentration was similar. There was no difference between groups in liver glycogen concentration before or after the three bouts of exercise, despite the relative hyperinsulinaemia in type 1 diabetes. There were also no differences in substrate oxidation rates between groups. In patients with type 1 diabetes, hyperinsulinaemic and hyperglycaemic conditions during moderate exercise did not suppress hepatic glycogen concentrations. These findings do not support the hypothesis that exercise-induced hypoglycaemia in patients with type 1 diabetes is due to suppression of hepatic glycogen mobilisation. [ABSTRACT FROM AUTHOR]

Aim: Membrane fatty acid transporters can modulate the balance between fatty acid uptake and subsequent storage and/or oxidation in muscle tissue. As such, skeletal muscle fatty acid transporter protein expression could play an important role in the etiology of insulin resistance and/or type 2 diabetes. Methods: In the present study, fatty acid translocase (FAT/CD36), plasma membrane-bound fatty acid-binding protein (FABPpm) and fatty acid transport protein 1 (FATP1) mRNA and protein expression were assessed in muscle tissue obtained from 10 sedentary, overweight type 2 diabetes patients (60 ± 2 years), 10 sedentary, weight-matched normoglycemic controls (60 ± 2 years) and 10 age-matched, endurance trained cyclists (57 ± 1 years). Results: Both FAT/CD36 and FATP1 mRNA and protein expression did not differ between groups. In contrast, FABPpm mRNA and protein expression were approx. 30–40% higher in the trained men compared with the diabetes patients ( P < 0.01) and sedentary controls ( P < 0.05). Conclusions: Skeletal muscle FAT/CD36, FABPpm and FATP1 mRNA and protein expression are not up- or downregulated in a sedentary and/or insulin resistant state. In contrast, FABPpm expression is upregulated in the endurance trained state and likely instrumental to allow greater fatty acid oxidation rates. [ABSTRACT FROM AUTHOR]

Aims: Calpain-10 and calpain-3 and the diabetes ankyrin repeat protein (DARP) have all been linked to insulin resistance and type 2 diabetes. We set out to measure the expression of these genes in human skeletal muscle and relate them to functional measurements of insulin action during fasting (which induces insulin resistance) and refeeding (which reverses it). Methods: Ten healthy male volunteers underwent 48 h of starvation followed by 24 h of high carbohydrate refeeding. On three occasions, before and after starvation and after refeeding, subjects underwent a 16 min insulin tolerance test to quantify insulin sensitivity. Muscle biopsies were obtained before and after fasting and after refeeding for the analysis of calpain-10 and calpain-3, GLUT4 and DARP expression by Western blotting and real-time PCR. Results: Fasting led to a marked reduction in whole body insulin sensitivity by approx. 45% ( P < 0.01) and skeletal muscle GLUT4 gene expression by approx. 40% ( P < 0.05). However, fasting had no effect on calpain-10 and calpain-3 mRNA or protein levels, or DARP mRNA expression. Refeeding only partly restored insulin sensitivity and GLUT4 gene expression to their pre-fast values, but did not effect the expression of calpain-10, calpain-3 or DARP. Conclusions: These findings demonstrate that in healthy non-diabetic humans induction of insulin resistance by fasting and its reversal by refeeding with a high CHO diet is mirrored by changes in skeletal muscle GLUT4 but not calpain-10 and calpain-3 expression. [ABSTRACT FROM AUTHOR]

We examined whole-body and muscle metabolism in patients with type 1 diabetes during moderate exercise at differing circulating insulin concentrations. Eight men (mean ± SEM age 36.4 ± 1.5 years; diabetes duration 11.3 ± 1.4 years; BMI 24.6 ± 0.7 kg/m2; HbA1c 7.9 ± 0.2% and VO2 peak 44.5 ± 1.2 ml kg−1 min−1) with type 1 diabetes were studied on two occasions at rest (2 h) and during 45 min of cycling at 60% maximum VO2 with insulin infused at the rate of either 15 (LO study) or 50 (HI) mU m−2 min−1 and blood glucose clamped at 8 mmol/l. Indirect calorimetry, insulin-glucose clamps and thigh muscle biopsies were employed to measure whole-body energy and muscle metabolism. Fat oxidation contributed 15 and 23% to total energy expenditure during exercise in the HI and LO studies, respectively. The respective carbohydrate (CHO) oxidation rates were 31.7 ± 2.7 and 27.8 ± 1.9 mg kg−1 min−1 ( p < 0.05). Exogenous glucose utilisation rate during exercise was substantially greater ( p < 0.001) in the HI study (18.4 ± 2.1 mg kg−1 min−1) than in the LO study (6.9 ± 1.2 mg kg−1 min−1). Muscle glycogen content fell by ∼40% during exercise in both trials. Muscle glycogen utilisation, muscle intermediary metabolism, and phosphorylation of protein kinase B/Akt, glycogen synthase kinase 3α/β and extracellular signal-regulated protein kinase 1 and 2 proteins were no different between interventions. In patients with type 1 diabetes, exercise under peak therapeutic insulin concentrations increases exogenous glucose utilisation but does not spare muscle glycogen utilisation. A disproportionate increase in exogenous glucose utilisation relative to the increase in CHO oxidation suggests an increase in glucose flux through non-oxidative pathways. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare whole-body glucose uptake in cycling and running performed during physiological hyperinsulinaemia. On three occasions, seven male subjects underwent a hyperinsulinaemic (30 mU m(-2) min(-1)), euglycaemic (5 mmol l(-1)) clamp for 120 min. On one occasion, subjects rested for the duration of the trial (CON). On the other two occasions, after an initial resting period of 30 min, subjects either cycled (CYC) or ran (RUN) for 90 min at 65% of maximal O(2) uptake (VO(2max)). Insulin infusion resulted in physiological hyperinsulinaemia that was maintained for the duration of each trial [CON: 61 (3) mU l(-1); CYC: 77 (7) mU l(-1); RUN: 77 (5) mU l(-1)]. The rate of glucose uptake was greater during RUN than during CYC [last 30 min of exercise: 140 (4) vs 109 (8) micromol kg(-1) min(-1), respectively; P <0.01]. A differential amount of active muscle mass and/or muscle fibre type recruitment might account for the observed differences in glucose disposal between cycling and running. [ABSTRACT FROM AUTHOR]

Carbohydrate (CHO) ingestion during exercise, in the form of CHO-electrolyte beverages, leads to performance benefits during prolonged submaximal and variable intensity exercise. However, the mechanism underlying this ergogenic effect is less clear. Euglycaemia and oxidation of blood glucose at high rates late in exercise and a decreased rate of muscle glycogen utilisation (i.e. glycogen ‘sparing’) have been proposed as possible mechanisms underlying the ergogenic effect of CHO ingestion. The prevalence of one or the other mechanism depends on factors such as the type and intensity of exercise, amount, type and timing of CHO ingestion, and pre-exercise nutritional and training status of study participants. The type and intensity of exercise and the effect of these on blood glucose, plasma insulin and catecholamine levels, may play a major role in determining the rate of muscle glycogen utilisation when CHO is ingested during exercise. The ingestion of CHO (except fructose) at a rate of >45 g/h, accompanied by a significant increase in plasma insulin levels, could lead to decreased muscle glycogen utilisation (particularly in type I fibres) during exercise. Endurance training and alterations in pre-exercise muscle glycogen levels do not seem to affect exogenous glucose oxidation during submaximal exercise. Thus, at least during low intensity or intermittent exercise, CHO ingestion could result in reduced muscle glycogen utilisation in well trained individuals with high resting muscle glycogen levels. Further research needs to concentrate on factors that regulate glucose uptake and energy metabolism in different types of muscle fibres during exercise with and without CHO ingestion. [ABSTRACT FROM AUTHOR]