Effects of replacing diet beverages with water on weight loss and weight maintenance: 18-month follow-up, randomized clinical trial.

BACKGROUND: Beneficial effects of replacing diet beverages (DBs) with water on weight loss, during a 24-week hypoenergetic diet were previously observed. However, it is not known whether this difference is sustained during a subsequent 12-month weight maintenance period. OBJECTIVE: To evaluate effects of replacing DBs with water on body weight maintenance over a 12-month period in participants who undertook a 6-month weight loss plan. DESIGN: Seventy-one obese and overweight adult women (body mass index (BMI): 27-40 kg m-2; age: 18-50 years) who usually consumed DBs in their diet were randomly assigned to either substitute water for DBs (water group: 35) or continue drinking DBs five times per week (DBs group: 36) after their lunch for the 6-month weight loss intervention and subsequent 12-month weight maintenance program. RESULTS: A total of 71 participants who were randomly assigned were included in the study by using an intention-to-treat analysis. Greater additional weight loss (mean±s.d.) in the water group was observed compared with the DBs group after the 12-month follow-up period (-1.7±2.8 vs -0.1±2.7 kg, P=0.001). BMI decreased more in the water group than in the DBs group (-0.7±1 vs -0.05±1.1 kg m-2, P=0.003). There was also a greater reduction in fasting insulin levels (-0.5±1.4 vs -0.02±1.5 mmol l-1, P=0.023), better improvement in homeostasis model assessment of insulin resistance (-0.2±0.4 vs -0.1±0.3, P=0.013) and a greater decrease in 2-h postprandial plasma glucose (-0.2±0.3 vs -0.1±0.3 mmol l-1, P<0.001) in the water group compared with the DBs over the 12-month weight maintenance period. CONCLUSIONS: Replacement of DBs with water after the main meal in women who were regular users of DBs may cause further weight reduction during a 12-month weight maintenance program. It may also offer benefits in carbohydrate metabolism including improvement of insulin resistance over the long-term weight maintenance period.

Salbutamol-induced electrophysiological changes show no correlation with electrophysiological changes during hyperinsulinaemic-hypoglycaemic clamp in young people with Type 1 diabetes.

AIMS: Hypoglycaemia causes QT-interval prolongation and appears pro-arrhythmogenic. Salbutamol, a ß2 -adrenoreceptor agonist also causes QT-interval prolongation. We hypothesized that the magnitude of electrophysiological changes induced by salbutamol and hypoglycaemia might relate to each other and that salbutamol could be used as a non-invasive screening tool for predicting an individual's electrophysiological response to hypoglycaemia. METHODS: Eighteen individuals with Type 1 diabetes were administered 2.5 mg of nebulized salbutamol. Participants then underwent a hyperinsulinaemic-hypoglycaemic clamp (2.5 mmol/l for 1 h). During both experiments, heart rate and serum potassium (and catecholamines during the clamp) were measured and a high-resolution electrocardiogram (ECG) was recorded at pre-set time points. Cardiac repolarization was measured by QT-interval duration adjusted for heart rate (QTc ), T-wave amplitude (Tamp ), T-peak to T-end interval duration (Tp Tend ) and T-wave area symmetry (Tsym ). The maximum changes vs. baseline in both experiments were assessed for their linear dependence. RESULTS: Salbutamol administration caused QTc and Tp Tend prolongation and a decrease in Tamp and Tsym . Hypoglycaemia caused increased plasma catecholamines, hypokalaemia, QTc and Tp Tend prolongation, and a decrease in Tamp and Tsym . No significant correlations were found between maximum changes in QTc [r = 0.15, 95% confidence interval (95% CI) -0.341 to 0.576; P = 0.553), Tp Tend (r = 0.075, 95% CI -0.406 to 0.524; P = 0.767), Tsym (r = 0.355, 95% CI -0.132 to 0.706; P = 0.149) or Tamp (r = 0.148, 95% CI -0.347 to 0.572; P = 0.558) in either experiment. CONCLUSIONS: Both hypoglycaemia and salbutamol caused pro-arrhythmogenic electrophysiological changes in people with Type 1 diabetes but were not related in any given individual. Salbutamol does not appear useful in assessing an individual's electrophysiological response to hypoglycaemia.

A review of recent evidence relating to sugars, insulin resistance and diabetes.

The potential impact on health of diets rich in free sugars, and particularly fructose, is of major concern. The focus of this review is the impact of these sugars on insulin resistance and obesity, and the associated risk of developing type 2 diabetes. Much of the concern is focussed on specific metabolic effects of fructose, which are argued to lead to increased fat deposition in the liver and skeletal muscle with subsequent insulin resistance and increased risk of diabetes. However, much of the evidence underpinning these arguments is based on animal studies involving very large intakes of the free sugars. Recent human studies, in the past 5 years, provide a rather different picture, with a clear dose response link between fructose intake and metabolic changes. In particular, the most marked effects are observed when a high sugars intake is accompanied by an excess energy intake. This does not mean that a high intake of free sugars does not have any detrimental impact on health, but rather that such an effect seems more likely to be a result of the high sugars intake increasing the chances of an excessive energy intake rather than it leading to a direct detrimental effect on metabolism.

Obesity-related insulin resistance: implications for the surgical patient.

In healthy surgical patients, preoperative fasting and major surgery induce development of insulin resistance (IR). IR can be present in up to 41% of obese patients without diabetes and this can rise in the postoperative period, leading to an increased risk of postoperative complications. Inflammation is implicated in the aetiology of IR. This review examines obesity-associated IR and its implications for the surgical patient. Searches of the Medline and Science Citation Index databases were performed using various key words in combinations with the Boolean operators AND, OR and NOT. Key journals, nutrition and metabolism textbooks and the reference lists of key articles were also hand searched. Adipose tissue has been identified as an active endocrine organ and the chemokines secreted as a result of macrophage infiltration have a role in the pathogenesis of IR. Visceral adipose tissue appears to be the most metabolically active, although results across studies are not consistent. Results from animal and human studies often provide conflicting results, which has rendered the pursuit of a common mechanistic pathway challenging. Obesity-associated IR appears, in part, to be related to inflammatory changes associated with increased adiposity. Postoperatively, the surgical patient is in a proinflammatory state, so this finding has important implications for the obese surgical patient.

A mathematical model of the human metabolic system and metabolic flexibility.

In healthy subjects some tissues in the human body display metabolic flexibility, by this we mean the ability for the tissue to switch its fuel source between predominantly carbohydrates in the postprandial state and predominantly fats in the fasted state. Many of the pathways involved with human metabolism are controlled by insulin and insulin-resistant states such as obesity and type-2 diabetes are characterised by a loss or impairment of metabolic flexibility. In this paper we derive a system of 12 first-order coupled differential equations that describe the transport between and storage in different tissues of the human body. We find steady state solutions to these equations and use these results to nondimensionalise the model. We then solve the model numerically to simulate a healthy balanced meal and a high fat meal and we discuss and compare these results. Our numerical results show good agreement with experimental data where we have data available to us and the results show behaviour that agrees with intuition where we currently have no data with which to compare.

Variability in fasting lipid and glycogen contents in hepatic and skeletal muscle tissue in subjects with and without type 2 diabetes: a 1H and 13C MRS study.

The measurement of tissue lipid and glycogen contents and the establishment of normal levels of variability are important when assessing changes caused by pathology or treatment. We measured hepatic and skeletal muscle lipid and glycogen levels using (1)H and (13)C MRS at 3 T in groups of subjects with and without type 2 diabetes. Within-visit reproducibility, due to repositioning and instrument errors was determined from repeat measurements made over 1 h. Natural variability was assessed from separate measurements made on three occasions over 1 month. Hepatic lipid content was greater in subjects with diabetes relative to healthy subjects (p = 0.03), whereas levels of hepatic and skeletal muscle glycogen, and of intra- and extra-myocellular lipid, were similar. The single-session reproducibility values (coefficient of variation, CV) for hepatic lipid content were 12% and 7% in groups of subjects with and without diabetes, respectively. The variability of hepatic lipid content over 1 month was greater than the reproducibility, with CV = 22% (p = 0.08) and CV = 44% (p = 0.004) in subjects with and without diabetes, respectively. Similarly, levels of variation in basal hepatic glycogen concentrations (subjects with diabetes, CV = 38%; healthy volunteers, CV = 35%) were significantly larger than single-session reproducibility values (CV = 17%, p = 0.02 and CV = 13%, p = 0.05, respectively), indicating substantial biological changes in basal concentrations over 1 month. There was a decreasing correlation in measurements of both hepatic lipid and glycogen content with increasing time between scans. Levels of variability in intra- and extra-myocellular lipid in the soleus muscle, and glycogen concentrations in the gastrocnemius muscle, tended to be larger than expected from single-session reproducibility, although these did not reach significance.

Elevation of alanine transaminase and markers of liver fibrosis after a mixed meal challenge in individuals with type 2 diabetes.

BACKGROUND: Hyperalimentation for 4 weeks is associated with raised liver enzymes and liver fat content (LFC), which are two common features found in individuals with diabetes. AIM: We evaluated the effect of two mixed meal challenges on LFC, liver enzymes and serum bio-markers of liver injury and fibrosis in 16 healthy volunteers (HV) and subjects with type 2 diabetes (T2DM). METHODS: Subjects (HV: 9 male, 7 female, aged 57.9 ± 1.7 years, body mass index (BMI) 27.1 kg/m(2); and T2DM: 11 male, 5 female, aged 62.1 ± 1.3 years, BMI 28.0 ± 0.4 kg/m(2)) consumed two meals at 1 h (884 kcal) and at 6 h (1,096 kcal). LFC determined by (1)H magnetic resonance spectroscopy, serum levels of liver enzymes, hyaluronic acid (HA), procollagen III N-terminal peptide (P3NP) and tissue inhibitor metalloproteinase-1 (TIMP-1) were estimated at time 0 (fasting) and 9 h (postprandial). RESULTS: Fasting LFC was higher in the T2DM group 7.6 % (4.9, 15.4) [median (inter-quartile range)] than in the HV group 2.3 % (0.8, 5.1) (p < 0.05) while levels of HA, P3NP and TIMP-1 were similar. Following the meal challenge there was no significant change in LFC. Subjects with T2DM had higher post-prandial rise in alanine transaminase (ALT) (p = 0.014), serum HA (p = 0.007) and P3NP (p = 0.015) compared with HV. Fasting LFC correlated with a greater post-prandial increase in P3NP levels in all subjects (Pearson correlation r = 0.53, p = 0.001). CONCLUSIONS: In subjects with T2DM, a mixed meal challenge is associated with a significant elevation in the serum levels of ALT, HA and P3NP without significant changes in LFC. These markers should be performed in the fasted state.

Age-related changes in muscle architecture and metabolism in humans: The likely contribution of physical inactivity to age-related functional decline.

In the United Kingdom (UK), it is projected that by 2035 people aged >65 years will make up 23 % of the population, with those aged >85 years accounting for 5% of the total population. Ageing is associated with progressive changes in muscle metabolism and a decline in functional capacity, leading to a loss of independence. Muscle metabolic changes associated with ageing have been linked to alterations in muscle architecture and declines in muscle mass and insulin sensitivity. However, the biological features often attributed to muscle ageing are also seen in controlled studies of physical inactivity (e.g. reduced step-count and bed-rest), and it is currently unclear how many of these ageing features are due to ageing per se or sedentarism. This is particularly relevant at a time of home confinements reducing physical activity levels during the Covid-19 pandemic. Current knowledge gaps include the relative contribution that physical inactivity plays in the development of many of the negative features associated with muscle decline in older age. Similarly, data demonstrating positive effects of government recommended physical activity guidelines on muscle health are largely non-existent. It is imperative therefore that research examining interactions between ageing, physical activity and muscle mass and metabolic health is prioritised so that it can inform on the "normal" muscle ageing process and on strategies for improving health span and well-being. This review will focus on important changes in muscle architecture and metabolism that accompany ageing and highlight the likely contribution of physical inactivity to these changes.

Effects of exenatide on circulating glucose, insulin, glucagon, cortisol and catecholamines in healthy volunteers during exercise.

AIMS/HYPOTHESIS: 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. METHODS: We studied eight non-diabetic men, who were 35.3 +/- 6.3 years of age with BMI of 24.7 +/- 1.7 kg/m(2) (mean +/- SD), using a randomised, crossover, double-blind design investigation. After an overnight fast, participants received 5 microg of subcutaneous exenatide or placebo and rested for 105 min before cycling at 60% of their maximal oxygen uptake (VO(2max)) for 75 min and then recovering for a further 60 min. RESULTS: 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. CONCLUSIONS/INTERPRETATION: In non-diabetic participants given exenatide, blood glucose concentrations rise rather than fall during aerobic exercise with an associated greater catecholamine response.

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin- and sulphonylurea-treated Type 2 diabetes.

AIMS: Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non-diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non-diabetic controls (CON). METHODS: Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU-treated and 10 treated with twice-daily premixed insulin, and 10 age- and weight-matched non-diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA(1c)) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. RESULTS: Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU-treated than INS-treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. CONCLUSIONS: Sulphonylurea-treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin-treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.

Effect of magnesium sulphate on urinary catecholamine excretion in severe tetanus.

Severe tetanus is characterised by muscle spasms and autonomic dysfunction. We recently reported the results of a randomised placebo controlled trial of magnesium sulphate infusions for the treatment of severe tetanus which showed magnesium was associated with improved muscle spasm and cardiovascular control. We hypothesised that magnesium controlled autonomic dysfunction by reducing catecholamine release and thus urinary excretion. Urinary adrenaline and noradrenaline concentrations were measured during the first 24 h of therapy in 180 adults with severe tetanus randomised to treatment with magnesium (n = 92) or placebo (n = 88). Magnesium therapy was associated with lower urinary adrenaline excretion and higher urinary noradrenaline excretion. High urinary adrenaline concentrations were associated with documented autonomic dysfunction. Patients given magnesium had significantly less autonomic dysfunction, required less cardiovascular stabilising drugs, and had lower urinary concentrations of adrenaline. These findings suggest adrenaline is important in the pathophysiology of severe tetanus and magnesium controls autonomic dysfunction by reducing adrenaline release.

Dietary carbohydrates: a review of international recommendations and the methods used to derive them.

BACKGROUND/OBJECTIVES: Renewed dietary recommendations for carbohydrates have recently been published by various international health authorities. The present work (1) reviews the methods and processes (systematic approach/review, inclusion of public consultation) used to identify, select and grade the evidence underpinning the recommendations, particularly for total carbohydrate (CHO), fibre and sugar consumption, and (2) examines the extent to which variation in the methods and processes applied relates to any differences in the final recommendations. SUBJECTS/METHODS: A search of WHO, US, Canada, Australia and European sources identified 19 documents from 13 authorities with the desired detailed information. Processes and methods applied to derive recommendations were compiled and compared. RESULTS: (1) A relatively high total CHO and fibre intake and limited intake of (added or free) sugars are generally recommended. (2) Even where recommendations are similar, the specific justifications for quantitative/qualitative recommendations differ across authorities. (3) Differences in recommendations mainly arise from differences in the underlying definitions of CHO exposure and classifications, the degree to which specific CHO-providing foods and food components were considered, and the choice and number of health outcomes selected. (4) Differences in the selection of source material, time frames or data aggregation and grading methods appeared to have minor influence. CONCLUSIONS: Despite general consistency, apparent differences among the recommendations of different authorities would likely be minimized by: (1) More explicit quantitative justifications for numerical recommendations and communication of uncertainty, and (2) greater international harmonization, particularly in the underlying definitions of exposures and range of relevant nutrition-related outcomes.

High-fat/low-carbohydrate diet reduces insulin-stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: An important role for skeletal muscle pyruvate dehydrogenase kinase 4.

AIM: The aim of this report was to study the effect of high-fat (HF)/low-carbohydrate (CHO) diet on regulation of substrate metabolism in humans. METHODS: Ten healthy men consumed either a HF (75% energy as fat) or control (35%) diet for 6 d in random order. On d 7, blood glucose disappearance rate (Rd) was determined before and during a hyperinsulinemic euglycemic clamp. Substrate oxidation was determined by indirect calorimetry. Muscle biopsies were obtained prediet, postdiet, and postclamps. RESULTS: Rd was similar under basal conditions but slightly elevated (approximately 10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by approximately 40%, P < 0.05) and clamp conditions (by approximately 20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by approximately 25%, P < 0.05). Muscle pyruvate dehydrogenase complex activity was blunted under basal and clamp conditions after HF compared with control (P < 0.05) and was accompanied by an approximately 2-fold increase (P < 0.05) in pyruvate dehydrogenase kinase 4 (PDK4) mRNA and protein expression. CONCLUSION: Short-term HF/low-CHO dietary intake did not induce whole-body insulin resistance, but caused a shift in im glucose metabolism from oxidation to glycogen storage. Insulin-stimulated CHO oxidation and muscle pyruvate dehydrogenase complex activity were blunted after the HF diet. Up-regulation of muscle PDK4 expression was an early molecular adaptation to these changes, and we showed for the first time in healthy humans, unlike insulin-resistant individuals, that insulin can suppress PDK4 but not PDK2 gene expression in skeletal muscle.

Increased acetyl group availability enhances contractile function of canine skeletal muscle during ischemia.

Skeletal muscle contractile function is impaired during acute ischemia such as that experienced by peripheral vascular disease patients. We therefore, examined the effects of dichloroacetate, which can alter resting metabolism, on canine gracilis muscle contractile function during constant flow ischemia. Pretreatment with dichloroacetate increased resting pyruvate dehydrogenase complex activity and resting acetylcarnitine concentration by approximately 4- and approximately 10-fold, respectively. After 20-min contraction the control group had demonstrated an approximately 40% reduction in isomeric tension whereas the dichloroacetate group had fatigued by approximately 25% (P < 0.05). Dichloroacetate resulted in less lactate accumulation (10.3 +/- 3.0 vs 58.9 +/- 10.5 mmol.kg-1 dry muscle [dm], P < 0.05) and phosphocreatine hydrolysis (15.6 +/- 6.3 vs 33.8 +/- 9.0 mmol.kg-1 dm, P < 0.05) during contraction. Acetylcarnitine concentration fell during contraction by 5.4 +/- 1.8 mmol.kg-1 dm in the dichloroacetate group but increased by 10.0 +/- 1.9 mmol.kg-1 dm in the control group. In conclusion, dichloroacetate enhanced contractile function during ischemia, independently of blood flow, such that it appears oxidative ATP regeneration is limited by pyruvate dehydrogenase complex activity and acetyl group availability.

Substrate availability limits human skeletal muscle oxidative ATP regeneration at the onset of ischemic exercise.

We have demonstrated previously that dichloroacetate can attenuate skeletal muscle fatigue by up to 35% in a canine model of peripheral ischemia (Timmons, J.A., S.M. Poucher, D. Constantin-Teodosiu, V. Worrall, I.A. Macdonald, and P.L. Greenhaff. 1996. J. Clin. Invest. 97:879-883). This was thought to be a consequence of dichloroacetate increasing acetyl group availability early during contraction. In this study we characterized the metabolic effects of dichloroacetate in a human model of peripheral muscle ischemia. On two separate occasions (control-saline or dichloroacetate infusion), nine subjects performed 8 min of single-leg knee extension exercise at an intensity aimed at achieving volitional exhaustion in approximately 8 min. During exercise each subject's lower limbs were exposed to 50 mmHg of positive pressure, which reduces blood flow by approximately 20%. Dichloroacetate increased resting muscle pyruvate dehydrogenase complex activation status by threefold and elevated acetylcarnitine concentration by fivefold. After 3 min of exercise, phosphocreatine degradation and lactate accumulation were both reduced by approximately 50% after dichloroacetate pretreatment, when compared with control conditions. However, after 8 min of exercise no differences existed between treatments. Therefore, it would appear that dichloroacetate can delay the accumulation of metabolites which lead to the development of skeletal muscle fatigue during ischemia but does not alter the metabolic profile when a maximal effort is approached.