Pharmacological activation of PDC flux reverses lipid-induced inhibition of insulin action in muscle during recovery from exercise.

Insulin resistance is a risk factor for type 2 diabetes and exercise can improve insulin sensitivity. However, following exercise high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a cross-over design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemiceuglycemic clamp five hours after one-legged exercise with: 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, and 3) infusion of intralipid + oral PDC-activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (∼40%) and Ser300 (∼80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimulate insulin-stimulated glucose uptake during recovery.

Associations Between Physical Activity and Gastrointestinal Transit Times in People with Normal Weight, Overweight, and Obesity.

BACKGROUND: Rapid gastric emptying is associated with obesity and overeating, whereas delayed gastric emptying is associated with anorexia. Acute effects of exercise on gastric emptying have been investigated extensively, but the influence of habitual physical activity on gastric emptying and transit time in other regions of the gastrointestinal tract is poorly understood. OBJECTIVE: The objective was to investigate associations between objectively measured habitual physical activity and gastrointestinal transit times in adults with varying degrees of adiposity. METHODS: 50 adults (58% women) were included in this cross-sectional study. Physical activity was measured by an accelerometer placed on the lower back for 7 d. Gastric emptying time, small bowel transit time, colonic transit time, and whole gut transit time were simultaneously evaluated by a wireless motility capsule, which was ingested together with a standardized mixed meal. Linear regression models were applied to assess the associations of total activity counts and time spent at different intensities-sedentary activity (0-100 counts/min), low light activity (101-759 counts/min), high light activity (760-1951 counts/min); moderate and vigorous activity (≥1952 counts/min)) with gastrointestinal transit times. RESULTS: Median [Q1; Q3] age was 56.5 [46.6-65.5] y, and body mass index (BMI) was 32.1 [28.5-35.1] kg/m2. For every additional hour spent performing high light intensity physical activity, colonic transit time was 25.5 % [95% CI: 3.10, 42.7] more rapid (P = 0.028), and whole gut transit time was 16.2 % [95% CI: 1.84, 28.4] more rapid (P = 0.028) when adjusted for sex, age, and body fat. No other associations were observed. CONCLUSIONS: More time spent on physical activity at high light intensity was associated with more rapid colonic and whole gut transit time, independent of age, sex, and body fat, whereas other intensities of physical activity and gastrointestinal transit times were not associated. TRIAL REGISTRATION: Clinicaltrials.gov IDs (NCT03894670, NCT03854656).

Gastric Aspiration Improves Postprandial Glucose Tolerance Without Causing a Compensatory Increase in Appetite and Food Intake.

INTRODUCTION: AspireAssist® allows aspiration of ~30% of an ingested meal through a percutaneous gastrostomy tube, reducing caloric uptake. We evaluated the acute effects of gastric aspiration on postprandial glucose tolerance, responses of gluco-regulatory and appetite-regulating hormones, appetite sensations, and food intake. METHODS: Seven AspireAssist®-treated individuals underwent two separate experimental days each involving a mixed meal test (MMT) with double-blinded aspiration and sham aspiration, respectively. Seven age and body mass index (BMI)-matched controls underwent one MMT. MMTs were followed by an ad libitum meal. RESULTS: Postprandial glucose tolerance was improved during aspiration vs. sham visits (median [interquartile range] baseline-subtracted area under the curve (bsAUC) 170 [88.4;356] vs. 388 [239;456] mmol/L × min, p = 0.025). Reduced responses (bsAUCs) of C-peptide (113 [28.4;224] vs. 302 [215;433] nmol/L × min, p = 0.014), cholecystokinin (223 [59.4;402] vs. 467 [416;546] pmol/L × min, p = 0.005), glucose-dependent insulinotropic polypeptide (4.63 [1.49;9.04] vs. 15.4 [9.59;18.9] nmol/L × min, p = 0.025), and glucagon-like peptide 1 (532.8 [274.5;1,278] vs. 1,296 [746.2;1,618] pmol/L × min, p = 0.032) were observed during aspiration vs. sham visits. Responses of glucagon, gastrin, ghrelin and peptide YY, appetite sensations, and ad libitum food intake were unaffected by aspiration. Responses of plasma glucose, gut hormones, appetite sensations, and food intake were similar during sham and control visits. CONCLUSION: Gastric aspiration improved postprandial glucose tolerance without causing compensatory increases in appetite or food intake, pointing to acute beneficial metabolic effects of aspiration therapy together with previously reported body weight-lowering effects.

The day-night pattern of colonic contractility is not impaired in type 1 diabetes and distal symmetric polyneuropathy.

Colonic contractility normally shows circadian variability regulated by sleep and especially food intake. However, individuals with type 1 diabetes have a reduced or even absent gastrocolic response to a meal, indicating that colonic contractility may be affected by the disease. We hypothesized that individuals with type 1 diabetes and distal symmetric polyneuropathy (DSPN) have decreased motility (expressed as the motility index) and contractility of the colon and a reduced increase in motility index from night to morning compared to healthy controls and individuals with type 1 diabetes without DSPN. Cohorts of 35 individuals with type 1 diabetes and DSPN, 40 individuals with type 1 diabetes without DSPN, and 28 healthy controls were included in this post-hoc, cross-sectional analysis. We investigated, using a wireless motility capsule that measures pH, temperature, and pressure throughout the gastrointestinal tract, whether individuals with type 1 diabetes with and without DSPN, compared to healthy controls, exhibit altered colonic contractility in the evening, night, and morning. Max amplitude, mean peak amplitude, mean contraction, and motility index of the colon were calculated at the afore-designated times. Motility index of the colon tended to be higher in individuals with type 1 diabetes and DSPN compared to controls in the evening (P = .064), but the effect size was small (1.74%). There was no difference in motility index between the groups in the morning or evening. Furthermore, there was no difference in max amplitude, mean peak amplitude, or mean contraction between groups in the morning, evening, and night. As expected, overall contractility increased from night to morning in all groups, but there was no difference between groups in the increase in contractility from night to morning. Colonic contractility generally peaked in the morning, decreased in the evening, and was almost absent at night. Type 1 diabetes and/or DSPN did not impair contractility of the colon at any time point. Contractility and motility increased from morning to night unaffected by type 1 diabetes and/or DSPN.

Protocol for a single-centre, parallel-group, randomised, controlled, superiority trial on the effects of time-restricted eating on body weight, behaviour and metabolism in individuals at high risk of type 2 diabetes: the REStricted Eating Time (RESET) study.

INTRODUCTION: The aim of this study is to investigate the effects of time-restricted eating (TRE) on change in body weight and describe changes in behaviour and metabolism in individuals at high risk of type 2 diabetes. METHODS AND ANALYSIS: The REStricted Eating Time (RESET) study is a randomised controlled parallel-group open-label trial. 100 women and men with (1) overweight (body mass index (BMI)≥25 kg/m2) and prediabetes (glycated haemoglobin 39-47 mmol/mol); or (2) obesity (BMI≥30 kg/m2) will be randomised to a control group (habitual living) or TRE (self-selected 10-hours eating window within the period from 06:00 to 20:00 in a 1:1 ratio. Testing is scheduled at baseline and after 6 weeks (mid-intervention), 3 months (post-intervention) and 6 months (follow-up). The primary outcome is change in body weight after 3 months of intervention. Secondary outcomes include changes in body composition; measures of glucose metabolism including glycaemic variability, hormones and metabolites; subjective and metabolic markers of appetite, food preferences and reward; dietary intake; physical activity, sleep, chronotype; gastric emptying, gastrointestinal transit time and motility; respiratory and glycolytic capacities; the plasma proteome and metabolome; blood pressure, resting heart rate and heart rate variability; and resting energy expenditure and substrate oxidation. Motivation and feasibility will be examined based on interviews at baseline and after 3 months. After the 3-month intervention, a 3-month follow-up period and subsequent testing are scheduled to assess maintenance and longer-term effects. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the Capital Region of Denmark (H-18059188) and the Danish Data Protection Agency. The study will be conducted in accordance with the Declaration of Helsinki. Results from the study will address whether TRE is effective and feasible in improving health outcomes in individuals at risk of lifestyle-related diseases and can potentially inform the design of feasible health recommendations. TRIAL REGISTRATION NUMBER: NCT03854656.

Linking Place and Mind: Localness As a Factor in Socio-Cognitive Salience.

This paper investigates the salience of vernacular Tyneside forms on the basis of theories of enregisterment and exemplar processing. On one level, exemplar theory provides a psycholinguistic account of how the link between social value and linguistic features is possible. Conversely, integrating the notion of social value into exemplar theory extends the value of this originally cognitive theory to social domains. It is suggested that the association of social value and particular local, linguistic forms may contribute to the salience of these forms among local speakers. The empirical work reported here takes the form of a questionnaire study, which aims to uncover Tyneside inhabitants' awareness of forms as well as their affiliation with the local community. Results showed differences in frequency perceptions between participants themselves and others which indicate that speakers can identify local forms as such, but that the variety is stigmatized. The strength of local affiliation correlated with participants' own language use and it is suggested that this can be accounted for by employing a social personae explanation, where speakers use certain salient forms to index local belonging despite overt stigma.

Cost-effectiveness of rosuvastatin in comparison with generic atorvastatin and simvastatin in a Swedish population at high risk of cardiovascular events.

BACKGROUND: To assess the long-term cost-effectiveness of rosuvastatin therapy compared with generic simvastatin and generic atorvastatin in reducing the incidence of cardiovascular events and mortality in a Swedish population with Framingham risk ≥20%. METHODS: A PROBABILISTIC MONTE CARLO SIMULATION MODEL BASED ON DATA FROM JUPITER (THE JUSTIFICATION FOR THE USE OF STATINS IN PREVENTION: an Intervention Trial Evaluating Rosuvastatin) was used to estimate the long-term cost-effectiveness of rosuvastatin 20 mg daily versus simvastatin or atorvastatin 40 mg for the prevention of cardiovascular death and morbidity. The three- stage model included cardiovascular event prevention simulating the 4 years of JUPITER, initial prevention beyond the trial, and subsequent cardiovascular event prevention. A Swedish health care payer perspective (direct costs only) was modeled for a lifetime horizon, with 2008/2009 as the costing period. Univariate and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost per quality-adjusted life-year (QALY) gained with rosuvastatin 20 mg over simvastatin or atorvastatin 40 mg ranged from SEK88,113 (rosuvastatin 20 mg versus simvastatin 40 mg; Framingham risk ≥30%; net avoidance of 34 events/1000 patients) to SEK497,542 (versus atorvastatin 40 mg: Framingham risk ≥20%; net avoidance of 11 events/1000 patients) over a lifetime horizon. Probabilistic sensitivity analyses indicated that at a willingness-to-pay threshold of SEK500,000/QALY, rosuvastatin 20 mg would be cost-effective for approximately 75%-85% of simulations relative to atorvastatin or simvastatin 40 mg. Sensitivity analyses indicated the findings to be robust. CONCLUSION: Rosuvastatin 20 mg is cost-effective over a lifetime horizon compared with generic simvastatin or atorvastatin 40 mg in patients at high cardiovascular risk in Sweden.

Cost-effectiveness of rosuvastatin 20 mg for the prevention of cardiovascular morbidity and mortality: a Swedish economic evaluation of the JUPITER trial.

OBJECTIVE: This study estimated the long-term health outcomes, healthcare costs, and cost-effectiveness of rosuvastatin 20 mg therapy in primary prevention of major cardiovascular disease (CVD) in a Swedish population. METHODS: Based on data from the JUPITER trial, long-term CVD outcomes with rosuvastatin vs no active treatment were estimated for patients with an elevated baseline CVD risk (Framingham CVD score >20%, sub-population of JUPITER population) and for a population similar to the total JUPITER population. Using a decision-analytic model, trial CVD event rates were combined with epidemiological and cost data specific for Sweden. First and subsequent CVD events and death were estimated over a lifetime perspective. The observed relative risk reduction was extrapolated beyond the trial duration. Incremental effectiveness was measured as life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. RESULTS: Treating 100,000 patients with rosuvastatin 20 mg was estimated to avoid 14,692 CVD events over the lifetime (8021 non-fatal MIs, 3228 non-fatal strokes, and 4924 CVD deaths) compared to placebo. This translated into an estimated gain of 42,122 QALYs and 36,865 total life years (LYG). Rosuvastatin was both more effective and less costly over a lifetime perspective, and rosuvastatin is subsequently a dominant alternative compared to no treatment in the assessed population. Using the overall JUPITER population, rosuvastatin was dominant for the lifetime horizon. In the sensitivity analysis, rosuvastatin was the dominant treatment strategy over a 20-year time horizon, and cost-effective with an incremental cost-effectiveness ratio (cost per QALY) of SEK 1783 over a 10-year time horizon. LIMITATIONS: Some model inputs were derived from literature or other data sources, but uncertainty was controlled by sensitivity analyses. CONCLUSIONS: Results indicate that rosuvastatin 20 mg treatment is a cost-effective option vs no-treatment in patients with Framingham CVD risk >20% in Sweden and might even be cost saving if taking a long-term perspective.

Cost effectiveness of rosuvastatin in patients at risk of cardiovascular disease based on findings from the JUPITER trial.

OBJECTIVE: This study assessed the long-term cost effectiveness of rosuvastatin therapy compared with placebo in reducing the incidence of major cardiovascular (CVD) events and mortality. METHODS: A probabilistic Monte Carlo simulation model estimated long-term cost effectiveness of rosuvastatin therapy (20 mg daily) for the prevention of CVD mortality and morbidity. The model included three stages: (1) CVD prevention simulating the 4 years of the JUPITER trial, (2) initial CVD prevention beyond the trial, and (3) subsequent CVD event prevention. A US payer perspective was assessed reflecting direct medical costs, and up to a lifetime horizon. Sensitivity analyses tested the robustness of the model estimates. RESULTS: For a hypothetical cohort of 100,000 patients at moderate and high risk of CVD events based on Framingham risk of ≥10%, estimated quality-adjusted life-years (QALYs) gained with rosuvastatin therapy compared with placebo was 33,480 over a lifetime horizon, and 25,380 and 9916 over 20-year and 10-year horizons, respectively. Approximately 12,073 events were avoided over the lifetime; 6,146 non-fatal MIs, 2905 non-fatal strokes, and 4030 CVD deaths avoided. Estimated incremental cost-effectiveness ratio (ICER) for cost per QALY was $7062 (lifetime), $10,743 (20-year horizon), and $44,466 (10-year horizon). For a hypothetical cohort similar to the overall JUPITER population, the cost per QALY ICER was $11,025 for the lifetime and $60,112 for a 10-year horizon. LIMITATIONS: The cost-effectiveness comparison of rosuvastatin 20 mg was against no active treatment (as opposed to an alternative statin) due to lack of comparative cardiovascular morbidity and mortality risk reduction data for other statins in a population similar to the JUPITER trial population. The analysis was conducted from the payer perspective and lack of inclusion of indirect costs limit interpretability of results from a societal perspective. CONCLUSIONS: Treatment with rosuvastatin 20 mg daily, is a cost-effective treatment alternative to no treatment in patients at a higher risk (Framingham risk≥10%) of CVD.