Glucose turnover at whole-body and skeletal muscle level in response to parenteral nutrition in male patients with alcoholic liver cirrhosis.

BACKGROUND & AIMS: Cirrhosis is associated with insulin resistance and impaired glucose tolerance, which may be caused by impairments at different tissue levels (liver, skeletal muscle, and/or beta cell). METHODS: Here, glucose kinetics at whole-body and skeletal muscle level in patients with cirrhosis (Child-Pugh A and B) were studied during parenteral nutrition using the isotope dilution technique and arteriovenous balance approach across the leg. As opposed to the euglycemic hyperinsulinemic clamp or glucose tolerance tests applied in previous studies, this approach provides a nutrient composition more similar to a normal meal while circumventing any possible portal-systemic shunting, impaired hepatic uptake and incretin effect. RESULTS: We confirmed the presence of hepatic and peripheral insulin resistance in our patient population. Endogenous glucose production was less suppressed in response to parenteral nutrition. However, glucose uptake in skeletal muscle was increased. CONCLUSION: Our results suggests that in our study participants with cirrhosis, the hepatic and peripheral insulin resistance is compensated for by increased insulin secretion and thus, increased glucose uptake in muscle. Hereby, glucose homeostasis is maintained.

Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.

OBJECTIVE: In the Semaglutide Treatment Effect in People with obesity (STEP) trials, once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention reduced body weight and improved cardiometabolic parameters in adults with obesity (or overweight with weight-related comorbidities). Effects on the risk of developing type 2 diabetes (T2D) require investigation. METHODS: STEP 1 (68 weeks) and 5 (104 weeks) randomized participants to semaglutide 2.4 mg or placebo. STEP 4 included a 20-week semaglutide run-in followed by randomization to 48 weeks of continued semaglutide or withdrawal (placebo). Ten-year T2D risk scores were calculated post hoc using Cardiometabolic Disease Staging. RESULTS: In STEP 1 (N = 1583), relative risk score reductions were greater with semaglutide versus placebo (semaglutide: -61.1%; placebo: -12.9%; p < 0.0001). These reductions were maintained to week 104 in STEP 5 (N = 295; semaglutide: -60.0%; placebo: 3.5%; p < 0.0001). Risk scores during the STEP 4 run-in period (N = 776) were reduced from 20.6% to 11.1% and further to 7.7% at week 68 with continued semaglutide, increasing to 15.4% with withdrawal (relative risk score change: semaglutide: -32.1%; placebo: +40.6%; p < 0.0001). Risk score reductions mirrored weight loss. CONCLUSIONS: Cardiometabolic Disease Staging risk assessment suggests that once-weekly semaglutide 2.4 mg may substantially lower 10-year T2D risk in people with overweight or obesity.

Skeletal muscle protein turnover responses to parenteral nutrition in patients with alcoholic liver cirrhosis and sarcopenia.

Alcoholic liver cirrhosis (ALC) is accompanied by sarcopenia. The aim of this study was to investigate the acute effects of balanced parenteral nutrition (PN) on skeletal muscle protein turnover in ALC. Eight male patients with ALC and seven age- and sex-matched healthy controls were studied for 3 h of fasting followed by 3 h of intravenous PN (SmofKabiven 1,206 mL: amino acid = 38 g, carbohydrates = 85 g, and fat = 34 g) 4 mL/kg/h. We measured leg blood flow and sampled paired femoral arteriovenous concentrations and quadriceps muscle biopsies while providing a primed continuous infusion of [ring-2d5]-phenylalanine to quantify muscle protein synthesis and breakdown. Patients with ALC exhibited shorter 6-min walking distance (ALC: 487 ± 38 vs. controls: 722 ± 14 m, P < 0.05), lower hand-grip strength (ALC: 34 ± 2 vs. controls: 52 ± 2 kg, P < 0.05), and computed tomography (CT)-verified leg muscle loss (ALC: 5,922 ± 246 vs. controls: 8,110 ± 345 mm2, P < 0.05). Net leg muscle phenylalanine uptake changed from negative (muscle loss) during fasting to positive (muscle gain) in response to PN (ALC: -0.18 ± +0.01 vs. 0.24 ± 0.03 µmol/kg muscle·min-1; P < 0.001 and controls: -0.15 ± 0.01 vs. 0.09 ± 0.01 µmol/kg muscle·min-1; P < 0.001) but with higher net muscle phenylalanine uptake in ALC than controls (P < 0.001). Insulin concentrations were substantially higher in patients with ALC during PN. Our results suggest a higher net muscle phenylalanine uptake during a single infusion of PN in stable patients with ALC with sarcopenia compared with healthy controls.NEW & NOTEWORTHY Muscle protein turnover responses to parenteral nutritional (PN) supplementation have not previously been studied in stable alcoholic liver cirrhosis (ALC). We applied stable isotope tracers of amino acids to directly quantify net muscle protein turnover responses to PN in sarcopenic males with ALC and healthy controls. We found a higher net muscle protein gain in ALC during PN, thereby providing the physiological rationale for future clinical trials of PN as a potential countermeasure to sarcopenia.

Physical exercise for people with cirrhosis.

BACKGROUND: Loss of muscle mass and muscle weakness are common complications to cirrhosis and are associated with increased morbidity and mortality. Therefore, physical exercise may benefit people with cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of physical exercise versus sham exercise or no exercise for people with cirrhosis. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, and three other databases, including manual searches through reference lists, abstracts, and presentations at conferences and meetings, Google Scholar, and online trial registers in February 2018. SELECTION CRITERIA: We included randomised clinical trials regardless of publication status or language. Inclusion criteria were cirrhosis irrespective of the aetiology or stage. Interventions were physical exercise compared with sham exercise or no intervention. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. We undertook meta-analyses and presented results using risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, both with 95% confidence intervals (CI) and I2 values as markers of imprecision and heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains and determined the credibility of the evidence using GRADE. MAIN RESULTS: We included six randomised clinical trials with 173 participants. All participants had Child-Pugh stage A or B cirrhosis. The intervention groups participated in eight to 14 weeks of physical exercise (aerobic: three trials; resistance: one trial; or aerobic plus resistance training: two trials). Control groups underwent sham exercise (supervised relaxation: one trial) or no intervention (five trials). None of the 89 participants allocated to exercise versus two of 84 participants in the control group died (RR 0.19, 95% CI 0.01 to 3.73; moderate-quality evidence). The cause of death was acute-on-chronic liver disease for both participants. Nine participants in the exercise group and 13 in the control group experienced serious adverse events (RR 0.61, 95% CI 0.19 to 1.94; low-quality evidence).Physical exercise showed no beneficial or detrimental effect on health-related quality of life assessed by the Chronic Liver Disease Questionnaire (MD 0.11, 95% CI -0.44 to 0.67; low-quality evidence). Likewise, physical exercise had no clear effect on physical fitness measured by peak exercise oxygen uptake (MD 0.3 mL/kg/minute, 95 % CI -2.74 to 3.35; low-quality evidence) and Six-Minute Walk Test (MD 56.06 min, 95% CI -9.14 to 121.26; very low-quality evidence). Physical exercise showed no clear effect on mid-thigh circumference (MD 1.76 cm, 95% CI -0.26 to 3.77; low-quality evidence), but showed an increase in mid-arm circumference (MD 2.61 cm, 95% CI 0.36 to 4.85; low-quality evidence). AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effect of physical exercise on mortality, morbidity, or health-related quality of life. Further evidence is needed to evaluate the beneficial and harmful effects of physical exercise on clinical outcomes.

Comparative Effectiveness of Low-Volume Time-Efficient Resistance Training Versus Endurance Training in Patients With Heart Failure.

PURPOSE: Cardiorespiratory fitness is positively related to heart failure (HF) prognosis, but lack of time and low energy are barriers for adherence to exercise. We, therefore, compared the effect of low-volume time-based resistance exercise training (TRE) with aerobic moderate-intensity cycling (AMC) on maximal and submaximal exercise capacity, health-related quality of life, and vascular function. METHODS: Twenty-eight HF patients (New York Heart Association class I-II) performed AMC (n = 14) or TRE (n = 14). Maximal and submaximal exercise capacity, health-related quality of life, and vascular function were evaluated before and after a 6-wk training intervention with 3 training sessions per week. The AMC group and the TRE group trained for 45 and 25 min per training session, respectively. During the training sessions, the TRE and AMC groups trained at 60 ± 4% and 59 ± 2% (mean ± standard deviation) of (Equation is included in full-text article.)O2peak, respectively. RESULTS: The energy expenditure was significantly greater in AMC than in TRE (P < .05). The (Equation is included in full-text article.)O2peak and Wattpeak increased in AMC group (P < .001) and TRE group (P = .001), with no differences between groups. Six-minute walk distance also increased in both groups (AMC, P = .006 and TRE, P = .036), with no difference between groups. Health-related quality of life improved equally in the 2 groups, whereas vascular function did not change in either group. CONCLUSION: These results demonstrate that AMC and TRE equally improved exercise capacity and health-related quality of life in lower New York Heart Association-stage HF patients, despite less time required as well as lower energy expenditure during TRE than during AMC. Therefore, TRE might represent a time-efficient exercise modality for improving adherence to exercise in patients with class I-II HF.

Effect of endurance versus resistance training on quadriceps muscle dysfunction in COPD: a pilot study.

INTRODUCTION: Exercise is an important countermeasure to limb muscle dysfunction in COPD. The two major training modalities in COPD rehabilitation, endurance training (ET) and resistance training (RT), may both be efficient in improving muscle strength, exercise capacity, and health-related quality of life, but the effects on quadriceps muscle characteristics have not been thoroughly described. METHODS: Thirty COPD patients (forced expiratory volume in 1 second: 56% of predicted, standard deviation [SD] 14) were randomized to 8 weeks of ET or RT. Vastus lateralis muscle biopsies were obtained before and after the training intervention to assess muscle morphology and metabolic and angiogenic factors. Symptom burden, exercise capacity (6-minute walking and cycle ergometer tests), and vascular function were also assessed. RESULTS: Both training modalities improved symptom burden and exercise capacity with no difference between the two groups. The mean (SD) proportion of glycolytic type IIa muscle fibers was reduced after ET (from 48% [SD 11] to 42% [SD 10], P<0.05), whereas there was no significant change in muscle fiber distribution with RT. There was no effect of either training modality on muscle capillarization, angiogenic factors, or vascular function. After ET the muscle protein content of phosphofructokinase was reduced (P<0.05) and the citrate synthase content tended increase (P=0.08) but no change was observed after RT. CONCLUSION: Although both ET and RT improve symptoms and exercise capacity, ET induces a more oxidative quadriceps muscle phenotype, counteracting muscle dysfunction in COPD.

Impaired Follistatin Secretion in Cirrhosis.

CONTEXT: Follistatin is a liver-derived inhibitor of the muscle-growth inhibitor myostatin. Reduction in acute follistatin release may help explain muscle loss in liver cirrhosis. OBJECTIVE: The study aimed to investigate the capacity of acute follistatin release in patients with liver cirrhosis compared to healthy control participants. DESIGN, SETTING, AND PARTICIPANTS: To experimentally increase the glucagon-insulin ratio (mimicking the hormonal effect of exercise), we infused glucagon/somatostatin (to inhibit insulin secretion) and compared the acute follistatin increase in eight male cirrhosis patients with eight healthy control participants. Patients and controls received 1-hour glucagon/somatostatin and saline infusions on 2 separate days. MAIN OUTCOME MEASURE: Follistatin was measured during and 5 hours after termination of infusions. RESULTS: The peak follistatin change was significantly decreased in patients with liver cirrhosis compared to healthy control participants (1.9 (interquartile range, 1.4-2.5) versus 3.6 (interquartile range, 3.0-4.0), respectively; P = .003). Patients with liver cirrhosis demonstrated significantly decreased amounts of appendicular lean mass compared to healthy controls (27.6 ± 3.8 vs 34.5 ± 2.9%, respectively; P = .001). CONCLUSIONS: Patients with cirrhosis show impaired capacity to acutely secrete follistatin. The decrease in acute follistatin release may contribute to the loss of muscle mass in liver cirrhosis.

Plasma YKL-40 during pregnancy and gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is characterised by hyperglycaemia during pregnancy. The clinical circumstances involved in the development of GDM leaves the patient at a high risk of the subsequent development of type 2 diabetes. Plasma levels of the inflammation marker YKL-40 are elevated in type 2 diabetes and correlate with fasting plasma glucose levels and insulin resistance in patients with type 2 diabetes. With the present study we aimed to determine if pregnancy (and associated insulin resistance) with or without GDM affects plasma YKL-40 levels. Plasma from women diagnosed with GDM and healthy normal glucose-tolerant pregnant women (non-GDM) was obtained at the third trimester of pregnancy and again 3-4 months following delivery, and levels of YKL-40 and interleukin 6 (IL-6; known to regulate YKL-40) were measured. Plasma YKL-40 levels were similarly low during pregnancy in both groups and increased significantly after delivery, but remained lower in the GDM group compared with the non-GDM group postpartum. In contrast, plasma IL-6 levels were not affected by pregnancy or diagnosis of GDM, Nevertheless, YKL-40 levels were associated with IL-6 levels in the non-GDM group (but not in the GDM group). Pregnancy seems to be associated with a temporary reduction in circulating YKL-40, which increases after delivery, but to a much lesser extent in women with GDM than in non-GDM women.

Obesity and low-grade inflammation increase plasma follistatin-like 3 in humans.

BACKGROUND: Rodent models suggest that follistatin-like 3 (fstl3) is associated with diabetes and obesity. In humans, plasma fstl3 is reduced with gestational diabetes. In vitro, TNF-α induces fstl3 secretion, which suggests a link to inflammation. OBJECTIVE: To elucidate the association between plasma fstl3 and obesity, insulin resistance, and low-grade inflammation in humans. STUDY DESIGN: Plasma fstl3 levels were determined in a cross-sectional study including three groups: patients with type 2 diabetes, impaired glucose tolerance, and healthy controls. In addition, lipopolysaccharide (LPS), TNF-α, or interleukin-6 (IL-6) as well as a hyperinsulinemic euglycemic clamp were used to examine if plasma fstl3 was acutely regulated in humans. RESULTS: Plasma fstl3 was increased in obese subjects independent of glycemic state. Moreover, plasma fstl3 was positively correlated with fat mass, plasma leptin, fasting insulin, and HOMA B and negatively with HOMA S. Furthermore plasma fstl3 correlated positively with plasma TNF-α and IL-6 levels. Infusion of LPS and TNF-α, but not IL-6 and insulin, increased plasma fstl3 in humans. CONCLUSION: Plasma fstl3 is increased in obese subjects and associated with fat mass and low-grade inflammation. Furthermore, TNF-α increased plasma fstl3, suggesting that TNF-α is one of the inflammatory drivers of increased systemic levels of fstl3.

The miRNA plasma signature in response to acute aerobic exercise and endurance training.

MiRNAs are potent intracellular posttranscriptional regulators and are also selectively secreted into the circulation in a cell-specific fashion. Global changes in miRNA expression in skeletal muscle in response to endurance exercise training have been reported. Therefore, our aim was to establish the miRNA signature in human plasma in response to acute exercise and chronic endurance training by utilizing a novel methodological approach. RNA was isolated from human plasma collected from young healthy men before and after an acute endurance exercise bout and following 12 weeks of endurance training. Global miRNA (742 miRNAs) measurements were performed as a screening to identify detectable miRNAs in plasma. Using customized qPCR panels we quantified the expression levels of miRNAs detected in the screening procedure (188 miRNAs). We demonstrate a dynamic regulation of circulating miRNA (ci-miRNA) levels following 0 hour (miR-106a, miR-221, miR-30b, miR-151-5p, let-7i, miR-146, miR-652 and miR-151-3p), 1 hour (miR-338-3p, miR-330-3p, miR-223, miR-139-5p and miR-143) and 3 hours (miR-1) after an acute exercise bout (P<0.00032). Where ci-miRNAs were all downregulated immediately after an acute exercise bout (0 hour) the 1 and 3 hour post exercise timepoints were followed by upregulations. In response to chronic training, we identified seven ci-miRNAs with decreased levels in plasma (miR-342-3p, let-7d, miR-766, miR-25, miR-148a, miR-185 and miR-21) and two miRNAs that were present at higher levels after the training period (miR-103 and miR-107) (P<0.00032). In conclusion, acute exercise and chronic endurance training, likely through specific mechanisms unique to each stimulus, robustly modify the miRNA signature of human plasma.

Endurance training enhances skeletal muscle interleukin-15 in human male subjects.

Regular endurance exercise promotes metabolic and oxidative changes in skeletal muscle. Overexpression of interleukin-15 (IL-15) in mice exerts similar metabolic changes in muscle as seen with endurance exercise. Muscular IL-15 production has been shown to increase in mice after weeks of regular endurance running. With the present study we aimed to determine if muscular IL-15 production would increase in human male subjects following 12 weeks of endurance training. In two different studies we obtained plasma and muscle biopsies from young healthy subjects performing: (1) 12 weeks of ergometer cycling exercise five times per week with plasma and biopsies before and after the intervention, and (2) 3 h of ergometer cycling exercise with plasma and biopsies before and after the exercise bout and well into recovery. We measured changes in plasma IL-15, muscle IL-15 mRNA and IL-15 protein. Twelve weeks of regular endurance training induced a 40% increase in basal skeletal muscle IL-15 protein content (p < 0.01), but with no changes in either muscle IL-15 mRNA or plasma IL-15 levels. However, an acute bout of 3-h exercise did not show significant changes in muscle IL-15 or plasma IL-15 levels. The induction of muscle IL-15 protein in humans following a regular training period supports previous findings in mice and emphasizes the hypothesis of IL-15 taking part in skeletal muscle adaptation during training.

Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy.

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P<0.0001). The patients and controls demonstrated an increase in peripheral tissue insulin sensitivity of 14 and 11% respectively (P<0.05), with no effect on hepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (P<0.05 and P<0.01 respectively). Body weight (P<0.0001) and whole-body fat mass (FM) (P<0.01) were reduced, while lean body mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (P<0.01), subcutaneous (P<0.05), and visceral (P<0.01) FM amounts. The concentrations of plasma markers of systemic inflammation were unchanged in response to the training. No group × time interactions were observed, except for thigh intermuscular adipose tissue (IMAT) (P=0.01), reflecting a significant reduction in the amount of IMAT in the controls (P<0.05) not observed in the patients (P=0.64). In response to endurance training, ADT-treated prostate cancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men.