Prolonged lipopolysaccharide-induced illness elevates glucagon-like peptide-1 and suppresses peptide YY:A human-randomized cross-over trial

Severe systemic inflammation is associated with nausea, loss of appetite, and delayed gastric emptying, which increases hospitalization admission length and mortality rate. There is a lack of human controlled studies exploring gastric emptying rates and underlying mechanisms during inflammatory conditions. We aimed to investigate if systemic inflammation in young men delays gastro‐intestinal transit times, lowers motility, and affects gastrointestinal hormone secretion. This substudy of a randomized crossover trial investigated eight healthy young men on two separate occasions; (I) following an overnight fast (healthy conditions/HC) and (II) fasting and bedrest combined with two lipopolysaccharide (LPS) injections of 1 ng kg(−1) following an overnight fast and 0.5 ng kg(−1) following another 24 h (systemic inflammation/SI). A standardized protein beverage and a SmartPill capsule (a wireless gastrointestinal monitoring system) were swallowed during each occasion. Whole gut transit time was comparable between HC and SI. SI decreased gastric mean pressure peak amplitude (p = 0.04) and increased pH rise across the pylorus and small bowel pH (p = 0.02) compared with HC. Glucagon‐like peptide‐1 was elevated during SI compared with HC (p = 0.04). Peptide YY was lower during SI compared with HC (p = 0.007). Prolonged LPS exposure combined with fasting and bedrest elevated glucagon‐like peptide 1 concentrations, which may play a role for the nausea and loss of appetite typically associated with SI

Dose-response of myofibrillar protein synthesis to ingested whey protein during energy restriction in overweight postmenopausal women: a randomized, controlled trial

BackgroundDiet-induced weight loss is associated with a decline in lean body mass, as mediated by an impaired response of muscle protein synthesis (MPS). The dose-response of MPS to ingested protein, with or without resistance exercise, is well characterized during energy balance but limited data exist under conditions of energy restriction in clinical populations.ObjectiveTo determine the dose-response of MPS to ingested whey protein following short-term diet-induced energy restriction in overweight, postmenopausal, women at rest and postexercise.DesignForty middle-aged (58.6±0.4 y), overweight (BMI: 28.6±0.4), postmenopausal women were randomly assigned to 1 of 4 groups: Three groups underwent 5 d of energy restriction (∼800 kcal/d). On day 6, participants performed a unilateral leg resistance exercise bout before ingesting either a bolus of 15g (ERW15, n = 10), 35g (ERW35, n = 10) or 60g (ERW60, n = 10) of whey protein. The fourth group (n = 10) ingested a 35g whey protein bolus after 5 d of an energy balanced diet (EBW35, n = 10). Myofibrillar fractional synthetic rate (FSR) was calculated under basal, fed (FED) and postexercise (FED-EX) conditions by combining an L-[ring-13C6] phenylalanine tracer infusion with the collection of bilateral muscle biopsies.ResultsMyofibrillar FSR was greater in ERW35 (0.043±0.003%/h, P = 0.013) and ERW60 (0.042±0.003%/h, P = 0.026) than ERW15 (0.032 ± 0.003%/h), with no differences between ERW35 and ERW60 (P = 1.000). Myofibrillar FSR was greater in FED (0.044 ± 0.003%/h, P < 0.001) and FED-EX (0.048 ± 0.003%/h, P < 0.001) than BASAL (0.027 ± 0.003%/h), but no differences were detected between FED and FED-EX (P = 0.732) conditions. No differences in myofibrillar FSR were observed between EBW35 (0.042 ± 0.003%/h) and ERW35 (0.043 ± 0.003%/h, P = 0.744).ConclusionA 35 g dose of whey protein, ingested with or without resistance exercise, is sufficient to stimulate a maximal acute response of MPS following short-term energy restriction in overweight, postmenopausal women, and thus may provide a per serving protein recommendation to mitigate muscle loss during a weight loss program.Trial registryclinicaltrials.gov (ID: NCT03326284)

β-Lactoglobulin Elevates Insulin and Glucagon Concentrations Compared with Whey Protein—A Randomized Double-Blinded Crossover Trial in Patients with Type Two Diabetes Mellitus

Whey protein is an insulinotropic fraction of dairy that reduces postprandial glucose levels in patients with type 2 diabetes mellitus (T2DM). We have recently shown that β-lactoglobulin (BLG), the largest protein fraction of whey, elevates insulin concentrations compared with iso-nitrogenous whey protein isolate (WPI) in healthy individuals. We therefore hypothesized that BLG pre-meals would lower glucose levels compared with WPI in patients with T2DM. We investigated 16 participants with T2DM using a randomized double-blinded cross-over design with two pre-meal interventions, (i) 25 g BLG and (ii) 25 g WPI prior to an oral glucose tolerance test (OGTT), followed by four days of continuous glucose monitoring (CGM) at home. BLG increased concentrations of insulin with 10%, glucagon with 20%, and glucose with 10% compared with WPI after the OGTT (all p &lt; 0.05). Both BLG and WPI reduced the interstitial fluid (ISF) glucose concentrations (using CGM) with 2 mM and lowered glycemic variability with 10–15%, compared with tap-water (p &lt; 0.05), and WPI lowered the ISF glucose with 0.5 mM compared with BLG from 120 min and onwards (p &lt; 0.05). In conclusion, BLG pre-meals resulted in higher insulin, glucagon, and glucose concentrations compared with WPI in participants with T2DM. Pre-meal servings of WPI remains the most potent protein in terms of lowering postprandial glucose excursions

β-Lactoglobulin Elevates Insulin and Glucagon Concentrations Compared with Whey Protein—A Randomized Double-Blinded Crossover Trial in Patients with Type Two Diabetes Mellitus

Whey protein is an insulinotropic fraction of dairy that reduces postprandial glucose levels in patients with type 2 diabetes mellitus (T2DM). We have recently shown that β-lactoglobulin (BLG), the largest protein fraction of whey, elevates insulin concentrations compared with iso-nitrogenous whey protein isolate (WPI) in healthy individuals. We therefore hypothesized that BLG pre-meals would lower glucose levels compared with WPI in patients with T2DM. We investigated 16 participants with T2DM using a randomized double-blinded cross-over design with two pre-meal interventions, (i) 25 g BLG and (ii) 25 g WPI prior to an oral glucose tolerance test (OGTT), followed by four days of continuous glucose monitoring (CGM) at home. BLG increased concentrations of insulin with 10%, glucagon with 20%, and glucose with 10% compared with WPI after the OGTT (all p p p < 0.05). In conclusion, BLG pre-meals resulted in higher insulin, glucagon, and glucose concentrations compared with WPI in participants with T2DM. Pre-meal servings of WPI remains the most potent protein in terms of lowering postprandial glucose excursions

A model mimicking catabolic inflammatory disease; a controlled randomized study in humans.

ObjectiveInflammatory disease is catabolic and associated with insulin resistance, increased energy expenditure, lipolysis and muscle protein loss. The main contributors to these metabolic adaptations are inflammation, malnutrition and immobilisation. Controlled experimental models incorporating these central elements of hospitalisation are lacking. The aim of this study was to validate such a human experimental model.MethodsIn a randomized crossover design, six healthy young men underwent; (i) overnight fast (CTR), or (ii) exposure to systemic lipopolysaccharide (1 ng/kg) combined with 36-hour fast and bed rest (CAT). The difference in insulin sensitivity between CAT and CTR was the main outcome, determined by a hyperinsulinemic euglycemic glucose clamp. Palmitate, glucose, urea, phenylalanine and tyrosine tracers were infused to estimate metabolic shifts during interventions. Indirect calorimetry was used to estimate energy expenditure and substrate oxidation.ResultsInsulin sensitivity was 41% lower in CAT than in CTR (M-value, mg/kg/min): 4.3 ± 0.2 vs 7.3 ± 1.3, pConclusionWe found that combined systemic inflammation, fasting and bed rest induced marked insulin resistance and increased energy expenditure and lipolysis, rendering this controlled experimental model suitable for anti-catabolic intervention studies, mimicking clinical conditions

STAT2 is involved in the pathogenesis of psoriasis by promoting CXCL11 and CCL5 production by keratinocytes

<div><p>The JAK/STAT signaling pathway is suggested to play an important role in the pathogenesis of psoriasis, and recently JAK/STAT inhibitors have shown promising results in psoriasis treatment. The present study aimed to characterize the role of STAT2 in psoriasis. We demonstrated an increased expression of <i>STAT2</i> and an increased level of phosphorylated/activated STAT2 in lesional compared with nonlesional psoriatic skin. Gene silencing of <i>STAT2</i> by siRNA in human keratinocytes revealed that upon IFNα stimulation CXCL11 and CCL5 were the only two cytokines, among 102 analyzed, found to be regulated through a STAT2-dependent mechanism. Moreover, the regulation of CXCL11 and CCL5 depended on IRF9, but not on STAT1 and STAT6. The <i>CXCL11</i> and <i>CCL5</i> expression was increased in lesional compared with nonlesional psoriatic skin, and analysis demonstrated positive correlation between the expression of <i>CXCL11</i> and <i>IFNγ</i> and between the expression of <i>CCL5</i> and <i>IFNγ</i> in lesional psoriatic skin. In contrast, no correlation between the expression of <i>CXCL11</i> and <i>IL-17A</i> and the expression of <i>CCL5</i> and <i>IL-17A</i> in lesional psoriatic skin was found. Our data suggest that STAT2 plays a role in the psoriasis pathogenesis by regulating the expression of CXCL11 and CCL5, and thereby attracting IFNγ-producing immune cells to the skin.</p></div

IFNα-induced CXCL11 and CCL5 expression involves STAT2 and IRF9, but not STAT1.

<p>Cultured human keratinocytes were transfected with siRNA directed against STAT2 (siSTAT2), STAT1 (siSTAT1), IRF9 (siIRF9), or control siRNA (siCon) before IFNα (1000 U/ml) stimulation for 24 hours. (A) Protein extracts were isolated from the cells and the protein level of STAT2, STAT1, and IRF9 examined by western blotting. β-actin was used as a loading control. One representative gel out of three is shown. (B, C) The protein level of (B) CXCL11 and (C) CCL5 in the cell culture medium was analyzed by ELISA (n = 3). Results are expressed as mean ± standard deviation. *<i>P</i> < 0.05.</p