The Influence of Face Gaze by Physicians on Patient Trust: an Observational Study.

BACKGROUND: Physicians' gaze towards their patients may affect patients' trust in them. This is especially relevant considering recent developments, including the increasing use of Electronic Health Records, which affect physicians' gaze behavior. Moreover, socially anxious patients' trust in particular may be affected by the gaze of the physician. OBJECTIVE: We aimed to evaluate if physicians' gaze towards the face of their patient influenced patient trust and to assess if this relation was stronger for socially anxious patients. We furthermore explored the relation between physicians' gaze and patients' perception of physician empathy and patients' distress. DESIGN: This was an observational study using eye-tracking glasses and questionnaires. PARTICIPANTS: One hundred patients and 16 residents, who had not met before, participated at an internal medicine out-patient clinic. MEASURES: Physicians wore eye-tracking glasses during medical consultations to assess their gaze towards patients' faces. Questionnaires were used to assess patient outcomes. Multilevel analyses were conducted to assess the relation between physicians' relative face gaze time and trust, while correcting for patient background characteristics, and including social anxiety as a moderator. Analyses were then repeated with perceived empathy and distress as outcomes. RESULTS: More face gaze towards patients was associated with lower trust, after correction for gender, age, education level, presence of caregivers, and social anxiety (ß=-0.17, P=0.048). There was no moderation effect of social anxiety nor a relation between face gaze and perceived empathy or distress. CONCLUSIONS: These results challenge the notion that more physician gaze is by definition beneficial for the physician-patient relationship. For example, the extent of conversation about emotional issues might explain our findings, where more emotional talk could be associated with more intense gazing and feelings of discomfort in the patient. To better understand the relation between physician gaze and patient outcomes, future studies should assess bidirectional face gaze during consultations.

Clinical validation of clinical decision support systems for medication review: A scoping review.

The aim of this scoping review is to summarize approaches and outcomes of clinical validation studies of clinical decision support systems (CDSSs) to support (part of) a medication review. A literature search was conducted in Embase and Medline. In total, 30 articles validating a CDSS were ultimately included. Most of the studies focused on detection of adverse drug events, potentially inappropriate medications and drug-related problems. We categorized the included articles in three groups: studies subjectively reviewing the clinical relevance of CDSS's output (21/30 studies) resulting in a positive predictive value (PPV) for clinical relevance of 4-80%; studies determining the relationship between alerts and actual events (10/30 studies) resulting in a PPV for actual events of 5-80%; and studies comparing output of CDSSs to chart/medication reviews in the whole study population (10/30 studies) resulting in a sensitivity of 28-85% and specificity of 42-75%. We found heterogeneity in the methods used and in the outcome measures. The validation studies did not report the use of a published CDSS validation strategy. To improve the effectiveness and uptake of CDSSs supporting a medication review, future research would benefit from a more systematic and comprehensive validation strategy.

Short-Term High-Fat Diet Alters Acetaminophen Metabolism in Healthy Individuals.

BACKGROUND: Acetaminophen is metabolized through a nontoxic sulfation and glucuronidation pathway and toxic oxidation pathway (via CYP2E1 and CYP1A2). A short-term high-fat diet induces alterations in the steatotic liver and may alter hepatic drug enzyme activity. In the case of acetaminophen, these alterations may result in an increased risk of hepatotoxicity. Therefore, this study was conducted to assess the effect of a 3-day hypercaloric high-fat diet on the plasma levels of acetaminophen metabolites. METHODS: Nine healthy subjects participated in this randomized, crossover intervention study. The subjects consumed a regular diet or a regular diet supplemented with 500 mL of cream (1700 kcal) for 3 days and then fasted overnight. After ingesting 1000-mg acetaminophen, the plasma concentration of acetaminophen (APAP) and its metabolites [acetaminophen glucuronide, acetaminophen sulfate, 3-cysteinyl-acetaminophen, and 3-(N-acetyl-L-cystein-S-yl)-acetaminophen, and 3-methoxy-acetaminophen] were measured. RESULTS: The 3-day high-fat diet increased the extrapolated area under the concentration-time curve from 0 to infinity (area under the curve 0-inf ) of APAP-Cys by approximately 20% ( P = 0.02) and that from 0 to 8 hours (area under the curve 0-8 ) of APAP-Cys-NAC by approximately 39% ( P = 0.01). The 3-day high-fat diet did not alter the pharmacokinetic parameters of the parent compound acetaminophen and other metabolites. CONCLUSIONS: A short-term, hypercaloric, high-fat diet increases the plasma levels of the APAP metabolites formed by the oxidation pathway, which may increase the risk of hepatotoxicity.

Potentially inappropriate medications and their effect on falls during hospital admission.

OBJECTIVE: to investigate the effect of potentially inappropriate medications (PIMs) on inpatient falls and to identify whether PIMs as defined by STOPPFall or the designated section K for falls of STOPP v2 have a stronger association with inpatient falls when compared to the general tool STOPP v2. METHODS: a retrospective observational matching study using an electronic health records dataset of patients (≥70 years) admitted to an academic hospital (2015-19), including free text to identify inpatient falls. PIMs were identified using the STOPP v2, section K of STOPP v2 and STOPPFall. We first matched admissions with PIMs to those without PIMs on confounding factors. We then applied multinomial logistic regression analysis and Cox proportional hazards analysis on the matched datasets to identify effects of PIMs on inpatient falls. RESULTS: the dataset included 16,678 hospital admissions, with a mean age of 77.2 years. Inpatient falls occurred during 446 (2.7%) admissions. Adjusted odds ratio (OR) (95% confidence interval (CI)) for the association between PIM exposure and falls were 7.9 (6.1-10.3) for STOPP section K, 2.2 (2.0-2.5) for STOPP and 1.4 (1.3-1.5) for STOPPFall. Adjusted hazard ratio (HR) (95% CI) for the effect on time to first fall were 2.8 (2.3-3.5) for STOPP section K, 1.5 (1.3-1.6) for STOPP and 1.3 (1.2-1.5) for STOPPFall. CONCLUSIONS: we identified an independent association of PIMs on inpatient falls for all applied (de)prescribing tools. The strongest effect was identified for STOPP section K, which is restricted to high-risk medication for falls. Our results suggest that decreasing PIM exposure during hospital stay might benefit fall prevention, but intervention studies are warranted.

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women.

Retinol-binding protein-4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity-induced insulin resistance and correlates inversely with insulin-stimulated glucose disposal. But its role in insulin-mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux-en-Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin-mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4-activated macrophages markedly increased basal lipolysis and impaired insulin-mediated lipolysis suppression. RBP4 treatment of macrophages increased TNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro-inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed to determine whether this mechanism explains RBP4-induced insulin resistance in humans.

Potentially inappropriate prescribing in older hospitalized Dutch patients according to the STOPP/START criteria v2: a longitudinal study.

PURPOSE: To investigate prevalence, independent associations, and variation over time of potentially inappropriate prescriptions in a population of older hospitalized patients. METHODS: A longitudinal study using a large dataset of hospital admissions of older patients (≥ 70 years) based on an electronic health records cohort including data from 2015 to 2019. Potentially inappropriate medication (PIM) and potential prescribing omission (PPO) prevalence during hospital stay were identified based on the Dutch STOPP/START criteria v2. Univariate and multivariate logistic regression were used for analyzing associations and trends over time. RESULTS: The data included 16,687 admissions. Of all admissions, 56% had ≥ 1 PIM and 58% had ≥ 1 PPO. Gender, age, number of medications, number of diagnoses, Charlson score, and length of stay were independently associated with both PIMs and PPOs. Additionally, number of departments and number of prescribing specialties were independently associated with PIMs. Over the years, the PIM prevalence did not change (OR = 1.00, p = .95), whereas PPO prevalence increased (OR = 1.08, p < .001). However, when corrected for changes in patient characteristics such as number of diagnoses, the PIM (aOR = 0.91, p < .001) and PPO prevalence (aOR = 0.94, p < .001) decreased over the years. CONCLUSION: We found potentially inappropriate prescriptions in the majority of admissions of older patients. Prescribing relatively improved over time when considering complexity of the admissions. Nevertheless, the high prevalence shows a clear need to better address this issue in clinical practice. Studies seeking effective (re)prescribing interventions are warranted.

Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders.

PURPOSE OF REVIEW: The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. RECENT FINDINGS: In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients.

Loss of arginine vasopressin- and vasoactive intestinal polypeptide-containing neurons and glial cells in the suprachiasmatic nucleus of individuals with type 2 diabetes.

AIMS/HYPOTHESIS: The central pacemaker of the mammalian biological timing system is located within the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. Together with the peripheral clocks, this central brain clock ensures a timely, up-to-date and proper behaviour for an individual throughout the day-night cycle. A mismatch between the central and peripheral clocks results in a disturbance of daily rhythms in physiology and behaviour. It is known that the number of rhythmically expressed genes is reduced in peripheral tissue of individuals with type 2 diabetes mellitus. However, it is not known whether the central SCN clock is also affected in the pathogenesis of type 2 diabetes. In the current study, we compared the profiles of the SCN neurons and glial cells between type 2 diabetic and control individuals. METHODS: We collected post-mortem hypothalamic tissues from 28 type 2 diabetic individuals and 12 non-diabetic control individuals. We performed immunohistochemical analysis for three SCN neuropeptides, arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP) and neurotensin (NT), and for two proteins expressed in glial cells, ionised calcium-binding adapter molecule 1 (IBA1, a marker of microglia) and glial fibrillary acidic protein (GFAP, a marker of astroglial cells). RESULTS: The numbers of AVP immunoreactive (AVP-ir) and VIP-ir neurons and GFAP-ir astroglial cells in the SCN of type 2 diabetic individuals were significantly decreased compared with the numbers in the SCN of the control individuals. In addition, the relative intensity of AVP immunoreactivity was reduced in the individuals with type 2 diabetes. The number of NT-ir neurons and IBA1-ir microglial cells in the SCN was similar in the two groups. CONCLUSIONS/INTERPRETATION: Our data show that type 2 diabetes differentially affects the numbers of AVP- and VIP-expressing neurons and GFAP-ir astroglial cells in the SCN, each of which could affect the daily rhythmicity of the SCN biological clock machinery. Therefore, for effectively treating type 2 diabetes, lifestyle changes and/or medication to normalise central biological clock functioning might be helpful.

Differential effects of a 40-hour fast and bile acid supplementation on human GLP-1 and FGF19 responses.

Bile acids, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response to 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In experiment 1: we tested 4-h mixed meal after an overnight fast and a 40-h fast. In experiment 2, we tested a 4-h mixed meal test with and without gDCA supplementation. Both studies measured postprandial glucose, insulin, bile acids, GLP-1, and FGF19. In experiment 1, 40 h of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA levels at specific time points. In experiment 2, administration of gDCA increased GLP-1 levels and lowered late postprandial glucose without effect on FGF19. Energy expenditure was not affected by gDCA administration. Unexpectedly, 40 h of fasting increased both GLP-1 and FGF19, where the former appeared bile acid independent and the latter bile acid dependent. Second, a single dose of gDCA increased postprandial GLP-1. Therefore, our data add complexity to the physiological regulation of the enterokines GLP-1 and FGF19 by bile acids.

Quantitative Method for Simultaneous Analysis of Acetaminophen and 6 Metabolites.

BACKGROUND: Hepatotoxicity after ingestion of high-dose acetaminophen [N-acetyl-para-aminophenol (APAP)] is caused by the metabolites of the drug. To gain more insight into factors influencing susceptibility to APAP hepatotoxicity, quantification of APAP and metabolites is important. A few methods have been developed to simultaneously quantify APAP and its most important metabolites. However, these methods require a comprehensive sample preparation and long run times. The aim of this study was to develop and validate a simplified, but sensitive method for the simultaneous quantification of acetaminophen, the main metabolites acetaminophen glucuronide and acetaminophen sulfate, and 4 Cytochrome P450-mediated metabolites by using liquid chromatography with mass spectrometric (LC-MS) detection. METHODS: The method was developed and validated for the human plasma, and it entailed a single method for sample preparation, enabling quick processing of the samples followed by an LC-MS method with a chromatographic run time of 9 minutes. The method was validated for selectivity, linearity, accuracy, imprecision, dilution integrity, recovery, process efficiency, ionization efficiency, and carryover effect. RESULTS: The method showed good selectivity without matrix interferences. For all analytes, the mean process efficiency was >86%, and the mean ionization efficiency was >94%. Furthermore, the accuracy was between 90.3% and 112% for all analytes, and the within- and between-run imprecision were <20% for the lower limit of quantification and <14.3% for the middle level and upper limit of quantification. CONCLUSIONS: The method presented here enables the simultaneous quantification of APAP and 6 of its metabolites. It is less time consuming than previously reported methods because it requires only a single and simple method for the sample preparation followed by an LC-MS method with a short run time. Therefore, this analytical method provides a useful method for both clinical and research purposes.

A single night of sleep curtailment increases plasma acylcarnitines: Novel insights in the relationship between sleep and insulin resistance.

We have previously shown that acute sleep curtailment induces insulin resistance, both in healthy individuals as well as in patients with type 1 diabetes, suggesting a causal role for sleep disturbances in pathogenesis of insulin resistance, independent of endogenous insulin production. However, the underlying mechanisms remain unclear. This study aimed to explore the metabolic pathways affected by sleep loss using targeted metabolomics in human fasting plasma samples. Healthy individuals (n = 9) and patients with type 1 diabetes (n = 7) were studied after a single night of short sleep (4 h) versus normal sleep (8 h) in a cross-over design. Strikingly, one night of short sleep specifically increased the plasma levels of acylcarnitines, essential intermediates in mitochondrial fatty acid oxidation (FAO). Specifically, short sleep increased plasma levels of tetradecenoyl-l-carnitine (C14:1) (+32%, p = 2.67*10(-4)), octadecanoyl-l-carnitine (C18:1) (+22%, p = 1.92*10(-4)) and octadecadienyl-l-carnitine (C18:2) (+27%, p = 1.32*10(-4)). Since increased plasma acylcarnitine levels could be a sign of disturbed FAO, it is possible that sleep curtailment acutely induces inefficient mitochondrial function. Our observations provide a basis for further research into the role of acylcarnitines as a potential mechanistic pathway by which sleep deprivation - even short term - causes adverse metabolic effects, such as insulin resistance.

Quantitative Method for Simultaneous Analysis of a 5-Probe Cocktail for Cytochrome P450 Enzymes.

BACKGROUND: The metabolic activity of P450 enzymes in vivo can be determined using selective probe drugs. The simultaneous administration of multiple CYP-specific probe drugs is commonly known as the "cocktail approach." Disadvantages of a cocktail are large volumes of samples required for analysis and time-consuming analyses. The aim of this study was to develop and validate a simplified but sensitive method for the simultaneous quantification of 5 probe drugs [caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19), and S-warfarin (CYP2C9)] in a previously validated cocktail using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. METHODS: The method entailed a single method for sample preparation that enables quick processing of the samples containing all 5 probe drugs in a small volume of blood (≥10 µL) followed by a chiral and nonchiral LC-MS/MS method. The method was validated for selectivity, specificity, resolution of racemic warfarin, linearity, accuracy, imprecision, recovery, process efficiency, ionization efficiency, and carryover effect. RESULTS: The method showed good selectivity without matrix interferences and differentiated S- and R-warfarin enantiomers with adequate resolution (Rs = 1.55). For all analytes, the mean process efficiency was >95%, and the mean ionization efficiency was >97%. Furthermore, the accuracy was between 94.9% and 108% for all analytes, and the within- and between-run imprecision were <11.7% for the lower limit of quantification and <12.6% for the middle level and upper limit of quantification. CONCLUSIONS: The method presented here enables the simultaneous quantification of the 5 probes in a very small blood volume (≥10 µL). Furthermore, it is less time consuming than previously reported methods because it requires only 1 simple method for sample preparation followed by a nonchiral and chiral LC-MS/MS method that can be performed sequentially.

Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT. METHODS: Lean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions. RESULTS: Central administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight. CONCLUSIONS/INTERPRETATION: Collectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

Short-term fasting alters cytochrome P450-mediated drug metabolism in humans.

Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P < 0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies.

Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent findings in the area of sympathetic control of TG metabolism. Various neuronal populations, such as neuropeptide Y (NPY)-expressing neurons and melanocortin-expressing neurons, as well as peripherally produced hormones (i.e., GLP-1, leptin, and insulin), modulate sympathetic outflow from the hypothalamus toward target organs and thereby influence peripheral TG metabolism. We conclude that sympathetic stimulation in general increases lipolysis in WAT, enhances VLDL-TG production by the liver, and increases the activity of BAT with respect to lipolysis of TG, followed by combustion of fatty acids toward heat. Moreover, the increased knowledge about the involvement of the neuroendocrine system in TG metabolism presented in this review offers new therapeutic options to fight hypertriglyceridemia by specifically modulating sympathetic nervous system outflow toward liver, BAT, or WAT.

Inhibition of the central melanocortin system decreases brown adipose tissue activity.

The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet for 4 weeks and infused intracerebroventricularly with the melanocortin 3/4 receptor (MC3/4R) antagonist SHU9119 or vehicle for 2 weeks. SHU9119 increased food intake (+30%) and body fat (+50%) and decreased EE by reduction in fat oxidation (-42%). In addition, SHU9119 impaired the uptake of VLDL-TG by BAT. In line with this, SHU9119 decreased uncoupling protein-1 levels in BAT (-60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Finally, SHU9119-treated mice pair-fed to the vehicle-treated group still exhibited these effects, indicating that MC4R inhibition impairs BAT activity independent of food intake. These effects were not specific to the APOE*3-Leiden.CETP background as SHU9119 also inhibited BAT activity in wild-type mice. We conclude that inhibition of central MC3/4R signaling impairs BAT function, which is accompanied by reduced EE, thereby promoting adiposity. We anticipate that activation of MC4R is a promising strategy to combat obesity by increasing BAT activity.

Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity.

BACKGROUND & AIMS: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS: Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters. CONCLUSIONS: Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566).

Impaired sustained attention in adult patients with type 1 diabetes is related to diabetes per se.

BACKGROUND: Patients with type 1 diabetes have altered sleep characteristics and are thought to have deficits in sustained attention. We compared the sustained attention to response task (SART) of patients with type 1 diabetes to that of healthy controls, and related results with sleep characteristics and disease-related factors. METHODS: SART was applied in 122 patients and 109 controls. Glucoregulation was assessed by HbA1c values and a questionnaire assessing glycaemic history. Clinical parameters were obtained from medical charts. Polyneuropathy was assessed by neurological examination and quantitative sensory testing. Sleep characteristics were assessed with sleep questionnaires. Anxiety and depression scores were assessed by the Hospital Anxiety and Depression Scale. RESULTS: The SART reaction time (RT) was significantly longer than in controls (327 ± 5 vs. 285 ± 3 ms, p < 0.001), although there were no significant differences in error scores. Repeated measurement analyses showed that diabetes per se was associated with prolonged RT (p < 0.001) and more commission errors (p = 0.010). None of the sleep-related and diabetes-related factors were significantly associated with these SART parameters. CONCLUSIONS: Patients with type 1 diabetes had impaired sustained attention, which was associated with diabetes per se but not with disturbed sleep characteristics.

Short-term effects of a standardized glucose load on region-specific aortic pulse wave velocity assessed by MRI.

PURPOSE: To assess the short-term effects of a standardized oral glucose load on regional aortic pulse wave velocity (PWV) using two-directional in-plane velocity encoded MRI. MATERIALS AND METHODS: A randomized, controlled intervention was performed in 16 male subjects (mean ± standard deviation: age: 59±7 years, body mass index: 28±3 kg/m2) with impaired fasting glucose. The intervention consisted of an oral glucose load (75 grams of carbohydrates in 300 mL water) at 1 study day and water (300 mL) at the other study day. PWV was measured using multislice two-directional in-plane velocity-encoded MRI. RESULTS: PWV in the proximal aorta at 1 h post-glucose load decreased compared with PWV 1-h post-water (delta PWV: -1.0±2.6 m/s versus 0.6±2.0 m/s, P=0.02). Eight responding subjects showed a significant decrease in PWV of the proximal aorta after the glucose load and had a decreased waist circumference (P=0.037) compared with nonresponders, being one of the major criteria of the metabolic syndrome. There was no significant change in PWV of the distal aorta at 1 h post-load comparing both intervention groups. CONCLUSION: A standardized oral glucose load induces a decrease of the proximal, but not of the distal, aortic PWV. Regional response of aortic PWV may be associated with features of the metabolic syndrome.

Detrimental effects of constant light exposure and high-fat diet on circadian energy metabolism and insulin sensitivity.

Circadian rhythm disturbances are observed in, e.g., aging and neurodegenerative diseases and are associated with an increased incidence of obesity and diabetes. We subjected male C57Bl/6J mice to constant light [12-h light-light (LL) cycle] to examine the effects of a disturbed circadian rhythm on energy metabolism and insulin sensitivity. In vivo electrophysiological recordings in the central pacemaker of the suprachiasmatic nuclei (SCN) revealed an immediate reduction in rhythm amplitude, stabilizing at 44% of normal amplitude values after 4 d LL. Food intake was increased (+26%) and energy expenditure decreased (-13%), and we observed immediate body weight gain (d 4: +2.4%, d 14: +5.0%). Mixed model analysis revealed that weight gain developed more rapidly in response to LL as compared to high fat. After 4 wk in LL, the circadian pattern in feeding and energy expenditure was completely lost, despite continuing low-amplitude rhythms in the SCN and in behavior, whereas weight gain had stabilized. Hyperinsulinemic-euglycemic clamp analysis revealed complete abolishment of normal circadian variation in insulin sensitivity in LL. In conclusion, a reduction in amplitude of the SCN, to values previously observed in aged mice, is sufficient to induce a complete loss of circadian rhythms in energy metabolism and insulin sensitivity.