Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS: We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS: All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION: Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION: Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY: Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING: The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time.

OBJECTIVE: Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects. DESIGN: Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks. RESULTS: We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa. CONCLUSION: Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects. TRIAL REGISTRATION NUMBER: NTR4327.

Dapagliflozin for prednisone-induced hyperglycaemia in acute exacerbation of chronic obstructive pulmonary disease.

The aim of the present study was to compare the effectiveness and safety of add-on treatment with dapagliflozin to placebo in patients with prednisone-induced hyperglycaemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicentre double-blind randomized controlled study in which add-on treatment with dapagliflozin 10 mg was compared with placebo. Glycaemic control and incidence of hypoglycaemia were measured through a blinded subcutaneous continuous glucose monitoring device. Participants in the dapagliflozin group spent 54 ± 27.7% of the time in target range (3.9-10 mmol/L) and participants in the placebo group spent 53.6 ± 23.4% of the time in target range (P = .96). The mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (P = .66). One participant using dapagliflozin and 2 participants using placebo experienced symptomatic hypoglycaemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycaemia compared with placebo. Dapagliflozin did not result in better glycaemic control compared with placebo in participants with prednisone-induced hyperglycaemia during AECOPD.

Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study.

OBJECTIVE: Environmental factors driving the development of type 1 diabetes (T1D) are still largely unknown. Both animal and human studies have shown an association between altered fecal microbiota composition, impaired production of short-chain fatty acids (SCFA) and T1D onset. However, observational evidence on SCFA and fecal and oral microbiota in adults with longstanding T1D vs healthy controls (HC) is lacking. RESEARCH DESIGN AND METHODS: We included 53 T1D patients without complications or medication and 50 HC matched for age, sex and BMI. Oral and fecal microbiota, fecal and plasma SCFA levels, markers of intestinal inflammation (fecal IgA and calprotectin) and markers of low-grade systemic inflammation were measured. RESULTS: Oral microbiota were markedly different in T1D (eg abundance of Streptococci) compared to HC. Fecal analysis showed decreased butyrate producing species in T1D and less butyryl-CoA transferase genes. Also, plasma levels of acetate and propionate were lower in T1D, with similar fecal SCFA. Finally, fecal strains Christensenella and Subdoligranulum correlated with glycemic control, inflammatory parameters and SCFA. CONCLUSIONS: We conclude that T1D patients harbor a different amount of intestinal SCFA (butyrate) producers and different plasma acetate and propionate levels. Future research should disentangle cause and effect and whether supplementation of SCFA-producing bacteria or SCFA alone can have disease-modifying effects in T1D.

Intestinal Ralstonia pickettii augments glucose intolerance in obesity.

An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram-negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice.

An email-based intervention to improve the number and timeliness of letters sent from the hospital outpatient clinic to the general practitioner: A pair-randomized controlled trial.

OBJECTIVE: Letters from the hospital to the general practitioner are important for maintaining continuity of care. Although doctors feel letters are important, they are often not written on time. To improve the number and timeliness of letters sent from the hospital outpatient department to the general practitioner using an email-based intervention evaluated in a randomized controlled trial. MATERIALS AND METHODS: Users were interviewed to determine the requirements for the intervention. Due to high between-doctor variation at baseline, doctors were matched for baseline performance and pair-randomized. The effectiveness of the intervention was assessed using meta-analytic methods. The primary outcome was the number of patient visits which should have generated a letter that had a letter by 90 days after the visit. Satisfaction was assessed with an anonymous survey. RESULTS: The intervention consisted of a monthly email reminder for each doctor containing a list of his or her patients who were (over)due for a letter. Doctors in the intervention group had 21% fewer patient visits which did not have a letter by 90 days (OR = 5.7, p = 0.0020). Satisfaction with the system was very high. DISCUSSION: This study examines the effect of a simple reminder in absence of other interventions, and provides an example of an effective non-interruptive decision support intervention. CONCLUSION: A simple email reminder improved the number and timeliness of letters from the outpatient department to the general practitioner, and was viewed as a useful service by its users.

18F-FDG uptake in the colon is modulated by metformin but not associated with core body temperature and energy expenditure.

PURPOSE: Physiological colonic 18F-fluorodeoxyglucose (18F-FDG) uptake is a frequent finding on 18F-FDG positron emission tomography computed tomography (PET-CT). Interestingly, metformin, a glucose lowering drug associated with moderate weight loss, is also associated with an increased colonic 18F-FDG uptake. Consequently, increased colonic glucose use might partly explain the weight losing effect of metformin when this results in an increased energy expenditure and/or core body temperature. Therefore, we aimed to determine whether metformin modifies the metabolic activity of the colon by increasing glucose uptake. METHODS: In this open label, non-randomized, prospective mechanistic study, we included eight lean and eight overweight males. We measured colonic 18F-FDG uptake on PET-CT, energy expenditure and core body temperature before and after the use of metformin. The maximal colonic 18F-FDG uptake was measured in 5 separate segments (caecum, colon ascendens,-transversum,-descendens and sigmoid). RESULTS: The maximal colonic 18F-FDG uptake increased significantly in all separate segments after the use of metformin. There was no significant difference in energy expenditure or core body temperature after the use of metformin. There was no correlation between maximal colonic 18F-FDG uptake and energy expenditure or core body temperature. CONCLUSION: Metformin significantly increases colonic 18F-FDG uptake, but this increased uptake is not associated with an increase in energy expenditure or core body temperature. Although the colon might be an important site of the glucose plasma lowering actions of metformin, this mechanism of action does not explain directly any associated weight loss.

Impact of hyperglycemia on the efficacy of chemotherapy-A systematic review of preclinical studies.

BACKGROUND: Antineoplastic agents can provoke hyperglycemia in cancer patients with and without diabetes mellitus. We systematically reviewed the impact of hyperglycemia on the efficacy of chemotherapy. METHODS: MEDLINE was searched for preclinical intervention studies which compared chemotherapy response in hyperglycemic and euglycemic conditions. RESULTS: Thirteen preclinical studies, including 23 cell lines and 2 animal experiments were identified. In 14 cell lines and 2 animal studies, chemotherapy response was lower in a hyperglycemic (>15mmol/L) compared to a euglycemic environment (5mmol/L). The response was similar in 4 cell lines. In the remaining 5 cell lines, the hyperglycemic environment potentiated chemotherapy efficacy. CONCLUSION: Hyperglycemia attenuated the antiproliferative effect of chemotherapy in preclinical experiments, but the results are inconsistent. Whether hyperglycemia influences efficacy of chemotherapy in patients needs to be explored.

Hot heads & cool bodies: The conundrums of human brown adipose tissue (BAT) activity research.

Brown adipose tissue is able to increase energy expenditure by converting glucose and fatty acids into heat. Therefore, BAT is able to increase energy expenditure and could thereby facilitate weight loss or at least weight maintenance. Since cold is a strong activator of BAT, most prospective research is performed during cold to activate BAT. In current research, there are roughly two methods of cooling. Cooling by lowering ambient air temperature, which uses a fixed temperature for all subjects and personalized cooling, which uses cooling blankets or vests with temperatures that can be adjusted to the individual set point of shivering. These methods might trigger mechanistically different cold responses and hence result in a different BAT activation. This hypothesis is underlined by two studies with the same research question (difference in BAT activity between Caucasians and South Asians) one study found no differences in BAT activity whereas the other did found differences in BAT activity. Since most characteristics (e.g. age, BMI) were similar in the two studies, the best explanation for the differences in outcomes is the use of different cooling protocols. One of the reasons for differences in outcomes might be the sensory input from the facial skin, which might be important for the activation of BAT. In this review we will elaborate on the differences between the two cooling protocols used to activate BAT.

Higher glucose variability in type 1 than in type 2 diabetes patients admitted to the intensive care unit: A retrospective cohort study.

PURPOSE: Although the course of disease of type 1 and type 2 diabetes differs, the distinction is rarely made when patients are admitted to the intensive care unit (ICU). Here, we report patient- and admission-related characteristics in relation to glycemic measures of patients with type 1 and type 2 diabetes admitted to the ICU. MATERIALS AND METHODS: A retrospective chart review was performed of 1574 patients with diabetes admitted between 2004 and 2011 to our ICU. Glycemic measures included mean glucose, the incidence of hypoglycemia and hyperglycemia, percentage of glucose values in/below/above target, and glucose variability. The ICU and hospital mortality were secondary outcomes. RESULTS: We classified 2% (n=27) of patients as having type 1 diabetes and 98% (n=1547) as having type 2 diabetes. Patients with type 1 diabetes were significantly younger, had a lower body mass index, and were more frequently admitted to the ICU for medical diagnoses. No differences in glycemic measures were found, apart from a 20% higher glucose variability in the type 1 diabetes group. CONCLUSIONS: Patients with type 1 diabetes showed a higher glucose variability, but overall glycemic control was not different between patients with type 1 and type 2 diabetes. Very few diabetes patients admitted to the ICU have type 1 diabetes.

Seasonal influence on stimulated BAT activity in prospective trials: a retrospective analysis of BAT visualized on 18F-FDG PET-CTs and 123I-mIBG SPECT-CTs.

Retrospective studies have shown that outdoor temperature influences the prevalence of detectable brown adipose tissue (BAT). Prospective studies use acute cold exposure to activate BAT. In prospective studies, BAT might be preconditioned in winter months leading to an increased BAT response to various stimuli. Therefore the aim of this study was to assess whether outdoor temperatures and other weather characteristics modulate the response of BAT to acute cold. To assess metabolic BAT activity and sympathetic outflow to BAT, 64 (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) and 56 additional (123)I-meta-iodobenzylguanidine ((123)I-mIBG) single-photon emission computed tomography-CT (SPECT-CT) scans, respectively, of subjects participating in previously executed trials were retrospectively included. BAT activity was measured in subjects after an overnight fast, following 2 h of cold exposure (∼17°C). The average daytime outdoor temperatures and other weather characteristics were obtained from the Dutch Royal Weather Institute. Forty-nine subjects were BAT positive. One week prior to the scan, outdoor temperature was significantly lower in the BAT-positive group compared with the BAT-negative group. Higher outdoor temperatures on preceding days resulted in lower stimulated metabolic BAT activity and volume (all P < 0.01). Outdoor temperatures did not correlate with sympathetic outflow to BAT. In conclusion, outdoor temperatures influence metabolic BAT activity and volume, but not sympathetic outflow to BAT, in subjects exposed to acute cold. To improve the consistency of the findings of future BAT studies in humans and to exclude bias introduced by outdoor temperatures, these studies should be planned in periods of similar outdoor temperatures.

Metformin-related colonic glucose uptake; potential role for increasing glucose disposal?--A retrospective analysis of (18)F-FDG uptake in the colon on PET-CT.

AIM: The use of metformin has been associated with diffusely increased colonic (18)F-fluorodeoxyglucose ((18)F-FDG) uptake. Interestingly, metformin use is associated with moderate weight loss. It could be hypothesized that increased colonic glucose disposal is related to this weight loss. It is unknown whether other factors influence (18)F-FDG uptake in the colon. The aim of this study was to retrospectively assess independent determinants of colonic (18)F-FDG uptake. METHODS: We retrospectively analysed 270 (18)F-FDG PET-CTs which were made for diagnostic purposes. Colonic (18)F-FDG uptake was assessed using a 4-point scale using the liver as a reference (1; lower, 2; similar, 3; moderately higher than hepatic activity, 4; intense diffuse increased uptake). Determinants of (18)F-FDG uptake in the colon were assessed using forward logistic regression (i.e., grade 1&2 vs 3&4). RESULTS: The patients had a mean age of 60.2±14.8 years, a BMI of 25.8±5.2kg/m(2) and 52% were female. Most patients had a grade 2 (44%) or grade 3 (39%) (18)F-FDG uptake in the colon. Diabetes mellitus type 2 was observed in 14% of the patients. In total, 5% of the patients used insulin, 12% used metformin and 5% used sulfonylurea derivatives (SU). While there seemed to be an effect of SU on (18)F-FDG uptake in the ileum [OR 3.6 (95% CI: 1.3-33.1), p=0.03], metformin was the only drug associated with (18)F-FDG uptake for both the whole colon [OR 10.0 (95% CI: 2.9-34.7), p<0.001] and all individual segments. CONCLUSION: Metformin use is an independent determinant of increased colonic (18)F-FDG uptake, suggesting a potential role for increasing colonic glucose disposal.

Differences in Sympathetic Nervous Stimulation of Brown Adipose Tissue Between the Young and Old, and the Lean and Obese.

UNLABELLED: Brown adipose tissue (BAT) could facilitate weight loss by increasing energy expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through the sympathetic nervous system (SNS). Older or overweight individuals have less metabolic BAT activity than the lean and young, but the role of the SNS in this decline is unknown. We aimed to determine whether this lower metabolic BAT activity in older or overweight individuals can be explained by a lower SNS response to cold. METHODS: This was a prospective observational study. We included 10 young obese, 11 old lean, and 14 young lean healthy men. All subjects underwent (18)F-FDG PET/CT and (123)I-meta-iodobenzylguanidine ((123)I-mIBG) SPECT/CT after an overnight fast and 2 h of cold exposure. Metabolic BAT activity was expressed as volume and as SUVmax of (18)F-FDG. BAT SNS activity was expressed as volume and as the ratio between (123)I-mIBG uptake in BAT and a reference region (SQUVmax of (123)I-mIBG). RESULTS: SUVmax, BAT volume, and SQUVmax were significantly different between young and old (SUVmax, 7.9 [range, 4.2-17.3] vs. 2.9 [range, 0.0-4.0]; volume, 124.8 [range, 10.9-338.8] vs. 3.4 [range, 0.0-10.9]; and SQUVmax, 2.7 [range, 1.9-4.7] vs. 0.0 [range, 0.0-2.2], respectively) (all P < 0.01) but not between lean and obese (SUVmax, 7.9 [range, 4.2-17.3] vs. 4.0 [range, 0.0-13.5] [P = 0.69]; volume, 124.8 [range, 10.9-338.8] vs. 11.8 [range, 0.0-190.2] [P = 0.64]; and SQUVmax, 2.7 [range, 1.9-4.7] vs. 1.7 [range, 0-3.5] [P = 0.69], respectively). We found a strong positive correlation between BAT activity measured with (18)F-FDG and (123)I-mIBG in the whole group of BAT-positive subjects (ρ = 0.82, P < 0.01). CONCLUSION: Both sympathetic drive and BAT activity are lower in older but not in obese men.

Interobserver and intraobserver variability for the assessment of brown adipose tissue activity on 18F-FDG PET-CT.

OBJECTIVE: Measurement of brown adipose tissue (BAT) activity is the focus of intensive research, among others as a potential target for weight-lowering strategies. In this, BAT activity is visualized and quantified using F-fluorodeoxyglucose (F-FDG) PET-CT. The aim of this study was to determine the interobserver and intraobserver variability for detecting and quantifying BAT on F-FDG PET-CTs. METHODS: Three observers retrospectively independently assessed 55 F-FDG PET-CTs (performed between April 2013 and January 2014) for BAT activity parameters: BAT volume, the maximal and mean standardized uptake value (SUVmax and SUVmean) obtained in healthy male controls. One observer reassessed the scans after 2 months for the intraobserver variability. Interobserver and intraobserver variability were expressed using Lin's concordance coefficient (LCC) and Bland-Altman plots. Correlations between the three parameters were assessed using Spearman's correlation. RESULTS: The LCCs for the interobserver and intraobserver concordance for SUVmax were the highest (LCC SUVmax varied between 0.998 and 0.999, for SUVmean between 0.989 and 0.991 and for volume between 0.947 and 0.972). The Bland-Altman analysis showed a small absolute mean difference between all observers for both SUVmax and SUVmean, but the differences for volume were markedly higher. All parameters correlated statistically strongly and positively. CONCLUSION: The SUVmax showed the lowest interobserver and intraobserver variation. Although SUVmean and BAT volume had a higher interobserver and intraobserver variation, the variation is still within acceptable limits. Therefore, all parameters can be used to describe BAT activity. However, for an adequate comparison between studies, we recommend the use of SUVmax.

Lowering blood glucose during hip surgery does not influence coagulation activation.

BACKGROUND: Hyperglycaemia during and after hip surgery is associated with coagulation activation and an increased risk of venous thromboembolism. Whether lowering of glucose levels during hip surgery diminishes coagulation activation is unknown. We investigated the efficacy of the human GLP-1 analogue liraglutide to lower glucose during and after hip surgery and studied its influence on coagulation activation. METHODS: A total of 37 obese subjects who underwent hip surgery were randomized to subcutaneous liraglutide or placebo for 4 consecutive days, starting one day prior to surgery. Glucose levels and coagulation indices at three fixed time-points (pre-operative, 2 h post-operative and 3 days post-operative) were measured. RESULTS: Liraglutide reduced glucose at day three post-surgery (median glucose (IQR) liraglutide 5.5 (5.2-5.7) vs. placebo 5.8 (5.5-6.2); difference 0.3 mmol/L, P = 0.04). Changes in 6 out of 8 coagulation indices studied did not differ between the two groups. Only D-dimer levels were significantly lower in the liraglutide group at day three post-surgery and FVIII levels were significantly higher in the liraglutide group 2 h post-surgery. CONCLUSION: Although the human GLP-1 analogue liraglutide moderately reduced post-operative blood glucose levels in non-diabetic and prediabetic obese patients undergoing elective hip surgery, no changes were observed with respect to coagulation activation.

Oral health information from the dentist to the diabetologist.

BACKGROUND: Diabetes care includes annual evaluation of micro- and macrovascular complications, however, oral pathologies are not included. We studied retrieving oral health information, in particular periodontal disease, from the dentist and studied the association between the reported periodontal condition and variables of both diabetes and dental care. METHODS: During their annual comprehensive diabetes evaluation, patients were asked to deliver an oral health questionnaire (OHQ) to their dentist. Based on the returned OHQs, the process of retrieving oral health information from the dentist was analyzed. In addition, reported oral health measures with special emphasis to periodontitis, using a Periodontal Screening Index (PSI), were related to diabetes-related variables. RESULTS: We included 889 patients of whom 102 patients (11%) did not visit a dentist at all and 252 (28%) were edentulous. The response rate was <50% for oral information on patients with diabetes. For the second aim, OHQs of 207 patients could be further analyzed. A moderate to high PSI-score was found in 106 patients, of whom 65% were untreated for periodontitis. Furthermore high PSI-scores were associated with poor oral hygiene, soft tissue pathologies and periodontal treatment, but not significantly with glycemic control and presence of diabetes complications. CONCLUSION: The transfer of information from the dentist to the diabetologist is far from optimal. An OHQ can be a valuable tool for the identification of patients with diabetes with poor oral health especially untreated periodontal disease, which is helpful for proper diabetes management.

(18)F-fluorodeoxyglucose uptake in brown adipose tissue during insulin-induced hypoglycemia and mild cold exposure in non-diabetic adults.

OBJECTIVE: Hypoglycemia is associated with increased heat production and, despite of this, hypothermia. Heat production is likely to be mediated by sympathetic innervation. Brown adipose tissue is activated by cold exposure and stimulated by the sympathetic nervous system. We therefore examined the effect of hypoglycemia on uptake of the labeled glucose analogue (18)F-fluorodeoxyglucose in brown adipose tissue using positron emission tomography and computer tomography. METHODS: In nine healthy adults (18)F-fluorodeoxyglucose uptake as measure of brown adipose tissue activity was assessed in a cold environment (17 °C) during euglycemia (blood glucose 4.5 mmol/L) and hypoglycemia (2.5 mmol/L) using a hyperinsulinemic glucose clamp. RESULTS: Brown adipose tissue activity was observed in all participants. No difference was observed in the median (range) maximal standardized uptake values of (18)F-fluorodeoxyglucose in brown adipose tissue between euglycemia and hypoglycemia: 4.2 (1.0-7.7) versus 3.1 (2.2-12.5) g/mL (p=0.7). Similarly there were no differences in mean standardized (18)F-fluorodeoxyglucose uptake values or total brown adipose tissue volume between euglycemia and hypoglycemia. Body temperature dropped by 0.6 °C from baseline during the hypoglycemic condition and remained unchanged during the euglycemic condition. There was no correlation between the maximal standardized uptake values of (18)F-fluorodeoxyglucose in brown adipose tissue and levels of counterregulatory hormones. CONCLUSIONS: This study shows that there is a similar amount of (18)F-fluorodeoxyglucose uptake in brown adipose tissue during hypoglycemia when compared to euglycemia, which makes a role for systemic catecholamines in brown adipose tissue activation and a role for brown adipose tissue thermogenesis in hypoglycemia associated hypothermia unlikely. Future studies in humans should determine whether hypoglycemia indeed increases energy expenditure, and if so which alternative source can explain this increase.

[Doctoral research by physicians: it goes without saying!]. / Promotieonderzoek door medici: vanzelfsprekend!

It is important that junior doctors in training conduct research for a number of years, culminating in a PhD. This is crucial to their development as critical and versatile doctors, which is exactly what is required now, in 2014. Hospitals are keen to have doctors with a broad education, and conducting scientific research is an enrichment for the investigators themselves. It is not necessarily undesirable that they do this principally to increase their chances of trainee posts; even those who have almost completed a PhD can be rejected for trainee positions if they do not seem to be competent.

[Complaint to the disciplinary board about a resident]. / Een klacht bij het tuchtcollege tegen een aios.

We describe the course of two complaints that were filed by patients to the Dutch Medical Disciplinary Board against two internal medicine residents. In the procedure following the complaints the supervisor and the teacher were actively involved, which resulted in one complaint being dropped. We describe the importance of adequate moral support in such cases, as the complaint may lead to loss of work satisfaction or self-esteem, especially for those in training. We make some recommendations on how the resident and the supervisor/head of the department should engage in complaints filed to the Medical Disciplinary Board. In addition, we suggest that routine 'error-meetings' may help to provide an open atmosphere where disclosure of errors and the various procedures at the hospital or disciplinary boards are promoted.

Feasibility of a portable bihormonal closed-loop system to control glucose excursions at home under free-living conditions for 48 hours.

BACKGROUND: This study assessed the feasibility of a portable bihormonal closed-loop system at home. SUBJECTS AND METHODS: Sixteen pump-treated patients with type 1 diabetes received 48 h of closed-loop therapy with a telemonitored insulin- and glucagon-delivering closed-loop system and 48 h of patient-managed open-loop therapy. RESULTS: Owing to technical problems in five cases, only 11 patients could be analyzed. Whereas median (interquartile range) glucose levels were not significantly different during Day 1 of open-loop control (OL1) from closed-loop control (CL1) (8.27 [0.83] mmol/L vs. 8.84 [1.47] mmol/L; P=0.206), they were significantly lower during Day 2 of closed-loop control (CL2) versus open-loop control (OL2) (7.70 [2.29] mmol/L vs. 8.84 [0.87] mmol/L; P=0.027). Time spent in euglycemia (3.9-10 mmol/L) was comparable with 67.2% (38.5%) in OL1 versus 79.2% (16.9%) in CL1 (P=0.189) and 66.0% (29.8%) in OL2 versus 76.5% (23.9%) in CL2 (P=0.162). Time spent in hypoglycemia (<3.9 mmol/L) was comparable on Day 1 of control (OL1, 0.68% [8.68%]; CL1, 2.08% [7.61%]; P=0.593) but significantly higher during Day 2 of control (OL2, 0.00% [11.07%]; CL2, 2.8% [9.8%]; P=0.0172) (P=0.017). CONCLUSIONS: Bihormonal closed-loop control is feasible at home, with comparable time in euglycemia to open-loop control and significantly lower median glucose levels on Day 2 of control at the expense of more time in hypoglycemia, albeit still at a very low percentage of time.