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.

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.

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.

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.

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.

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).

[Lifestyle-recommendations on weight loss in type 2 diabetes--useful, or not?]. / Leefstijladvies over afvallen bij diabetes type 2--zinvol of niet?

Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but the long-term effects of weight loss on cardiovascular disease are unknown. The recently published Look AHEAD (Action for health in diabetes) study investigated the 10-year effect of an intensive lifestyle intervention designed to achieve weight loss on cardiovascular morbidity and mortality among overweight or obese adults with type 2 diabetes. In this commentary, we discuss the results and clinical implications of this study.

Microcirculation and its relation to continuous subcutaneous glucose sensor accuracy in cardiac surgery patients in the intensive care unit.

OBJECTIVE: Continuous glucose monitoring could be helpful for glucose regulation in critically ill patients; however, its accuracy is uncertain and might be influenced by microcirculation. We investigated the microcirculation and its relation to the accuracy of 2 continuous glucose monitoring devices in patients after cardiac surgery. METHODS: The present prospective, observational study included 60 patients admitted for cardiac surgery. Two continuous glucose monitoring devices (Guardian Real-Time and FreeStyle Navigator) were placed before surgery. The relative absolute deviation between continuous glucose monitoring and the arterial reference glucose was calculated to assess the accuracy. Microcirculation was measured using the microvascular flow index, perfused vessel density, and proportion of perfused vessels using sublingual sidestream dark-field imaging, and tissue oxygenation using near-infrared spectroscopy. The associations were assessed using a linear mixed-effects model for repeated measures. RESULTS: The median relative absolute deviation of the Navigator was 11% (interquartile range, 8%-16%) and of the Guardian was 14% (interquartile range, 11%-18%; P = .05). Tissue oxygenation significantly increased during the intensive care unit admission (maximum 91.2% [3.9] after 6 hours) and decreased thereafter, stabilizing after 20 hours. A decrease in perfused vessel density accompanied the increase in tissue oxygenation. Microcirculatory variables were not associated with sensor accuracy. A lower peripheral temperature (Navigator, b = -0.008, P = .003; Guardian, b = -0.006, P = .048), and for the Navigator, also a higher Acute Physiology and Chronic Health Evaluation IV predicted mortality (b = 0.017, P < .001) and age (b = 0.002, P = .037) were associated with decreased sensor accuracy. CONCLUSIONS: The results of the present study have shown acceptable accuracy for both sensors in patients after cardiac surgery. The microcirculation was impaired to a limited extent compared with that in patients with sepsis and healthy controls. This impairment was not related to sensor accuracy but the peripheral temperature for both sensors and patient age and Acute Physiology and Chronic Health Evaluation IV predicted mortality for the Navigator were.

Safety and usability evaluation of a web-based insulin self-titration system for patients with type 2 diabetes mellitus.

OBJECTIVE: The rising incidence of type 2 diabetes mellitus (T2DM) induces severe challenges for the health care system. Our research group developed a web-based system named PANDIT that provides T2DM patients with insulin dosing advice using state of the art clinical decision support technology. The PANDIT interface resembles a glucose diary and provides advice through pop-up messages. Diabetes nurses (DNs) also have access to the system, allowing them to intervene when needed. The objective of this study was to establish whether T2DM patients can safely use PANDIT at home. To this end, we assessed whether patients experience usability problems with a high risk of compromising patient safety when interacting with the system, and whether PANDIT's insulin dosing advice are clinically safe. RESEARCH DESIGN AND METHODS: The study population consisted of patients with T2DM (aged 18-80) who used a once daily basal insulin as well as DNs from a university hospital. The usability evaluation consisted of think-aloud sessions with four patients and three DNs. Video data, audio data and verbal utterances were analyzed for usability problems encountered during PANDIT interactions. Usability problems were rated by a physician and a usability expert according to their potential impact on patient safety. The usability evaluation was followed by an implementation with a duration of four weeks. This implementation took place at the patients' homes with ten patients to evaluate clinical safety of PANDIT advice. PANDIT advice were systematically compared with DN advice. Deviating advice were evaluated with respect to patient safety by a panel of experienced physicians, which specialized in diabetes care. RESULTS: We detected seventeen unique usability problems, none of which was judged to have a high risk of compromising patient safety. Most usability problems concerned the lay-out of the diary, which did not clearly indicate which data entry fields had to be entered in order to obtain an advice. 27 out of 74 (36.5%) PANDIT advice differed from those provided by DNs. However, only one of these (1.4%) was considered unsafe by the panel. CONCLUSION: T2DM patients with no prior experience with the web-based self-management system were capable of consulting the system without encountering significant usability problems. Furthermore, the large majority of PANDIT advice were considered clinically safe according to the expert panel. One advice was considered unsafe. This could however easily be corrected by implementing a small modification to the system's knowledge base.

The effect of diabetes mellitus on the association between measures of glycaemic control and ICU mortality: a retrospective cohort study.

INTRODUCTION: In critical illness, four measures of glycaemic control are associated with ICU mortality: mean glucose concentration, glucose variability, the incidence of hypoglycaemia (≤2.2 mmol/l) or low glucose (2.3 to 4.7 mmol/l). Underlying diabetes mellitus (DM) might affect these associations. Our objective was to study whether the association between these measures of glycaemic control and ICU mortality differs between patients without and with DM and to explore the cutoff value for detrimental low glucose in both cohorts. METHODS: This retrospective database cohort study included patients admitted between January 2004 and June 2011 to a 24-bed medical/surgical ICU in a teaching hospital. We analysed glucose and outcome data from 10,320 patients: 8,682 without DM and 1,638 with DM. The cohorts were subdivided into quintiles of mean glucose and quartiles of glucose variability. Multivariable regression models were used to examine the independent association between the four measures of glycaemic control and ICU mortality, and for defining the cutoff value for detrimental low glucose. RESULTS: Regarding mean glucose, a U-shaped relation was observed in the non-DM cohort with an increased ICU mortality in the lowest and highest glucose quintiles (odds ratio=1.4 and 1.8, P<0.001). No clear pattern was found in the DM cohort. Glucose variability was related to ICU mortality only in the non-DM cohort, with highest ICU mortality in the upper variability quartile (odds ratio=1.7, P<0.001). Hypoglycaemia was associated with ICU mortality in both cohorts (odds ratio non-DM=2.5, P<0.001; odds ratio DM=4.2, P=0.001), while low-glucose concentrations up to 4.9 mmol/l were associated with an increased risk of ICU mortality in the non-DM cohort and up to 3.5 mmol/l in the DM cohort. CONCLUSION: Mean glucose and high glucose variability are related to ICU mortality in the non-DM cohort but not in the DM cohort. Hypoglycaemia (≤2.2 mmol/l) was associated with ICU mortality in both. The cutoff value for detrimental low glucose is higher in the non-DM cohort (4.9 mmol/l) than in the DM cohort (3.5 mmol/l). While hypoglycaemia (≤2.2 mmol/l) should be avoided in both groups, DM patients seem to tolerate a wider glucose range than non-DM patients.

Feasibility of a bihormonal closed-loop system to control postexercise and postprandial glucose excursions.

BACKGROUND: The aim of this pilot study was to test the feasibility of a bihormonal (glucagon and insulin) closed-loop (CL) system by challenging the system with two meals and 30 min exercise. METHODS: Ten patients with type 1 diabetes treated with continuous subcutaneous insulin infusion underwent a standardized protocol on three different occasions: 40 g carbohydrate breakfast followed 2 h later by 30 min of moderate-intensity exercise, followed 1.5 h later by a standardized 60 g carbohydrate lunch. An open-loop (OL) day served as control, the first CL day as tuning experiment, and the second CL day to compare with OL. RESULTS: The overall mean venous glucose was similar: 9 (5.4-13.5) mmol/liter in OL versus 8.7 (6.4-11.0) mmol/liter in CL, p = .74. The postbreakfast glucose concentrations tended to be lower in OL than in CL [9.5 (4.3-13.3) versus 11.4 (7-16.2) mmol/liter; p = .07] and higher in OL than in CL postlunch [9.4 (6.0-14.9) versus 7.7 (5.5-9.0) mmol/liter,p = .15]. The postexercise glucose concentrations were similar in OL and CL: 7.5 (4.6-13) versus 8.2 (5.5-13.1) mmol/liter; p = .45. In those patients coming in with baseline glucose above 7 mmol/liter, there was initial overinsulinization in CL. During OL, two hypoglycemic episodes occurred compared with four hypoglycemic episodes in three participants during CL. Glucagon seemed mostly effective in preventing hypoglycemia. CONCLUSIONS: Overall, CL glucose control was comparable to OL control, but there was overinsulinization in those patients with baseline glucose above 7 mmol/liter.

Formative usability evaluation of a web-based insulin self-titration system: preliminary results.

We developed a web-based system supporting patients in insulin self-titration and their caregivers in monitoring patients' self-management activities. Since usability flaws could cause user attrition and compromise patient safety, we evaluated the system's usability prior to its implementation in practice. Two pairs of researchers conducted cognitive walkthrough sessions and identified 81 unique usability problems, including four with a potential impact on patient safety. Usability evaluations could reveal many usability problems and allow solving the problems while avoiding user attrition and potential adverse patient events.

Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.

Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 µmol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota. Intestinal microbiota might be developed as therapeutic agents to increase insulin sensitivity in humans; www.trialregister.nl; registered at the Dutch Trial Register (NTR1776).