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.

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.

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.

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).

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).

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.

Hyposplenism: comparison of different methods for determining splenic function.

Asplenic patients are at risk for pneumococcal sepsis. Patients with hyposplenic function, such as associated with sickle cell disease (SCD), are also at risk. However, tests to assess splenic function are either unavailable or lacking standardization. The aim of this study was to compare different methods for determining splenic function. Eighteen patients with SCD (i.e., 10 heterozygous (SC) and 8 homozygous (SS) SCD patients), and eight splenectomized patients were compared to 10 controls. All subjects underwent spleen scintigraphy, after which functional splenic volumes (FSV) were calculated. FSV was compared to immunological function and B cell-subsets, as well as phagocytic function represented by the presence of Howell Jolly bodies (HJB) and percentages of pitted red cells (PIT). Heterozygous SCD (SC) patients had increased splenic volumes, but diminished FSV, homozygous SCD (SS) patients were asplenic. Splenectomized and SS patients had a strongly reduced phagocytic and immunological function. SC patients had reduced anti-polysaccharide responses without an increase in PIT. FSV correlated significantly with phagocytic and immunological function. HJB were indicative of splenic dysfunction, HJB absence was not indicative of normal functioning splenic tissue. Although visualizing HJB is methodologically advantageous to PIT, both are valid biomarkers of splenic dysfunction. The amount of non-switched memory B cells is strongly correlated to FSV.

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.

Early postoperative hyperglycemia is associated with postoperative complications after pancreatoduodenectomy.

OBJECTIVE: To investigate the relation between perioperative hyperglycemia and complications after pancreatoduodenectomy. BACKGROUND: Perioperative hyperglycemia is associated with complications after various types of surgery. This relation was never investigated for pancreatoduodenectomy. METHODS: In a consecutive series of 330 patients undergoing pancreatoduodenectomy, glucose values were collected from the hospital information system during 3 periods: pre-, intra-, and early postoperative. The average glucose value per period was calculated for each patient and divided in duals according to the median group value. Odds ratios for complications were calculated for the upper versus lower dual, adjusted for age, sex, American Society of Anesthesiologists Classification, body mass index, diabetes mellitus, intraoperative blood transfusion, duration of surgery, intraoperative insulin administration, and octreotide use. The same procedures were carried out to assess the consequences of increased glucose variability, expressed by the standard deviation. RESULTS: Average glucose values were 135 (preoperative), 133 (intraoperative) and 142 mg/dL (early postoperative). Pre- and intraoperative glucose values were not associated with postoperative complications. Early postoperative hyperglycemia (≥140 mg/dL) was significantly associated with complications [odds ratio (OR) 2.9, 95% confidence interval (CI), 1.7-4.9]. Overall, high glucose variability was not significantly associated with postoperative complications, but early postoperative patients who had both high glucose values and high variability had an OR for complications of 3.6 (95% CI, 1.9-6.8) compared to the lower glucose dual. CONCLUSIONS: Early postoperative hyperglycemia is associated with postoperative complications after pancreatoduodenectomy. High glucose variability may enhance this risk. Future research must demonstrate whether strict glucose control in the early postoperative period prevents complications after pancreatoduodenectomy.

The effect of diabetes on mortality in critically ill patients: a systematic review and meta-analysis.

INTRODUCTION: Critically ill patients with diabetes are at increased risk for the development of complications, but the impact of diabetes on mortality is unclear. We conducted a systematic review and meta-analysis to determine the effect of diabetes on mortality in critically ill patients, making a distinction between different ICU types. METHODS: We performed an electronic search of MEDLINE and Embase for studies published from May 2005 to May 2010 that reported the mortality of adult ICU patients. Two reviewers independently screened the resultant 3,220 publications for information regarding ICU, in-hospital or 30-day mortality of patients with or without diabetes. The number of deaths among patients with or without diabetes and/or mortality risk associated with diabetes was extracted. When only crude survival data were provided, odds ratios (ORs) and standard errors were calculated. Data were synthesized using inverse variance with ORs as the effect measure. A random effects model was used because of anticipated heterogeneity. RESULTS: We included 141 studies comprising 12,489,574 patients, including 2,705,624 deaths (21.7%). Of these patients, at least 2,327,178 (18.6%) had diabetes. Overall, no association between the presence of diabetes and mortality risk was found. Analysis by ICU type revealed a significant disadvantage for patients with diabetes for all mortality definitions when admitted to the surgical ICU (ICU mortality: OR [95% confidence interval] 1.48 [1.04 to 2.11]; in-hospital mortality: 1.59 [1.28 to 1.97]; 30-day mortality: 1.62 [1.13 to 2.34]). In medical and mixed ICUs, no effect of diabetes on all outcomes was found. Sensitivity analysis showed that the disadvantage in the diabetic surgical population was attributable to cardiac surgery patients (1.77 [1.45 to 2.16], P < 0.00001) and not to general surgery patients (1.21 [0.96 to 1.53], P = 0.11). CONCLUSIONS: Our meta-analysis shows that diabetes is not associated with increased mortality risk in any ICU population except cardiac surgery patients.

Hypoglycemia is associated with intensive care unit mortality.

OBJECTIVE: The implementation of intensive insulin therapy in the intensive care unit is accompanied by an increase in hypoglycemia. We studied the relation between hypoglycemia on intensive care unit mortality, because the evidence on this subject is conflicting. DESIGN: Retrospective database cohort study. SETTING: An 18-bed medical/surgical intensive care unit in a teaching hospital (Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, The Netherlands). PATIENTS: A total of 5961 patients admitted to from 2004 to 2007 were analyzed. Readmissions and patients with a withholding care policy or with hypoglycemia on the first glucose measurement were excluded. Patients were treated with a computerized insulin algorithm (target glucose range, 72-126 mg/dL). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All first episodes of hypoglycemia (glucose < or =45 mg/dL) were derived from 154,015 glucose values. Using Poisson regression, the incidence rates for intensive care unit death and incidence rate ratio comparing exposure and nonexposure to hypoglycemia were calculated. Patients were considered to be exposed to hypoglycemia from the event until the end of intensive care unit admittance. We corrected for severity of disease using the daily Sequential Organ Failure Assessment score. Age, sex, cardiothoracic surgery, sepsis, and diabetes mellitus were also included as possible confounders. Two hundred eighty-eight (4.8%) patients experienced at least one episode of hypoglycemia. Median age was 68 yrs (range, 58-75 yrs), 66% were male, and 6.4% died in the intensive care unit. The incidence rate of death in patients exposed to hypoglycemia was 40 per 1000 intensive care unit days compared with 17 per 1000 intensive care unit days in patients without exposure. The adjusted incidence rate ratio for intensive care unit death was 2.1 (95% confidence interval, 1.6-2.8; p < .001). CONCLUSIONS: Hypoglycemia is related to intensive care unit mortality, also when adjusted for a daily adjudicated measure of disease severity, indicating the possibility of a causal relationship.

No apparent impact of increased post-operative blood glucose levels on clinical outcome in kidney transplant recipients.

BACKGROUND: Our objective is to evaluate whether hyperglycemia in the first 48 h after renal transplantation is independently associated with rejection, post-operative infection and post-transplant diabetes mellitus (PTDM) in a retrospective cohort study. METHODS: Patients who received a renal transplant in our hospital in 2003 or 2004 were included. Glucose values until 48 h after surgery were retrieved from laboratory reports. Biopsy proven acute rejection, culture proven infections and PTDM were scored until four months after transplantation. Data were analyzed using univariate analysis and logistic multivariate analysis. RESULTS: At least one post-operative glucose value could be retrieved for 150/151 patients. Rejection occurred in 46/150 (30.5%), infection in 47/150 (31.1%) and PTDM in 19/150 (12.6%) patients. When corrected for other risk factors, no relation was found between post-operative glucose levels and rejection (weak inverse relation, OR = 0.82; 95% CI = 0.65-1.03; p = 0.09), post-operative glucose and infections (OR = 0.98; 95% CI = 0.80-1.21; p = 0.84) and post-operative glucose and PTDM (OR = 0.93; 95% CI = 0.70-1.23; p = 0.63). CONCLUSION: Increased post-operative blood glucose levels after renal transplantation were not found to be a risk factor for graft rejection. Also, post-operative glucose levels were not found to be associated with PTDM and post-operative infections.

High incidence of type 1 diabetes mellitus during or shortly after treatment with pegylated interferon alpha for chronic hepatitis C virus infection.

BACKGROUND: Development of diabetes mellitus (DM) during or shortly after treatment with interferon alpha (IFN-alpha) in patients with chronic hepatitis C virus (HCV) infection has been reported sporadically. We prospectively screened for DM during and after IFN-alpha therapy for chronic HCV infection. METHODS: Blood glucose levels of patients with chronic HCV infection were routinely assessed at all outpatient visits during and after treatment with pegylated-IFN-alpha (Peg-IFN-alpha) and ribavirin (Riba). RESULTS: Between December 2002 and October 2005, 189 non-diabetic patients were treated with Peg-IFN-alpha/Riba, of whom five developed type 1 DM (2.6%), three type 2 DM (1.6%) and one an indeterminate type of DM. Classical symptoms of DM were present in three patients who developed DM shortly after cessation of Peg-IFN-alpha/Riba. In the other patients, symptoms of DM were either indistinguishable from side effects caused by Peg-IFN-alpha/Riba or absent. CONCLUSION: Our study showed a high incidence of type 1 DM during Peg-IFN-alpha/Riba therapy for chronic HCV infection. Symptoms of DM may be absent or mistaken for Peg-IFN-alpha/Riba-associated side effects. To diagnose DM without delay, we propose routine assessment of blood glucose at all outpatient visits during and after Peg-IFN-alpha/Riba treatment in chronic HCV patients.

Hypoglycemia and strict glycemic control in critically ill patients.

PURPOSE OF REVIEW: In contrast to patients with diabetes mellitus, data on consequences of hypoglycemia in critically ill patients are sparse. The purpose of this review is to summarize available data on prevalence of hypoglycemia, risk factors, and possible consequences of hypoglycemia in critically ill patients. RECENT FINDINGS: There is strong evidence that strict glycemic control is beneficial for critically ill patients. Recent attempts to confirm these findings have not succeeded. Instead, they have increased the fear for negative consequences of hypoglycemia. Hypoglycemia is four to seven times more frequent in patients treated with strict glycemic control. Risk factors for hypoglycemia are a change in nutrition without adjustment of insulin treatment, diabetes mellitus, sepsis, shock, liver failure, and the need for renal replacement therapy. Consequences of hypoglycemia in critically ill patients are not well defined, but overall current evidence suggests that beneficial effects of strict glycemic control outweigh possible negative effects of hypoglycemia. SUMMARY: Hypoglycemia should be avoided in critically ill patients, but not at the cost of less stringent glycemic control. Strict glycemic control with a low incidence of hypoglycemia can be achieved with a validated (computerized) algorithm and increased surveillance in patients with an increased risk for hypoglycemia.

Prevalence of diabetes mellitus and the performance of a risk score among Hindustani Surinamese, African Surinamese and ethnic Dutch: a cross-sectional population-based study.

BACKGROUND: While the prevalence of type 2 diabetes mellitus (DM) is high, tailored risk scores for screening among South Asian and African origin populations are lacking. The aim of this study was, first, to compare the prevalence of (known and newly detected) DM among Hindustani Surinamese, African Surinamese and ethnic Dutch (Dutch). Second, to develop a new risk score for DM. Third, to evaluate the performance of the risk score and to compare it to criteria derived from current guidelines. METHODS: We conducted a cross-sectional population based study among 336 Hindustani Surinamese, 593 African Surinamese and 486 Dutch, aged 35-60 years, in Amsterdam. Logistic regressing analyses were used to derive a risk score based on non-invasively determined characteristics. The diagnostic accuracy was assessed by the area under the Receiver-Operator Characteristic curve (AUC). RESULTS: Hindustani Surinamese had the highest prevalence of DM, followed by African Surinamese and Dutch: 16.7, 8.1, 4.2% (age 35-44) and 35.0, 19.0, 8.2% (age 45-60), respectively. The risk score included ethnicity, body mass index, waist circumference, resting heart rate, first-degree relative with DM, hypertension and history of cardiovascular disease. Selection based on age alone showed the lowest AUC: between 0.57-0.62. The AUC of our score (0.74-0.80) was higher than that of criteria from guidelines based solely on age and BMI and as high as criteria that required invasive specimen collection. CONCLUSION: In Hindustani Surinamese and African Surinamese populations, screening for DM should not be limited to those over 45 years, as is advocated in several guidelines. If selective screening is indicated, our ethnicity based risk score performs well as a screening test for DM among these groups, particularly compared to the criteria based on age and/or body mass index derived from current guidelines.

Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes.

Chronic hyperglycemia underlies microvascular complications in patients with type 1 diabetes. The mechanisms leading to these vascular complications are not fully understood. Recently, we observed that acute hyperglycemia results in endothelial glycocalyx damage. To establish whether glycocalyx is associated with microvascular damage, we performed glycocalyx perturbation volume measurements in type 1 diabetic patients with microalbuminuria (DM1-MA group; n = 7), without microalbuminuria (DM1-NA group; n = 7), and in age-matched control subjects (CON; n = 7). Systemic glycocalyx volume was determined comparing intravascular distribution volume of a glycocalyx-permeable tracer (dextran 40) to that of a glycocalyx-impermeable tracer (labeled erythrocytes). Sublingual capillaries were visualized using orthogonal polarization spectral microscopy to estimate microvascular glycocalyx. Patients and control subjects were matched according to age and BMI. Glycocalyx volume decreased in a stepwise fashion from CON, DM1-NA, and finally DM1-MA subjects (1.5 +/- 0.1, 0.8 +/- 0.4, and 0.2 +/- 0.1 l, respectively, P < 0.05). Microvascular glycocalyx in sublingual capillaries was also decreased in type 1 diabetes versus the control group (0.5 +/- 0.1 vs. 0.9 +/- 0.1 microm, P < 0.05). Plasma hyaluronan, a principal glycocalyx constituent, and hyaluronidase were increased in type 1 diabetes. In conclusion, type 1 diabetic patients are characterized by endothelial glycocalyx damage, the severity of which is increased in presence of microalbuminuria.

Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo.

Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability. The systemic glycocalyx volume was estimated by comparing the distribution volume of a glycocalyx permeable tracer (dextran 40) with that of a glycocalyx impermeable tracer (labeled erythrocytes) in 10 healthy male subjects. Measurements were performed in random order on five occasions: two control measurements, two measurements during normoinsulinemic hyperglycemia with or without N-acetylcysteine (NAC) infusion, and one during mannitol infusion. Glycocalyx measurements were reproducible (1.7 +/- 0.2 vs. 1.7 +/- 0.3 l). Hyperglycemia reduced glycocalyx volume (to 0.8 +/- 0.2 l; P < 0.05), and NAC was able to prevent the reduction (1.4 +/- 0.2 l). Mannitol infusion had no effect on glycocalyx volume (1.6 +/- 0.1 l). Hyperglycemia resulted in endothelial dysfunction, increased plasma hyaluronan levels (from 70 +/- 6 to 112 +/- 16 ng/ml; P < 0.05) and coagulation activation (prothrombin activation fragment 1 + 2: from 0.4 +/- 0.1 to 1.1 +/- 0.2 nmol/l; d-dimer: from 0.27 +/- 0.1 to 0.55 +/- 0.2 g/l; P < 0.05). Taken together, these data indicate a potential role for glycocalyx perturbation in mediating vascular dysfunction during hyperglycemia.

Relationship between interstitial and blood glucose in type 1 diabetes patients: delay and the push-pull phenomenon revisited.

BACKGROUND: Interpretation of glucose sensor results requires clarification of the relationship between interstitial (IG) and blood (BG) glucose. We examined the delay of IG upon BG change and reinvestigated the push-pull phenomenon in type 1 diabetes patients. The push-pull phenomenon postulates that IG shows a delayed increase but earlier decrease compared to BG. If so, postprandial sensor curves should have narrower peak widths than BG curves. METHODS: For both sensors a two-point calibration procedure was used. Delay was assessed by shifting combined fitted postprandial glucose sensor curves horizontally. The sensor and BG peak widths of the separately fitted curves were assessed and compared. Peak width was re-assessed for the microdialysis sensor using raw current values to rule out any calibration effect on the shape of the curve. The contribution of instrumental delay to the earlier reported 7.1-min delay of the microdialysis sensor was calculated. RESULTS: No delay [-2.2 +/- 6.2 (SD) min] was seen for the needle-type sensor. Instrumental delay was >6.2 min for the microdialysis sensor, accounting for more than 87% of the total reported delay of 7.1 +/- 5.5 min. Mean peak width for the BG curves was 100.8 +/- 25.0 min, for the needle-type sensor curves 110.0 +/- 20.5 min, and for the microdialysis sensor curves 104.6 +/- 21.7 min (P = 0.052 and P = 0.11 vs. BG, respectively). Mean peak width for the uncalibrated microdialysis current values was 105.0 +/- 23.1 min, which was not different from the peak width of the BG curves (P = 0.347). CONCLUSIONS: IG-BG delay may be smaller than previously postulated. The sensor curves tended to have broader peaks than the BG curves, in contrast to the expected narrower peaks predicted by the push-pull phenomenon. This argues against the existence of the push-pull phenomenon.

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.