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Aims: To determine the effects of glucagon-like peptide (GLP)-1 receptor agonists (RA) on uric acid (UA) levels and kidney UA clearance. Material and methods: This study involved post-hoc analyses of 4 controlled clinical trials, which assessed actions of GLP-1RA administration on kidney physiology. The immediate effects of GLP-1RA exenatide infusion vs placebo were determined in 9 healthy overweight men (Study-A) and in 52 overweight T2DM patients (Study-B). The effects of 12 weeks of long-acting GLP-1RA liraglutide vs placebo in 36 overweight T2DM patients (Study-C) and of 8 weeks of short-acting GLP-1RA lixisenatide vs once-daily titrated insulin glulisine in 35 overweight T2DM patients (Study-D) were also examined. Plasma UA, fractional (inulin-corrected) and absolute urinary excretion of UA (UEUA) and sodium (UENa), and urine pH were determined. Results: Median baseline plasma UA level was 5.39 to 6.33 mg/dL across all studies (17%-22% of subjects were hyperuricaemic). In Study-A, exenatide infusion slightly increased plasma UA (+0.07 ± 0.02 mg/dL, P =.04), and raised absolute-UEUA (+1.58 ± 0.65 mg/min/1.73 m2, P =.02), but did not affect fractional UEUA compared to placebo. Fractional UEUA and absolute UEUA correlated with increases in urine pH (r:0.86, P =.003 and r:0.92, P

Aim Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1RA) is consistently associated with heart rate (HR) acceleration in type 2 diabetes patients. We explored the mechanisms underlying this potential safety concern. Methods Ten healthy overweight males (aged 20–27 years) were examined in an open label, crossover study. Automated oscillometric blood pressure measurements and finger photoplethysmography were performed throughout intravenous administration of placebo (saline 0.9%), exenatide (targeting therapeutic concentrations) and a combination of exenatide and the nitric oxide synthase inhibitor L-NG-monomethyl arginine (L-NMMA). Sympathetic nervous system (SNS) activity was measured by heart rate variability and rate-pressure product. Results Exenatide increased HR by a mean maximum of 6.8 (95% CI 1.7, 11.9) beats min–1 (P

Introduction Type 1 diabetes mellitus (T1DM) patients, especially with concomitant microvascular disease, such as proliferative retinopathy, have an increased risk of cognitive deficits. Local cortical gray matter volume reductions only partially explain these cognitive dysfunctions, possibly because volume reductions do not take into account the complex connectivity structure of the brain. This study aimed to identify gray matter network alterations in relation to cognition in T1DM. Methods: We investigated if subject‐specific structural gray matter network properties, constructed from T1‐weighted MRI scans, were different between T1DM patients with (n = 51) and without (n = 53) proliferative retinopathy versus controls (n = 49), and were associated to cognitive decrements and fractional anisotropy, as measured by voxel‐based TBSS. Global normalized and local (45 bilateral anatomical regions) clustering coefficient and path length were assessed. These network properties measure how the organization of connections in a network differs from that of randomly connected networks. Results: Global gray matter network topology was more randomly organized in both T1DM patient groups versus controls, with the largest effects seen in patients with proliferative retinopathy. Lower local path length values were widely distributed throughout the brain. Lower local clustering was observed in the middle frontal, postcentral, and occipital areas. Complex network topology explained up to 20% of the variance of cognitive decrements, beyond other predictors. Exploratory analyses showed that lower fractional anisotropy was associated with a more random gray matter network organization. Conclusion: T1DM and proliferative retinopathy affect cortical network organization that may consequently contribute to clinically relevant changes in cognitive functioning in these patients. Hum Brain Mapp 37:1194–1208, 2016. © 2015 Wiley Periodicals, Inc.

Background The aim of the present study was to determine trajectories of cognitive and cortical changes over time in middle‐aged patients with type 1 diabetes mellitus (T1DM) and proliferative retinopathy. Methods Twenty‐five patients and 25 controls underwent neuropsychological assessment and neuroimaging twice in a mean (±SD) of 3.56 ± 0.65 and 3.94 ± 0.91 years, respectively (P = 0.098). Cognitive assessment included the domains of general cognitive ability, memory, information processing speed, executive functions, attention, and motor and psychomotor speed. Symmetrized percentage change in local cortical thickness, surface area, and volume was determined using the FreeSurfer 6 vertex‐wise general linear model method. Analyses were performed uncorrected and corrected for baseline systolic blood pressure and depressive symptoms. Results In patients versus controls, accelerated executive function decline was accompanied by, but not related to, lower left frontal and temporal surface area, left parietal and right frontal thickness, and bilateral frontal and right posterior cingulate volume (family‐wise error [FWE]‐corrected P

Objective The neural correlates and pathophysiology of emotional eating are insufficiently known. Glucagon-like peptide-1 (GLP-1), a postprandial hormone, plays a role in feeding behavior by signaling satiety to the brain. GLP-1 receptor agonists, used for treatment of type 2 diabetes (T2DM), promote weight loss. This study investigated the association between emotional eating and responses to food-cues in brain areas involved in satiety and reward processing, as well as GLP-1 receptor agonist-induced effects on these brain responses. Methods T2DM patients with obesity, normoglycemic individuals with obesity, and lean individuals (n = 48) were studied in a randomized placebo-controlled crossover study. Using functional MRI, we determined the relation between emotional eating and regional brain responses to visual food stimuli and acute effects of intravenous administration of the GLP-1 receptor agonist exenatide on these responses. Results Emotional eating scores positively correlated with responses to food-cues in lean subjects in the insula, in normoglycemic subjects with obesity in the insula, and in T2DM patients in the amygdala, orbitofrontal cortex, and insula. Emotional eating scores negatively correlated with exenatide-induced reductions in responses to food-cues in normoglycemic subjects with obesity in the amygdala and in T2DM patients in the insula. Conclusions Our findings indicate that emotional eaters have altered brain responses to food-cues and are less sensitive to the central effects of GLP-1 receptor activation.

Purpose To compare cerebral blood flow (CBF) values measured using magnetic resonance imaging (MRI) arterial spin labeling (ASL) with those obtained with [15O]H2O positron emission tomography (PET), the gold standard for measuring CBF in vivo. Materials and Methods Data were collected in 11 healthy men and in 20 age- and body mass index (BMI)-matched type 1 diabetic men. Pseudo-continuous ASL (PCASL) data were acquired at 3 T and [15O]H2O PET scans were acquired using a high-resolution PET scanner. Input functions were obtained using on-line arterial blood sampling. Whole brain and regional CBF values were compared. Results For both modalities, whole brain CBF was similar in both subject groups. In groups combined, average whole brain CBF was 0.30 ± 0.05 mL·cm−3·min−1 for [15O]H2O PET and 0.34 ± 0.05 mL·cm−3·min−1 for ASL MRI (P < 0.01). A significant correlation between methods was observed for whole brain, gray and white matter. In 12 out of 33 brain regions a significant difference between methods was observed. Conclusion PCASL provides CBF values that correlate with [15O]H2O PET-derived values, but is less accurate. PCASL may be an attractive alternative when absolute quantification is not needed.J. Magn. Reson. Imaging 2014;40:1300–1309. © 2013 Wiley Periodicals, Inc.

Background: Bone metabolism is a dynamic process that is influenced by food ingestion. Endogenous incretins have been shown to be important regulators of bone turnover. The aim of the present study was to assess whether a dipeptidylpeptidase (DPP)-4 inhibitor affects markers of bone resorption and calcium homeostasis. Methods: The present study was a single-center, double blind, randomized clinical trail. Fifty-nine drug-naive patients with type 2 diabetes (T2D) were randomized to either 1year treatment with the DPP-4 inhibitor vildagliptin (100mg, once daily; n=29) or placebo (n=30). Patients received a standardized breakfast after measurement of serum concentrations of cross-linked C-terminal telopeptide (s-CTx), a bone resorption marker influenced by food intake, before and after 50weeks treatment. Results: Vildagliptin did not change postprandial s-CTx concentrations compared with pretreatment levels (between-group ratio 1.15±0.17; P=0.320). Fasting serum alkaline phosphatase, calcium, and phosphate were also unaffected y 1year treatment with vildagliptin. Conclusions: Treatment with vildagliptin for 1year was not associated with changes in markers of bone resorption and calcium homeostasis in drug-naive patients with T2D and mild hyperglycemia. © 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

Objective To investigate the dose-related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA). Methods A randomized, controlled, single-blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUCG) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed. Results Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m2 and 25.4 ± 4.2 kg/m2, respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C-reactive protein [CRP] level 14 mg/liter [interquartile range 6–34] and 19 mg/liter [interquartile range 3–39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUCG with erythrocyte sedimentation rate (β = 2.430 [95% confidence interval 0.179–4.681], P = 0.04) and with CRP level (β = 2.358 [95% confidence interval 0.210–4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUCG did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUCG (β = 3.626 [95% confidence interval 1.077–6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017–1.122], P = 0.009). Conclusion In this study, short-term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.

Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) β-cell mass and pancreatic insulin content. Studies in humans with T2DM have indicated improvement of islet-cell function, both in the fasted state and under postprandial conditions and these beneficial effects were sustained in studies with a duration up to 2 years. However, there is at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on β-cell function after cessation of therapy. Long-term, large-sized trials using an active blood glucose lowering comparator followed by a sufficiently long washout period after discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably preserve pancreatic islet-cell function in patients with T2DM.

Aims To study prospectively the impact of initiating insulin glargine in suboptimally controlled insulin-naive patients with Type 2 diabetes on health-related quality of life in relation to glycaemic control. Methods Insulin-naive Dutch patients with Type 2 diabetes in suboptimal glycaemic control (HbA1c >5 3 mmol⁄mol; 7%) on maximum dose of oral glucose-lowering medications were included from 363 primary care practices (n = 911). Patients started insulin glargine and were followed up for 6 months. At baseline (start insulin therapy), 3 and 6 months, HbA1c was measured and patients completed self-report health-related quality of life measures, including emotional well-being (World Health Organization-5 well-being index), fear of hypoglycaemia (Hypoglycaemia Fear Survey) and diabetes symptom distress (Diabetes Symptom Checklist—revised). Data were analysed using generalized estimating equations analysis. Results HbA1c (mmol ⁄mol; %) decreased from 69 16; 8.5 1.7 to 60 11; 7.61.0 and 57 11; 7.3 1.0 at 3 and 6 months,respectively(P < 0.001).Pre-insulinBMI(kg ⁄m 2 )was30 5.7,whichremainedstableat3 months(30 5.8)and increased to 31 5.9 at 6 months (P = 0.004); no significant changes in self-reported symptomatic and severe hypoglycaemia were observed, while nocturnal hypoglycaemia slightly decreased. The Hypoglycaemia Fear Survey score decreased from 14.6 16.2 to 12.1 15.2 and 10.8 14.4 at 3 and 6 months, respectively (P < 0.001). The Diabetes Symptom Checklist—revised score decreased from 15 14 to 10 12 and 10 13 (P < 0.001), with most pronounced reductions in hyperglycaemic symptoms and fatigue. The World Health Organization-5 score increased from 57 25.3 to 65 21.6 at 3-month follow-up and 67 21.8 at 6-month follow-up (P < 0.001). Conclusions Results of this observational study demonstrate combined glycaemic and health-related quality of life benefits of initiating insulin glargine in patients with Type 2 diabetes in routine primary care.

The current obesity and type 2 diabetes pandemics have causes beyond changes in eating and exercise habits against a susceptible genetic background. Gut bacteria seem to additionally contribute to the differences in body weight, fat distribution, insulin sensitivity and glucose- and lipid-metabolism. Data, mostly derived from preclinical studies, suggest that gut microbiota play an important role in conditions such as obesity, diabetes, metabolic syndrome and non-alcoholic fatty liver disease. Regulation of energy uptake from the gut, by digesting otherwise indigestible common polysaccharides in our diet, production or activation of signalling molecules involved in host metabolism, modification of gut permeability, the release of gut hormones and inflammation, are among the mechanisms by which gut microbiota may influence the host cardiometabolic phenotype. Recent evidence suggests that quantitative and qualitative differences in gut microbiota exist between lean and obese, and between diabetic and non-diabetic individuals. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may favourably affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are eagerly awaited.

Eukaryotic cells release vesicles into their environment by membrane shedding (ectosomes or microparticles) and secretion (exosomes). Microparticles and exosomes occur commonly in vitro and in vivo. The occurrence, composition and function(s) of these vesicles change during disease (progression). During the last decade, the scientific and clinical interest increased tremendously. Evidence is accumulating that microparticles and exosomes may be of pathophysiological relevance in autoimmune, cardiovascular and thromboembolic diseases, as well as inflammatory and infectious disorders. In this review, we will summarize the discovery, biology, structure and function of microparticles and exosomes, and discuss their (patho-) physiological role during normal and complicated pregnancy.

Microparticles are small membrane vesicles that are released from cells upon activation or during apoptosis. Cellular microparticles in body fluids constitute a heterogeneous population, differing in cellular origin, numbers, size, antigenic composition and functional properties. Microparticles support coagulation by exposure of negatively charged phospholipids and sometimes tissue factor, the initiator of coagulation in vivo. Microparticles may transfer bioactive molecules to other cells or microparticles, thereby stimulating cells to produce cytokines, cell-adhesion molecules, growth factors and tissue factor, and modulate endothelial functions. Microparticles derived from various cells, most notably platelets but also leucocytes, lymphocytes, erythrocytes and endothelial cells, are present in the circulation of healthy subjects. Rare hereditary syndromes with disturbances in membrane vesiculation leading to a decreased numbers of microparticles clinically present with a bleeding tendency. In contrast, elevated numbers of microparticles are encountered in patients with a great variety of diseases with vascular involvement and hypercoagulability, including disseminated intravascular coagulation, acute coronary syndromes, peripheral arterial disease, diabetes mellitus and systemic inflammatory disease. Finally, microparticles are a major component of human atherosclerotic plaques. In view of their functional properties, cell-derived microparticles may be an important intermediate in the cascade of cellular and plasmatic dysfunctions underlying the process of atherogenesis.

OBJECTIVE Most patients with differentiated thyroid carcinoma (DTC) undergo total thyroidectomy followed by routine radioiodide thyroid remnant ablation. Most centres that routinely perform radioiodide ablation prescribe a low-iodide diet (LID) to increase the radioiodide accumulation in thyroid remnants. The efficacy of an LID on thyroid remnant ablation, however, has never been demonstrated convincingly. DESIGN AND METHODS In a retrospective study, we studied two groups of DTC patients without distant metastases, who had received either a standard diet or an LID during ablation (LID group, n = 59, and control group, n = 61). Both groups were compared for radioiodide uptake in thyroid remnants during ablation and efficacy parameters of remnant ablation, 6 months after ablation. A subgroup without extrathyroidal tumour growth was analysed separately (stages T1-3, NO). RESULTS In the total group, the LID during ablation decreased the 24-h urinary iodide excretion to 26.6 μg compared with 158.8 μg in controls whereas radioiodide uptake in thyroid remnants was increased by 65% (P < 0.001). Six months after ablation, patients were investigated after thyroid hormone withdrawal. In the total group, no significant effects of the LID during ablation were observed on thyroglobulin (Tg) or the percentage of patients with persistent neck activity after 185 MBq 131 I. However, in the LID group, 65% of patients without Tg antibodies had undergone successful ablation (defined by absent neck activity and Tg