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OBJECTIVE While the apolipoprotein E ε4 allele (ApoE-ε4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-ε4 and T1DM on cognitive performance and hippocampal structure and connectivity as the brain area most vulnerable to ApoE-ε4 effects in adult patients with T1DM. RESEARCH DESIGN AND METHODS Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hippocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-ε4 presence was investigated and adjusted for age and mean systolic blood pressure. RESULTS ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-ε4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-ε4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-ε4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-ε4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning. CONCLUSIONS The results may suggest that ApoE-ε4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies.

Objective: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis. Approach and Results: Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after the hypercaloric diet in study participants and controls (n=5). The hypercaloric diet increased body weight (3.5 kg; P P P =0.041) and decreased the ratio between skeletal muscle and adipose tissue microvascular blood volume during hyperinsulinemia ( P =0.019). Insulin-induced vasodilation of isolated skeletal muscle arterioles was significantly lower in participants compared with controls ( P Conclusions: In lean men, short-term overfeeding reduces insulin-induced vasodilation of skeletal muscle resistance arteries and shifts the distribution of tissue perfusion during hyperinsulinemia from skeletal muscle to adipose tissue without affecting glucose uptake and lipolysis. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02628301.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are well-established glucose-lowering drugs for type 2 diabetes mellitus (T2DM) management. Acute GLP-1RA administration increases urinary excretion of sodium and other electrolytes. However, the renal tubular effects of prolonged GLP-1RA treatment are largely unknown. In this secondary analysis of a randomized trial, we determined the renal tubular effects of 8-wk treatment with 20 μg lixisenatide, a short-acting (prandial) GLP-1RA, versus titrated once-daily insulin glulisine in 35 overweight T2DM-patients on stable insulin glargine background therapy (age: 62 ± 7 yr, glycated hemoglobin: 8.0 ± 0.9%, estimated glomerular filtration rate: >60 ml·min−1·1.73 m−2). After a standardized breakfast, lixisenatide increased absolute and fractional excretions of sodium, chloride, and potassium and increased urinary pH. In contrast, lixisenatide reduced absolute and fractional excretions of magnesium, calcium, and phosphate. At week 8, patients treated with lixisenatide had significantly more phosphorylated sodium-hydrogen exchanger isoform 3 (NHE3) in urinary extracellular vesicles than those on insulin glulisine treatment, which suggested decreased NHE3 activity in the proximal tubule. A rise in postprandial blood pressure with lixisenatide partly explained the changes in the urinary excretion of sodium, potassium, magnesium, and phosphate and the changes in urinary pH. In conclusion, lixisenatide affects postprandial urinary excretion of several electrolytes and increases urinary pH compared with insulin glulisine in T2DM patients after 8 wk of treatment. This is most likely explained by a drug-induced rise in blood pressure or direct inhibitory effects on NHE3 in the proximal tubule.

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

The aim of this study was to evaluate whether psychological distress modifies the effect of continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D) and impaired awareness of hypoglycemia. Fifty-two patients with T1D and impaired awareness of hypoglycemia participated in an earlier reported randomized crossover trial with two 16-week intervention periods comparing CGM with self-monitoring of blood glucose (SMBG). During the CGM phase, time spent in euglycemia (4-10 mmol/L), the primary outcome, was 9.6% higher compared with the SMBG phase (P < 0.0001). Psychological distress was operationalized as low emotional well-being (World Health Organization Well-being Index 5 [WHO-5] < 50) high diabetes-related distress (Problem Areas in Diabetes 5 [PAID-5] ≥ 8) and/or high fear of hypoglycemia (Hypoglycemia Fear Survey [HFS] Worry > mean HFS Worry score +1 standard deviation). Modifying effects were assessed by analyzing psychological distress score × intervention - interaction effects. Results showed that both the low emotional well-being group and normal emotional well-being group had equal glycemic outcomes during the CGM phase. High diabetes distress and elevated fear of hypoglycemia did not result in significant interaction effects for glycemic outcomes. This study demonstrated that CGM is equally effective in terms of glycemic improvements in high versus low distressed patients with T1D and impaired awareness of hypoglycemia.

AIMS: To assess the effects of glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors on postprandial haemodynamics.METHODS: 57 patients with type 2 diabetes (mean±SD age 62.8±6.9years; BMI 31.8±4.1kg/m(2); HbA1c 7.3±0.6%) were included in an acute (exenatide- or placebo-infusion) and 12-week (liraglutide, sitagliptin or placebo) randomised, placebo-controlled, double-blind trial. Systemic haemodynamics (oscillometric technique and finger photoplethysmography), vascular stiffness (tonometry), and sympathetic nervous system (SNS)-activity (heart rate variability) were determined in the fasting state and following a standardised mixed meal.RESULTS: In both studies, postprandial blood pressure (BP) decreased during placebo-intervention. Compared with placebo, acute exenatide-infusion increased postprandial diastolic BP (6.7 [95%-confidence interval 3.6-9.9]mmHg, pCONCLUSIONS: Acute exenatide-infusion prevented the meal-induced decline in diastolic BP, although prolonged liraglutide intervention did not affect postprandial haemodynamics. The meal-induced drop in BP was augmented during sitagliptin-treatment.

Objective To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients. Design Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial. Methods In total, 57 type 2 diabetes patients (mean ± s.d. age: 62.8 ± 6.9 years; BMI: 31.8 ± 4.1 kg/m2; HbA1c: 7.3 ± 0.6%), treated with metformin and/or sulfonylureas, were included between July 2013 and August 2015. In the acute study, the GLP-1 receptor agonist exenatide (n = 29) or placebo (saline 0.9%; n = 28) was infused intravenously. Subsequently, patients were again randomised to receive the GLP-1 receptor agonist liraglutide (n = 19) or matching placebo (n = 17) for 12 weeks. RHR and blood pressure (BP) were measured by oscillometric technique, systemic haemodynamics by finger photoplethysmography, sympathetic nervous system (SNS) activity by heart rate variability and arterial stiffness by applanation tonometry. This trial was registered at ClinicalTrials.gov (Nbib1744236). Results Exenatide-infusion increased RHR (mean ± s.e.m. +7.5 ± 0.9 BPM, P P P P P > 0.05). Conclusions RHR acceleration with acute and 12-week GLP-1 receptor agonist treatment in type 2 diabetes patients is not explained by changes in SNS activity, and our data argue against vasodilation. In line with pre-clinical data, direct sino-atrial stimulation may be involved.

To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal hemodynamics, tubular functions, and markers of renal damage in overweight patients with type 2 diabetes without chronic kidney disease (CKD).In this 12-week, randomized, double-blind trial, 55 insulin-naïve patients with type 2 diabetes (mean ± SEM: age 63 ± 7 years, BMI 31.8 ± 4.1 kg/mAt week 12, GFR was not affected by sitagliptin (-6 mL/min/1.73 mTwelve-week treatment with sitagliptin or liraglutide does not affect measured renal hemodynamics. No sustained changes in tubular functions or alteration in renal damage markers were observed. The validity and clinical relevance of the slight sitagliptin-induced P

Aims/hypothesis This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients. Methods We included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA1c 48–75 mmol/mol; 6.5–9.0%) and estimated GFR ≥ 60 ml min−1 1.73 m−2. Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined. Results Of the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min−1 1.73 m−2, p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p

Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance. Both T2DM and obesity are associated with cerebral complications, including an increased risk of cognitive impairment and dementia, however the underlying mechanisms are largely unknown. In the current study, we aimed to determine the relative contributions of obesity and the presence of T2DM to altered white matter structure. We used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to measure white matter integrity and volume in obese T2DM patients without micro- or macrovascular complications, age- gender- and BMI-matched normoglycemic obese subjects and age- and gender-matched normoglycemic lean subjects. We found that obese T2DM patients compared with lean subjects had lower axial diffusivity (in the right corticospinal tract, right inferior fronto-occipital tract, right superior longitudinal fasciculus and right forceps major) and reduced white matter volume (in the right inferior parietal lobe and the left external capsule region). In normoglycemic obese compared with lean subjects axial diffusivity as well as white matter volume tended to be reduced, whereas there were no significant differences between normoglycemic obese subjects and T2DM patients. Decreased white matter integrity and volume were univariately related to higher age, being male, higher BMI, HbA1C and fasting glucose and insulin levels. However, multivariate analyses demonstrated that only BMI was independently related to white matter integrity, and age, gender and BMI to white matter volume loss. Our data indicate that obese T2DM patients have reduced white matter integrity and volume, but that this is largely explained by BMI, rather than T2DM per se.

OBJECTIVE Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced appetite and body weight. We investigated whether these effects could be mediated by the central nervous system (CNS). RESEARCH DESIGN AND METHODS We performed a randomized crossover study in obese patients with type 2 diabetes (n = 20, mean age 59.3 ± 4.1 years, mean BMI 32 ± 4.7 kg/m2), consisting of two periods of 12-week treatment with either liraglutide 1.8 mg or insulin glargine. Using functional MRI, we determined the effects of treatment on CNS responses to viewing food pictures in the fasted condition and 30 min after meal intake. RESULTS After 12 weeks, the decrease in HbA1c was larger with liraglutide versus insulin glargine (Δ−0.7% vs. −0.2%, P < 0.001). Body weight decreased during liraglutide versus insulin glargine (Δ−3.3 kg vs. 0.8 kg, P < 0.001). After 10 days, patients treated with liraglutide, compared with insulin glargine, showed decreased responses to food pictures in insula and putamen (P ≤ 0.02). In addition, liraglutide enhanced the satiating effect of meal intake on responses in putamen and amygdala (P ≤ 0.05). Differences between liraglutide and insulin glargine were not observed after 12 weeks. CONCLUSIONS Compared with insulin, liraglutide decreased CNS activation significantly only after short-term treatment, suggesting that these effects of GLP-1RA on the CNS may contribute to the induction of weight loss, but not necessarily to its maintenance, in view of the absence of an effect of liraglutide on CNS activation in response to food pictures after longer-term treatment.

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

AIMS: Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile.MATERIALS AND METHODS: A total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m(2) ; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12 weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236).RESULTS: Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027-0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22-68.21), p = 0.005] and in faeces [ratio 1.5 (1.03-2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p = 0.012], cholic acid [ratio 3.32 (1.26-8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p = 0.008].CONCLUSIONS: Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.

BACKGROUND: Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population.METHODS: We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903.FINDINGS: Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; pINTERPRETATION: CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population.FUNDING: Eli Lilly and Sanofi.

Objectives Patients with Type 1 diabetes mellitus (T1DM) are at an increased risk for major depression, but its underlying mechanisms are still poorly understood. In nondiabetic participants, mood disturbances are related to altered subgenual cingulate cortex (SGC) resting-state functional connectivity. We tested for SGC connectivity alterations in T1DM, whether these alterations were related to depressive symptoms, and if depressive symptoms were associated with cognition.Methods A bilateral SGC seed-based resting-state functional magnetic resonance imaging analysis was performed in 104 T1DM patients and 49 controls without known psychiatric diagnosis or treatment. Depressive symptoms were self-reported using the Center for Epidemiological Studies Depression scale. Cognition was assessed with a battery of standardized tests.Results In patients versus controls, SGC to right inferior frontal gyrus and frontal pole connectivity was decreased (52 voxels, z valuepeak = 3.56, pcluster-FWE = .002), whereas SGC to bilateral precuneus (33 voxels, z valuepeak = 3.34, pcluster-FWE = .04) and left inferior parietal lobule (50 voxels, z valuepeak = 3.50, pcluster-FWE = .003) connectivity was increased. In all participants, increased depressive symptoms was related to lower SGC to inferior frontal gyrus and frontal pole connectivity (β = −0.156, p = .053), and poorer general cognitive ability (β = −0.194, p = .023), information processing speed (β = −0.222, p = .008), and motor speed (β = −0.180, p = .035).Conclusions T1DM patients showed a pattern of SGC connectivity that is characterized by lower executive control and higher default mode network connectivity. Depressive symptoms are partially related to these alterations and seem to exacerbate T1DM-related cognitive dysfunction. Future studies should detail the effect of diagnosed major depressive disorder in this population and establish what alterations are diabetes specific.

Glucagon-like peptide-1 (GLP1) affects appetite, supposedly mediated via the central nervous system (CNS). In this study, we investigate whether modulation of CNS responses to palatable food consumption may be a mechanism by which GLP1 contributes to the central regulation of feeding. Using functional MRI, we determined the effects of endogenous GLP1 and treatment with the GLP1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP1 receptor antagonist exendin 9–39 (blocking actions of endogenous GLP1) and during placebo infusion. Study 2 was a randomised, cross-over intervention study carried out in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10 days and 12 weeks. Compared with lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P= 0.04). In lean individuals, blockade of endogenous GLP1 effects inhibited activation in bilateral insula (P≤ 0.03). Treatment in T2DM with liraglutide, vs insulin, increased activation to chocolate milk in right insula and caudate nucleus after 10 days (P≤ 0.03); however, these effects ceased to be significant after 12 weeks. Our findings in healthy lean individuals indicate that endogenous GLP1 is involved in the central regulation of feeding by affecting central responsiveness to palatable food consumption. In obese T2DM, treatment with liraglutide may improve the observed deficit in responsiveness to palatable food, which may contribute to the induction of weight loss observed during treatment. However, no long-term effects of liraglutide were observed.

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.

Type 2 diabetes (T2DM) is associated with structural cortical and subcortical alterations, although it is insufficiently clear if these alterations are driven by obesity or by diabetes and its associated complications. We used FreeSurfer5.3 and FSL-FIRST to determine cortical thickness, volume and surface area, and subcortical gray matter volume in a group of 16 normoglycemic obese subjects and 28 obese T2DM patients without clinically manifest micro- and marcoangiopathy, and compared them to 31 lean normoglycemic controls. Forward regression analysis was used to determine demographic and clinical correlates of altered (sub)cortical structure. Exploratively, vertex-wise correlations between cortical structure and fasting glucose and insulin were calculated. Compared with controls, obese T2DM patients showed lower right insula thickness and lower left lateral occipital surface area (PFWE < 0.05). Normoglycemic obese versus controls had lower thickness (PFWE < 0.05) in the right insula and inferior frontal gyrus, and higher amygdala and thalamus volume. Thalamus volume and left paracentral surface area were also higher in this group compared with obese T2DM patients. Age, sex, BMI, fasting glucose, and cholesterol were related to these (sub)cortical alterations in the whole group (all P < 0.05). Insulin were related to temporal and frontal structural deficits (all PFWE < 0.05). Parietal/occipital structural deficits may constitute early T2DM-related cerebral alterations, whereas in normoglycemic obese subjects, regions involved in emotion, appetite, satiety regulation, and inhibition were affected. Central adiposity and elevated fasting glucose may constitute risk factors.

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

Glucocorticoid treatment decreases liver insulin sensitivity and may modify fatty acid metabolism. We investigated the influence of oral prednisolone on indices for de novo lipogenesis (DNLi), stearoyl-CoA desaturase (SCDi) and Δ6-desaturase (D6Di) activity in healthy males. In addition, we explored whether the changes may be associated with prednisolone-induced changes in glucose and lipid metabolism and insulin sensitivity. Thirty-two healthy young males (mean ± SD age 22 ± 3 years, BMI 22.4 ± 1.7 kg/m2) were allocated to receive prednisolone 7.5 mg/day (PRED7.5; n = 12), prednisolone 30 mg/day (PRED30; n = 12), or placebo (n = 8) in a randomized double-blind fashion for 2 weeks. Fatty acid compositions of plasma cholesteryl esters (CE), phospholipids (PL) and triglycerides (TG) were measured at baseline and on day 14. DNLi, SCDi and D6Di were estimated from product/precursor ratios in CE, with DNLi primary deriving from 16:1ω7/18:2ω6, SCDi from 16:1ω7/16:0 and D6Di from 22:6ω3/20:5ω3. Ratios were also assessed in PL and TG. In CE, PRED30 increased DNLi by 51.2 [95%CI 14.8; 87.6]%, increased SCDi by 48.6 [18.7; 78.5]%, and decreased D6Di by 57.7 [-91.8; -23.5]% (p ≤ 0.01 for all, compared to placebo). The prednisolone-induced increases in DNLi and SCDi were positively correlated with insulin sensitivity (r = 0.35 and 0.50, respectively). Similar results were found in PL and TG. Prednisolone dose-dependently increases DNLi and SCDi and decreases D6Di in plasma CE, PL and TG in healthy males after 2 weeks. The observed unfavorable effects on fatty acid metabolism were related to the induction of glucocorticoid-induced insulin resistance.

Aim: To determine whether lixisenatide, a prandial short-acting glucagon-like peptide receptor agonist (GLP-1RA), ameliorates postprandial glomerular hyperfiltration in patients with type 2 diabetes mellitus (T2DM) compared with insulin-glulisine (iGlu). Methods: Postprandial renal haemodynamic effects of 8-week treatment with lixisenatide 20 µg vs once-daily titrated iGlu were measured in 35 overweight patients with T2DM inadequately controlled on insulin-glargine, with or without metformin [mean ± SD age 62 ± 7 years, HbA1c 8.0% ± 0.9%, estimated glomerular filtration rate (GFR) 85 ± 12 mL/min/1.73 m2, median (IQR) urinary albumin/creatinine ratio 1.5 (0.9-3.0) mg/mmol]. After a standardised breakfast, GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid renal clearance, respectively, based on timed urine sampling. Intrarenal haemodynamic functions were estimated using Gomez equations. Results: Compared with iGlu, lixisenatide did not affect GFR [+0.1 mL/min/1.73 m2 (95% CI −9 to 9)], ERPF [−17 mL/min/1.73 m2 (−61 to 26)], other (intra-)renal haemodynamics or renal damage markers, but increased fractional sodium excretion [+0.25% (0.09-0.41)] and urinary pH [+0.7 (0.3-1.2)]. Plasma renin, angiotensin-II and aldosterone were unchanged. Lixisenatide and iGlu reduced HbA1c similarly, by 0.8% ± 0.1% and 0.6% ± 0.1%, respectively, while postprandial glucose was lower with lixisenatide (P =.002). Compared with iGlu, lixisenatide reduced bodyweight [−1.4 kg (−2.5 to −0.2)] and increased postprandial mean arterial pressure [+9 mm Hg (4-14)]. Conclusion: Eight-week lixisenatide treatment does not affect postprandial (intra-)renal haemodynamics compared with iGlu when added to insulin-glargine in patients with T2DM without overt nephropathy. Prolonged lixisenatide treatment has a sustained natriuretic effect, which is in contrast to previous reports on long-acting GLP-1RA, reduces body weight and increases postprandial blood pressure compared with iGlu. Trial registration: ClinicalTrials.gov identifier NCT02276196.

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.

ObjectiveTo determine the health-related quality of life (HRQOL) of overweight and obese multi-ethnic children compared with normal-weight children; and to investigate differences in HRQOL between self- and parent-proxy reports and ethnic groups.DesignProspective cross-sectional study.SettingOut-patient clinic where children and their parents filled out a validated HRQOL questionnaire (KIDSCREEN-52) and height, weight, waist circumference and fat percentage were measured.SubjectsOverweight and obese children, aged 8–18 years (mean BMIZ-score 3·2 (sd0·6)), from the obesity out-patient clinic.ResultsThree hundred and eight self- and 213 parent-proxy reported questionnaires were completed. Global HRQOL and the Physical Wellbeing, Moods & Emotions and Self-Perception subscales were markedly reduced in our multi-ethnic obese cohort, relative to the Dutch reference values. Parent proxies reported significantly lower on the global HRQOL and the Physical Wellbeing, Moods & Emotions and Bullying subscales. In Caucasian children, multivariate analyses showed that BMI was associated with the quality-of-life subscales Moods & Emotions, Self-Perception and Bullying.ConclusionsHRQOL was markedly reduced in our multi-ethnic overweight and obese out-patient clinic cohort, with significantly lower parent-proxy scores compared with self-reported scores. We believe intervention programmes aiming to improve HRQOL should be directed to both parents and children, while ethnic-specific programmes to enhance HRQOL seem of less importance.

Objective— The insulinotropic gut–derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide–dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. Approach and Results— We included 10 healthy overweight men (age, 20–27 years; body mass index, 26–31 kg/m 2 ). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide–synthase inhibitor l - N G -monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P =0.016). Concomitant l - N G -monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements ( R =−5.6%; P =0.092), which was strongly and inversely associated with capillary perfusion ( R =−0.928; P =0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. Conclusions— Acute exenatide infusion increases capillary perfusion via nitric oxide–independent pathways in healthy overweight men, suggesting direct actions of this GLP-1RA on microvascular perfusion or interaction with vasoactive factors.

Background: Stress experienced during childhood or adulthood has been associated with cardiovascular disease (CVD), but it is not clear whether associations are already prevalent on a subclinical cardiovascular level. This study investigates associations between indicators of life stress and subclinical CVD, and whether these are mediated by depression and anxiety.Methods: Subjects were 650 participants of the Netherlands Study of Depression and Anxiety, aged 20-66 years, with or without (27.5%) depressive and anxiety disorders. Life stress included childhood trauma, negative life events and recently experienced daily hassles or job strain. Subclinical CVD was measured as 1) carotid atherosclerosis (intima-media thickness and the presence of plaques) using B-mode ultrasonography, and 2) central arterial stiffness (heart rate normalized augmentation index) using calibrated radial applanation tonometry.Results: Increased central arterial stiffness was shown in sub jects who had experienced childhood trauma (per SD increase: beta = .07; p = .01), or reported recently experienced daily hassles (per SD increase: beta = .06; p = .02), negative life events (per SD increase: beta = .05; p = .03), or job strain (high versus low: beta = .09; p = .01). Associations between life stress and arterial stiffness appeared to be partly mediated by severity of depressive and anxiety symptoms. No significant associations were found for childhood life events, nor between indicators of life stress and carotid atherosclerosis.Conclusions: Childhood trauma and recent life stress were associated with increased central arterial stiffness. This suggests that life stress - partly via depression and anxiety - might enhance the development and progression of CVD. (C) 2015 Elsevier Inc. All rights reserved.

AimTo test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward.MethodsAs part of a larger study, we determined the effects of GLP-1 receptor activation on brain responses to anticipation and receipt of chocolate milk versus a tasteless solution, using functional MRI (fMRI). Obese subjects with type 2 diabetes, and obese and lean subjects with normoglycaemia (n=48) underwent three fMRI sessions at separate visits with intravenous infusion of the GLP-1 receptor agonist exenatide, exenatide with prior GLP-1 receptor blockade by exendin-9-39 or placebo, during somatostatin pituitary-pancreatic clamps.ResultsBody mass index negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk compared with placebo, paralleled by reductions in food intake. Exendin-9-39 largely prevented these effects.ConclusionsOur findings show that GLP-1 receptor activation decreases anticipatory food reward, which may reduce cravings for food and increases consummatory food reward, which may prevent overeating.

We performed a randomized controlled trial with the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide as add-on to standard peri-operative insulin therapy in patients undergoing elective cardiac surgery. The aims of the study were to intensify peri-operative glucose control while minimizing the risk of hypoglycaemia and to evaluate the suggested cardioprotective effects of GLP-1-based treatments. A total of 38 patients with decreased left ventricular systolic function (ejection fraction ≤50%) scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either exenatide or placebo in a continuous 72-hour intravenous (i.v.) infusion on top of standard peri-operative insulin therapy. While no significant difference in postoperative echocardiographic variables was found between the groups, participants receiving exenatide showed improved peri-operative glucose control as compared with the placebo group (average glycaemia 6.4 ± 0.5 vs 7.3 ± 0.8 mmol/L; P

Background Multiple bloodglucose-lowering agents have been linked to cardiovascular events. Preliminary studies showed improvement in left ventricular (LV) function during glucagon-like peptide-1 receptor agonist administration. Underlying mechanisms, however, are unclear. The purpose of this study was to investigate myocardial perfusion and oxidative metabolism in type 2 diabetic (T2DM) patients with LV systolic dysfunction as compared to healthy controls. Furthermore, effects of 26-weeks of exenatide versus insulin glargine administration on cardiac function, perfusion and oxidative metabolism in T2DM patients with LV dysfunction were explored. Methods and results Twenty-six T2DM patients with LV systolic dysfunction (cardiac magnetic resonance (CMR) derived LV ejection fraction (LVEF) of 47 ± 13%) and 10 controls (LVEF of 59 ± 4%, P 15O]H2O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efficiency, measured using [11C]acetate PET and CMR derived stroke volume, were not different between the groups. Eleven patients in the exenatide group and 12 patients in the insulin glargine group completed the trial. Systemic metabolic control was improved after both treatments, although, no changes in cardiac function, perfusion and metabolism were seen after exenatide or insulin glargine. Conclusions T2DM patients with LV systolic dysfunction did not have altered myocardial efficiency as compared to healthy controls. Exenatide or insulin glargine had no effects on cardiac function, perfusion or oxidative metabolism. Trial registration NCT00766857

OBJECTIVE To assess the mechanistic effects of the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide and the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin on (exocrine) pancreatic physiology and morphology. RESEARCH DESIGN AND METHODS For this randomized, double-blind, parallel-group trial, 55 patients with type 2 diabetes treated with metformin and/or sulfonylurea agents were included. Participants received liraglutide 1.8 mg (n = 19), sitagliptin 100 mg (n = 19), or matching placebos (n = 17) once daily for 12 weeks. The primary end point was change in exocrine function (intraduodenal pancreatic fluid secretion, lipase activity, fecal elastase-1, and chymotrypsin). Secondary end points included changes in plasma enzyme concentrations and pancreatic morphology (per MRI). RESULTS No patient developed pancreatitis. Sitagliptin increased intraduodenal pancreatic fluid secretion by 16.3 mL (95% CI −0.3 to 32.9; P = 0.05), whereas liraglutide did not change exocrine pancreatic function. Neither therapy increased lipase/amylase levels after 12 weeks. However, liraglutide increased lipase levels after 6 weeks (23.5 U/L [95% CI 2.1–44.8]; P = 0.03) and sitagliptin increased amylase levels after 2 and 6 weeks (13.7 U/L [95% CI 3.4–23.9]; P = 0.03). Both drugs increased plasma trypsinogen after 12 weeks (liraglutide: 34.6 µg/mL [95% CI 15.1–54.2], P = 0.001; sitagliptin: 23.9 µg/mL [95% CI 4.9–42.9], P = 0.01). Neither changed pancreatic morphology, although liraglutide tended to increase pancreatic volume (7.7 cm3 [95% CI −1.2 to 16.6]; P = 0.09). Treatment-induced volume expansion was associated with increased amylase levels. CONCLUSIONS A 12-week treatment with liraglutide or sitagliptin only resulted in a brief and modest increase of plasma pancreatic enzyme concentrations in patients with type 2 diabetes. Apart from a minimal sitagliptin-induced increase in intraduodenal fluid secretion, pancreatic exocrine function was unaffected. The long-term clinical consequences of these discrete changes require further study.

Acute myocardial infarction (AMI) is accompanied by increased expression of Toll like receptors (TLR)-2 and TLR4 on circulating monocytes. In animal models, blocking TLR2/4 signaling reduces inflammatory cell influx and infarct size. The clinical consequences of TLR activation during AMI in humans are unknown, including its role in long-term cardiac functional outcome Therefore, we analyzed gene expression in whole blood samples from 28 patients with an acute ST elevation myocardial infarction (STEMI), enrolled in the EXenatide trial for AMI patients (EXAMI), both at admission and after 4-month follow-up, by whole genome expression profiling and real-time PCR. Cardiac function was determined by cardiac magnetic resonance (CMR) imaging at baseline and after 4-month follow-up. TLR pathway activation was shown by increased expression of TLR4 and its downstream genes, including IL-18R1, IL-18R2, IL-8, MMP9, HIF1A, and NFKBIA. In contrast, expression of the classical TLR-induced genes, TNF, was reduced. Bioinformatics analysis and in vitro experiments explained this noncanonical TLR response by identification of a pivotal role for HIF-1α. The extent of TLR activation and IL-18R1/2 expression in circulating cells preceded massive troponin-T release and correlated with the CMR-measured ischemic area (R=0.48, p=0.01). In conclusion, we identified a novel HIF-1-dependent noncanonical TLR activation pathway in circulating leukocytes leading to enhanced IL-18R expression which correlated with the magnitude of the ischemic area. This knowledge may contribute to our mechanistic understanding of the involvement of the innate immune system during STEMI and may yield diagnostic and prognostic value for patients with myocardial infarction.

The radical change of lifestyle during Ramadan fast has shown to affect cardiometabolic risk variables in adults. In youth, however, no studies are available. We aimed to evaluate the effect of Ramadan fast on Body Mass Index (BMI) and the cardiometabolic profile of obese adolescents. A prospective cohort study was conducted. We measured weight, height, body composition, blood pressure, heart rate, glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, triglycerides, and high sensitivity C-reactive protein (hs-CRP) levels before, during the last week of and at 6 weeks after Ramadan. Twenty-five obese adolescents were included. BMI and glucose metabolism did not change after Ramadan or at 6 week after cessation of Ramadan. At the end of Ramadan, a significant decrease in body fat percentage was observed, while significant increases in heart rate, total cholesterol, LDL cholesterol, HDL cholesterol, and hs-CRP were found (all P

Patients with coronary artery disease and/or type 2 diabetes mellitus (DM) generally exhibit more epicardial adipose tissue (EAT) than healthy controls. Recently, it has been proposed that EAT affects vascular function and structure by secreting proinflammatory and vasoactive substances, thereby potentially contributing to the development of cardiovascular disease. In the present study, the interrelation of EAT, coronary vasomotor function, and coronary artery calcium was investigated in patients with and without DM, who were evaluated for coronary artery disease. Myocardial blood flow (MBF) was assessed at rest and during adenosine-induced hyperemia using [(15)O]-water positron emission tomography combined with computed tomography to quantify coronary artery calcium and EAT in 199 patients (46 with DM). In this cohort (mean age 58 ± 10 years), the patients with DM had a greater body mass index, heart rate, and systolic blood pressure at rest (all p0.05). Coronary artery calcium and the EAT volumes were comparable between those with and without DM. Both patient groups showed comparable MBF at rest and coronary vascular resistance. A lower hyperemic MBF and coronary flow reserve (CFR) and greater hyperemic coronary vascular resistance (all p0.05) was observed in the patients with DM. A pooled analysis showed a positive association of EAT volume with hyperemic coronary vascular resistance but not with the MBF at rest, hyperemic MBF, or coronary vascular resistance at rest. In the group analysis, the EAT volume was inversely associated with hyperemic MBF (r = -0.16, p = 0.05) and CFR (r = -0.17, p = 0.04) and positively with hyperemic coronary vascular resistance (r = 0.26, p = 0.002) only in patients without DM. Multivariate regression analysis, adjusted for age, gender, and body mass index, showed an independent association between the EAT volume and hyperemic MBF (β = -0.16, p = 0.02), CFR (β = -0.16, p = 0.04), and hyperemic coronary vascular resistance (β = 0.25, p0.001) in the non-DM group. In conclusion, these results suggest a role for EAT in myocardial microvascular dysfunction; however, once DM has developed, other factors might be more dominant in contributing to impaired myocardial microvascular dysfunction.

Background: The recommended dose of vitamin D supplementation of 400 IU/day might be inadequate to treat obese children with vitamin D insufficiency. Therefore, we tested the efficacy and tolerability of a high loading dose vitamin D3 supplementation of 25,000 IU weekly in multiethnic obese children, 8-18 years of age, with vitamin D insufficiency/deficiency. Methods: Fasting blood samples were drawn for the assessment of vitamin D. Vitamin D-insufficient/-deficient children (50 nmol/l) was reached in >75% without side effects nor reaching toxic levels. Results: In total, 109 children (mean ± SD age 11.1 ± 3.0, 34.2% boys, 90.8% obese) received vitamin D supplementation. In 84.4% of the children, the vitamin D status improved from insufficiency/deficiency (Conclusion: A high loading dose vitamin D3 supplementation is effective and well-tolerated in our cohort of multiethnic obese children with vitamin D insufficiency/deficiency.

Objective Integrity of resting-state functional brain networks (RSNs) is important for proper cognitive functioning. In type 1 diabetes mellitus (T1DM) cognitive decrements are commonly observed, possibly due to alterations in RSNs, which may vary according to microvascular complication status. Thus, we tested the hypothesis that functional connectivity in RSNs differs according to clinical status and correlates with cognition in T1DM patients, using an unbiased approach with high spatio-temporal resolution functional network. Methods Resting-state magnetoencephalographic (MEG) data for T1DM patients with (n = 42) and without (n = 41) microvascular complications and 33 healthy participants were recorded. MEG time-series at source level were reconstructed using a recently developed atlas-based beamformer. Functional connectivity within classical frequency bands, estimated by the phase lag index (PLI), was calculated within eight commonly found RSNs. Neuropsychological tests were used to assess cognitive performance, and the relation with RSNs was evaluated. Results Significant differences in terms of RSN functional connectivity between the three groups were observed in the lower alpha band, in the default-mode (DMN), executive control (ECN) and sensorimotor (SMN) RSNs. T1DM patients with microvascular complications showed the weakest functional connectivity in these networks relative to the other groups. For DMN, functional connectivity was higher in patients without microangiopathy relative to controls (all p, Highlights • MEG RSN functional connectivity was estimated among T1DM+ and T1DM− patients and controls. • Lower alpha band in DMN, ECN and SMN significantly differed among groups. • Functional connectivity may play a key role in T1DM-related cognitive dysfunction.

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.

Subclinical systemic microvascular dysfunction exists in asymptomatic patients with type 1 diabetes. We hypothesized that microangiopathy, resulting from long-standing systemic hyperglycemia and hyperinsulinemia, may be generalized to the brain, resulting in changes in cerebral blood flow (CBF) and metabolism in these patients. We performed dynamic [15O]H2O and [18F]-fluoro-2-deoxy-d-glucose brain positron emission tomography scans to measure CBF and cerebral glucose metabolism (CMRglu), respectively, in 30 type 1 diabetic patients and 12 age-matched healthy controls after an overnight fast. Regions of interest were automatically delineated on coregistered magnetic resonance images and full kinetic analysis was performed. Plasma glucose and insulin levels were higher in patients versus controls. Total gray matter CBF was 9%, whereas CMRglu was 21% lower in type 1 diabetic subjects versus control subjects. We conclude that at real-life fasting glucose and insulin levels, type 1 diabetes is associated with decreased resting cerebral glucose metabolism, which is only partially explained by the decreased CBF. These findings suggest that mechanisms other than generalized microangiopathy account for the altered CMRglu observed in well-controlled type 1 diabetes.

Aim Glucocorticoids impair glucose tolerance by inducing insulin resistance. We investigated the dose-dependent effects of glucocorticoid treatment on islet-cell function in healthy males and studied the role of the autonomic nervous system. Design and Methods A randomized, placebo-controlled, double-blind, dose–response intervention study was conducted in 32 healthy males (age: 21 ± 2 years; BMI: 21.9 ± 1.7 kg/m 2 ). Participants were allocated to prednisolone 7.5 mg once daily (n = 12), prednisolone 30 mg once daily (n = 12), or placebo (n = 8) for two weeks. Beta-cell function was measured by hyperglycemic clamp with arginine stimulation, glucagon levels were measured following a standardized meal test. Results We found that prednisolone treatment dose-dependently reduced C-peptide secretion following arginine stimulation on top of hyperglycemia (ASI-iAUC CP ): − 2.8 (− 5.2;0.2) and − 3.1 (− 8.8; − 1.0) nmol L − 1 min − 1 for prednisolone 7.5 mg and prednisolone 30 mg, respectively ( P = 0.035 vs. placebo). Fasting glucagon levels increased dose-dependently (vs. placebo; P = 0.001), whereas postprandial glucagon levels were only increased by prednisolone 30 mg. Changes in parasympathetic activity related with changes in fasting glucose levels (r = − 0.407; P = 0.03) and showed a trend towards correlation with fasting glucagon concentrations (r = − 0.337; P = 0.07). The change in sympathovagal balance was inversely related to ASI-iAUC CP (r = − 0.365; P = 0.05). Conclusion We conclude that in addition to inducing insulin resistance, prednisolone treatment dose-dependently impaired islet-cell function. Altered sympathovagal balance may be related to these effects.

To determine the prevalence of microalbuminuria and its association with cardiometabolic risk factors in a multi-ethnic cohort of overweight and obese children. A retrospective analysis of prospectively collected data was performed using data from 408 overweight and obese children (age 3–19 years). In addition to administering an oral glucose tolerance test, we measured anthropometric variables, plasma lipid levels, alanine aminotransferase and the urinary albumin/creatinine ratio (ACR). Microalbuminuria was defined as an ACR of between 2.5 and 25 mg/mmol in boys and 3.5 and 25 mg/mmol in girls. In total, only 11 (2.7 %) of the children analyzed presented with microalbuminuria, with no differences between ethnic groups, sex or in the prevalence of hypertension compared to the children with normoalbuminuria. After adjustment for confounders, the body mass index Z-score tended to be different between the group with microalbuminuria versus that without (3.6 vs. 3.2, respectively; P = 0.054). ACR was not associated with hypertension, impaired glucose tolerance, high triglycerides or low high-density lipoprotein-cholesterol. In a large multi-ethnic cohort of overweight and obese children, we found a low prevalence of microalbuminuria (11 children, 2.7 %), and in this small number of individuals, we found no association with any of the cardiometabolic risk factors assessed. Therefore, our data do not support the routine measurement of microalbuminuria in asymptomatic overweight and obese children and adolescents.

Blocking the renin-angiotensin system reduces the incidence of type 2 diabetes mellitus in humans with impaired glucose metabolism (IGM). Nevertheless, underlying mechanisms remain to be established.The purpose of this study was to investigate the effects of the angiotensin II type 1 receptor blocker valsartan (VAL) on skeletal muscle fatty acid (FA) handling in subjects with IGM.This was a randomized, double-blind placebo-controlled trial at Maastricht University Medical Center. INTERVENTION/MAIN OUTCOMES/PARTICIPANTS: Fasting and postprandial skeletal muscle FA handling were assessed at baseline and after 26 weeks of treatment with VAL or placebo in 26 subjects with IGM. Fasting and postprandial skeletal muscle FA handling were determined by combining the forearm balance technique with stable isotopes of palmitate. [²H₂]-Palmitate was infused iv to label endogenous triacylglycerol (TAG) and free fatty acid (FFA) in the circulation, and [U-¹³C]-palmitate was incorporated in a high-fat mixed meal (2.6 MJ, 61% energy from fat) to label chylomicron TAG. Muscle biopsy samples were taken to determine im TAG, diacylglycerol (DAG), FFA, and phospholipid contents, their fractional synthetic rates and degree of saturation, and mRNA expression of oxidative genes.VAL decreased saturation of im TAG and DAG fractions but did not affect net muscle uptake of [²H₂]-palmitate, very low-density lipoprotein ([²H₂])-TAG and chylomicron ([U-¹³C])-TAG, and muscle mRNA expression. VAL decreased FA spillover, as estimated by circulating [U-¹³C]-palmitate, and FFA rate of appearance and tended to decrease chylomicron TAG concentrations.VAL treatment for 26 weeks decreased saturation of skeletal muscle TAG and DAG stores, suggesting altered intramuscular lipid partitioning of FA. The VAL-induced reduction in postprandial FA spillover, endogenous lipolysis, and chylomicron TAG concentrations indicate improved adipose tissue lipid buffering capacity.

OBJECTIVE It has been suggested that weight reduction and improvements in satiety after Roux-en-Y gastric bypass (RYGB) are partly mediated via postoperative neuroendocrine changes. Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted after food ingestion and is associated with appetite and weight reduction, mediated via effects on the central nervous system (CNS). Secretion of GLP-1 is greatly enhanced after RYGB. We hypothesized that postoperative elevated GLP-1 levels contribute to the improved satiety regulation after RYGB via effects on the CNS. RESEARCH DESIGN AND METHODS Effects of the GLP-1 receptor antagonist exendin 9-39 (Ex9-39) and placebo were assessed in 10 women before and after RYGB. We used functional MRI to investigate CNS activation in response to visual food cues (pictures) and gustatory food cues (consumption of chocolate milk), comparing results with Ex9-39 versus placebo before and after RYGB. RESULTS After RYGB, CNS activation was reduced in the rolandic operculum and caudate nucleus in response to viewing food pictures (P = 0.03) and in the insula in response to consumption of palatable food (P = 0.003). GLP-1 levels were significantly elevated postoperatively (P < 0.001). After RYGB, GLP-1 receptor blockade resulted in a larger increase in activation in the caudate nucleus in response to food pictures (P = 0.02) and in the insula in response to palatable food consumption (P = 0.002). CONCLUSIONS We conclude that the effects of RYGB on CNS activation in response to visual and gustatory food cues may be mediated by central effects of GLP-1. Our findings provide further insights into the mechanisms underlying the weight-lowering effects of RYGB.

OBJECTIVE This study assessed the efficacy and safety of LixiLan, a fixed-ratio, titratable, combination of 2 units insulin glargine (Gla-100) and 1 μg lixisenatide administered once daily via a single pen, versus Gla-100 in insulin-naïve type 2 diabetes on metformin. RESEARCH DESIGN AND METHODS Participants were randomized to once-daily LixiLan (n = 161) or Gla-100 (n = 162) for 24 weeks, while continuing metformin. LixiLan and Gla-100 were started at 10 units/5 μg and 10 units, respectively, and titrated based on the Gla-100 requirement according to fasting plasma glucose levels. The primary objective was to test noninferiority (upper bound of the 95% CI ≤0.4%) of LixiLan in reducing HbA1c; if met, statistical superiority was tested. Secondary objectives included body weight changes, hypoglycemia, and safety. RESULTS Baseline characteristics (mean age 57 years, diabetes duration 6–7 years, BMI 32 kg/m2) were similar between groups. At week 24, mean HbA1c was reduced from 8.0% (64 mmol/mol) at baseline to 6.3% (45 mmol/mol) and 6.5% (48 mmol/mol) with LixiLan and Gla-100, respectively, establishing statistical noninferiority and superiority of LixiLan (least-squared mean [95% CI] difference: −0.17% [−0.31, −0.04] {−1.9 mmol/mol [−3.4, −0.4]}; P = 0.01). HbA1c CONCLUSIONS LixiLan achieved statistically significant reductions to near-normal HbA1c levels with weight loss and no increased hypoglycemic risk, compared with insulin glargine alone, and a low incidence of gastrointestinal adverse events in type 2 diabetes inadequately controlled on metformin.

Aims/hypothesis Glucagon-like peptide (GLP)-1-based therapies have been suggested to improve hepatic steatosis. We assessed the effects of the GLP-1 receptor agonist liraglutide and the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin on hepatic steatosis and fibrosis in patients with type 2 diabetes. Methods In this 12 week, parallel, randomised, placebo-controlled trial, performed at the VU University Medical Center between July 2013 and August 2015, 52 overweight patients with type 2 diabetes treated with metformin and/or sulphonylurea agent ([mean ± SD] age 62.7 ± 6.9 years, HbA1c 7.3 ± 0.7% or 56 ± 1 mmol/mol) were allocated to once daily liraglutide 1.8 mg (n = 17), sitagliptin 100 mg (n = 18) or matching placebos (n = 17) by computer generated numbers. Both participants and researchers were blinded to group assignment. Hepatic fat content was measured using proton magnetic resonance spectroscopy (1H-MRS). Hepatic fibrosis was estimated using three validated formulae. Results One patient dropped out in the sitagliptin group owing to dizziness, but no serious adverse events occurred. At week 12, no between-group differences in hepatic steatosis were found. Liraglutide reduced steatosis by 10% (20.9 ± 3.4% to 18.8 ± 3.3%), sitagliptin reduced steatosis by 12.1% (23.9 ± 3.0% to 21.0 ± 2.7%) and placebo lessened it by 9.5% (18.7 ± 2.7% to 16.9 ± 2.7%). Neither drug affected hepatic fibrosis scores compared with placebo. Conclusions/interpretation Twelve-week liraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01744236 Funding Funded by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282521 – the SAFEGUARD project. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4100-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background: Diabetic retinopathy (DRP) is a common microvascular complication seen in patients with type 1 diabetes mellitus (T1DM). The effects of T1DM and concomitant (proliferative) DRP on retinal blood flow are currently unclear. Therefore, we measured retinal vascular blood flow in T1DM patients with and without DRP and non-diabetic controls. We further assessed the acute effects of panretinal photocoagulation on retinal microvascular bloodflow in eight patients with diabetes. Methods: Thirty-three T1DM patients with proliferative DRP, previously treated with panretinal photocoagulation (pDRP), 11 T1DM patients with untreated non-proliferative retinopathy (npDRP) and 32 T1DM patients without DRP (nDRP) were compared with 44 non-diabetic gender-matched controls. Using scanning laser Doppler flowmetry (HRF, Heidelberg) blood flow in the retinal microvasculature was measured temporal and nasal of the optic disc and averaged into one flow value per eye. The right eye was used as a default for further analyses. Eight patients with novel proliferative retinopathy (4 T1DM and 4 with type 2 diabetes) were measured before and several months after photocoagulation. Between-group differences in retinal blood flow were assessed using ANOVA corrected for multiple comparisons (Bonferroni). Results: Retinal blood flow was higher in the treated pDRP compared with the nDRP group and controls (all P-Bonferroni 0.05). Using regression analysis, no variables were found as predictors of retinal blood flow. Conclusions: In comparison with controls and nDRP patients, retinal blood flow significantly increased in the pDRP group, which previously underwent photocoagulation treatment, but not in the npDRP patients. These changes may be a consequence of a failing vascular autoregulation in advanced diabetic retinopathy.

CONTEXT:Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonist treatment in type 2 diabetes (T2DM) reduce blood glucose and food intake. It has been suggested that these effects are partly mediated through central GLP-1 receptors (GLP-1Rs). The rodent and nonhuman primate hypothalamus show clear GLP-1R expression. However, a detailed description of GLP-1R expression in the human hypothalamus is lacking, and it is unknown whether this expression is altered in T2DM patients.OBJECTIVE:The objective of the study was to investigate the GLP-1R distribution in the human postmortem hypothalamus and to determine whether hypothalamic GLP-1R expression is altered in T2DM patients.DESIGN:We investigated the distribution of GLP-1R expression throughout the human hypothalamus by means of in situ hybridization. We also performed quantifications of GLP-1R mRNA expression in two hypothalamic nuclei (ie, the paraventricular nucleus [PVN] and infundibular nucleus [IFN]), comparing patients with T2DM and control subjects.RESULTS:We found that GLP-1R mRNA was expressed in a number of hypothalamic nuclei including the PVN and the IFN, both involved in the regulation of energy metabolism. We observed sporadic colocalization of the GLP-1R in the IFN with the orgexigenic neuropeptide Y, agouti-related peptide, or proopiomelanocortin transcripts. Comparison of GLP-1R mRNA in the PVN and IFN between T2DM patients and control subjects revealed a decreased expression in T2DM patients.CONCLUSIONS:Our studies show that GLP-1R is widely expressed throughout the human hypothalamus. The decreased expression of GLP-1R in the PVN and IFN of T2DM patients may be related to the dysregulation of feeding behavior and glucose homeostasis in T2DM.