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.

Aim To assess the effects of Roux-en-Y gastric bypass surgery (RYGB)-related changes in glucagon-like peptide-1 (GLP-1) on cerebral resting-state functioning in obese women. Materials and Methods In nine obese females aged 40-54 years in the fasted state, we studied the effects of RYGB and GLP-1 on five a priori selected networks implicated in food- and reward-related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). Results Before surgery, GLP-1 receptor blockade (using exendin9-39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP-1 receptor blockade had a larger effect on connectivity in this region than GLP-1 receptor blockade before RYGB (all P-FWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. Conclusions These findings suggest GLP-1 involvement in resting-state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP-1-induced changes in resting-state connectivity in RYGB-mediated weight loss and appetite control.

1 Department of Medical Psychology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 2 Amsterdam Diabetes Center / Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 3 Instituto Estadual do Cérebro Paulo Niemeyer, Center for Epilepsy, Rio de Janeiro, RJ, Brazil 4 Department of Neurology, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil 5 Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 6 Institute of Neurology and Healthcare Engineering, University College London, London, United Kingdom 7 Department of Ophthalmology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands 8 Department of Medical Psychology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands † Deceased

NAFLD is closely related with the metabolic syndrome (MetS) and increased risk of cardiovascular disease. Liver fat associates with post‐prandial hypertriglyceridemia, potentially contributing to triglyceride‐enrichment of high‐density lipoproteins (HDL‐TG), and subsequent HDL dysfunction. We assessed liver fat by MR spectroscopy, and its association with HDL physiochemical properties, and endothelial function, measured as flow‐mediated dilation (FMD), before and following three consecutive meals, in 36 men with type 2 diabetes mellitus (T2DM), with the MetS, and controls. Plasma triglycerides increased significantly following the meals ( P < .001). Fasting HDL‐TG was highest in T2DM, relative to MetS and controls ( P = .002), and increased post‐prandially in all groups ( P < .001). HDL function was negatively associated with HDL‐TG following three meals ( r = −.32, P <.05). Liver fat associated with HDL‐TG after three meals ( r = .65, P < .001). HDL‐TG was independently associated with FMD following three consecutive meals ( r = −.477, P = .003). We conclude liver fat is associated with post‐prandial HDL‐TG enrichment which was closely related with endothelial and HDL dysfunction.

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<0.001) and fat percentage (3.5%; P<0.001) but did not affect glucose uptake nor lipolysis. The hypercaloric diet increased adipose tissue microvascular recruitment (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<0.001). The hypocaloric diet reversed all of these changes, except the increase in adipose tissue microvascular recruitment.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.

OBJECTIVE:Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. We aimed to identify cerebral microangiopathy and skin microvascular dysfunction-as a surrogate marker for generalized microvascular function-as predictors of cognitive performance over time.METHODS:In this prospective cohort study, 25 type 1 diabetes patients with proliferative retinopathy and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (3.8 ± 0.8 years). At baseline, 1.5-T cerebral magnetic resonance imaging was used to detect WML and cerebral microbleeds. Skin capillary perfusion was assessed by means of capillary microscopy.RESULTS:In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß = -0.419; P = 0.037) as well as lower skin capillary perfusion (baseline: ß = 0.753; P < 0.001; peak hyperemia: ß = 0.743; P = 0.001; venous occlusion: ß = 0.675; P = 0.003; capillary recruitment: ß = 0.549; P = 0.022) at baseline was associated with lower cognitive performance over time, independent of age, sex, HbA1c, and severe hypoglycemia. The relationship between WML and lower cognitive performance was significantly reduced after adjusting for capillary perfusion.CONCLUSIONS:These data fit the hypothesis that cerebral microangiopathy is a manifestation of generalized microvascular dysfunction, leading to lower cognitive performance.

On page 2048 of the article cited above, the word “increases” was corrected to read “decreases.” The …

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 < 0.05 for all). In patients, lower executive performance was related to loss of right precuneus surface area (PFWE  = 0.005). Higher HbA1c during follow-up was related to executive function decline (r = -0.509, P = 0.016) and loss of left hemisphere surface area (rcorrected analysis  = -0.555, P = 0.007). CONCLUSIONS:After 3.5 years of follow-up, middle-aged T1DM patients with proliferative retinopathy, mild focal changes in executive functions, and cortical structure were found, which may indicate accelerated aging.

AimsTo determine the effects of glucagon‐like peptide (GLP)‐1 receptor agonists (RA) on uric acid (UA) levels and kidney UA clearance.Material and methodsThis 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.ResultsMedian 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 < .001, respectively). Fractional UEUA correlated with increased fractional UENa (r:0.76, P = .02). In Study‐B, exenatide infusion did not affect plasma UA, but increased fractional UEUA (+0.76 ± 0.38%, P = .049) and absolute UEUA (+0.75 ± 0.27 mg/min/1.73 m2, P = .007), compared to placebo. In regression analyses, both parameters were explained by changes in urine pH and, in part, by changes in UENa. In Study‐C, liraglutide treatment did not affect plasma UA, UEUA, UENa or urine pH, compared to placebo. In Study‐D, lixisenatide treatment increased UENa and urine pH from baseline, but did not affect plasma UA or UEUA.ConclusionImmediate exenatide infusion increases UEUA in overweight healthy men and in T2DM patients, probably by inhibiting Na+/H+‐exchanger type‐3 in the renal proximal tubule. Prolonged treatment with a long‐acting or short‐acting GLP‐1RA does not affect plasma UA or UEUA in T2DM patients with normal plasma UA levels and at relatively low cardiovascular risk. Our results suggest that the cardio‐renal benefits of GLP‐1RA are not mediated through changes in UA.

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 (P (FWE) < 0.05). Normoglycemic obese versus controls had lower thickness (P (FWE) < 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 P (FWE) < 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.

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.

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.

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 m 2 , 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 m 2 (95% CI −9 to 9)], ERPF [−17 mL /min/1.73 m 2 (−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

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.

Vendrik, Karuna E.W. MD; Tonneijck, Lennart MD; Muskiet, Marcel H.A. MD; Kramer, Mark H.H. MD, PhD; Pouwels, Petra J.W. PhD; Pieters-van den Bos, Indra C. MD, PhD; Diamant, Michaela MD, PhD; Cahen, Djuna L. MD, PhD; van Raalte, Daniël H. MD, PhD; Smits, Mark M. MDAuthor Information

INTRODUCTION:Longstanding type 1 diabetes (T1DM) is associated with microangiopathy and poorer cognition. In the brain, T1DM is related to increased functional resting-state network (RSN) connectivity in patients without, which was decreased in patients with clinically evident microangiopathy. Subcortical structure seems affected in both patient groups. How these localized alterations affect the hierarchy of the functional network in T1DM is unknown. Eigenvector centrality mapping (ECM) and degree centrality are graph theoretical methods that allow determining the relative importance (ECM) and connectedness (degree centrality) of regions within the whole-brain network hierarchy. METHODS:Therefore, ECM and degree centrality of resting-state functional MRI-scans were compared between 51 patients with, 53 patients without proliferative retinopathy, and 49 controls, and associated with RSN connectivity, subcortical gray matter volume, and cognition. RESULTS:In all patients versus controls, ECM and degree centrality were lower in the bilateral thalamus and the dorsal striatum, with lowest values in patients without proliferative retinopathy (PFWE < 0.05). Increased ECM in this group versus patients with proliferative retinopathy was seen in the bilateral lateral occipital cortex, and in the right cuneus and occipital fusiform gyrus versus controls (PFWE < 0.05). In all patients, ECM and degree centrality were related to altered visual, sensorimotor, and auditory and language RSN connectivity (PFWE < 0.05), but not to subcortical gray matter volume or cognition (PFDR > 0.05). CONCLUSION:The findings suggested reorganization of the hierarchy of the cortical connectivity network in patients without proliferative retinopathy, which is lost with disease progression. Centrality seems sensitive to capture early T1DM-related functional connectivity alterations, but not disease progression. Hum Brain Mapp 38:3623-3636, 2017. © 2017 Wiley Periodicals, Inc.

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 < 0.01 as compared to patients) were analyzed. Both myocardial perfusion during adenosine-induced hyperemia (P < 0.01), and coronary flow reserve (P < 0.01), measured by [ 15 O]H 2 O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efficiency, measured using [ 11 C]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