Objective Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota–immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT). Design Patients with recent-onset (<6 weeks) T1D (18–30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition. Results Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics. Conclusion FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D. Trial registration number NTR3697.

Background: Depressive and anxiety disorders are highly overlapping, heterogeneous conditions that both have been associated with an increased risk of cardiovascular disease (CVD). Cognitive vulnerability traits for these disorders could help to specify what exactly drives CVD risk in depressed and anxious subjects. Our aim is to examine sensitivity to depression or anxiety in association with indicators of subclinical CVD.Methods: Data from 635 participants (aged 20-66 years) of the Netherlands Study of Depression and Anxiety were analyzed. Depression sensitivity was measured by the revised Leiden Index of Depression Sensitivity. Anxiety sensitivity was measured by the Anxiety Sensitivity Index. Subclinical CVD was measured as (1) carotid intima-media thickness and plaque presence using B-mode ultrasonography and (2) central arterial stiffness (augmentation index) using calibrated radial applanation tonometry.Results: After adjustment for sociodemographics, blood pressure, and LDL cholesterol, higher scores of anxiety sensitivity were associated with both increased likelihood of carotid plaques (OR per SD increase=1.34, 95%CI=1.06-1.68) and increased arterial stiffness (beta=.06, p=.01). No significant associations were found with carotid intima-media thickness nor for depression sensitivity.Limitations: The cross-sectional design precludes causal inference. Current mood state could have influenced the self-reported sensitivity data.Conclusions: The presence of carotid plaques and central arterial stiffness was especially increased in subjects who tend to be highly fearful of anxiety-related symptoms. These observations suggest that vulnerability to anxiety, rather than to depression, represents a correlate of subclinical CVD. (C) 2012 Elsevier B.V. All rights reserved.

Background & aims: Liver fat associates with postprandial hypertriglyceridemia, thus potentially contributing to postprandial triglyceride-enrichment of HDL (HDL-TG), and subsequent HDL dysfunction and finally cardiovascular disease.

Objectives: The partly modifiable risk factors, that constitute the metabolic syndrome (MetS), do not fully account for the associated functional and structural vascular abnormalities and increased cardiovascular disease risk. Cell-derived microparticles, which reflect ongoing cellular stress but also associate with cardiovascular disease, are elevated in subjects with MetS in the fasting state. We studied the relation between arterial stiffness and circulating microparticles under postprandial conditions in males with and without MetS. Methods: In 15 males with MetS and 15 controls, blood was collected before and following 3 consecutive meals during 24h. Arterial stiffness was measured as distensibility coefficient by carotid ultrasound. Microparticles were measured by flowcytometry. Results: MetS versus control males (both mean age 56 years) had higher body mass index, waist, blood pressure, fasting triglycerides and lower HDL-cholesterol. Twenty-four hour area under the curve (24h-AUC) triglycerides and insulin were elevated in MetS males compared to controls (both P<0.01), whereas 24h-AUC glucose was similar. The 24h-AUC of erythrocyte-derived, activated granulocyte and platelet-derived microparticles differed significantly (both P<0.05), whereas 24h-AUC of total and platelet-derived microparticles did not differ. Distensibility coefficient was negatively associated with 24h-AUC of triglycerides, insulin, and erythrocyte-derived-Conclusions: Postprandial changes in subpopulations of microparticles in healthy males and males with MetS were associated with arterial stiffness. Our findings suggest protective and deleterious effects of microparticles on arterial stiffness that may be associated with the cellular origin of these microparticles.

Objective. Mental health and cardiovascular disease have been associated, whereas the temporal course and underlying mechanisms are still incompletely understood. Our aims were to examine the presence of subclinical atherosclerosis in subjects with depressive or anxiety disorder, also taking into account disorder characteristics (subtype, severity, duration, age of onset, medication). Methods. The sample included 470 depression or anxiety cases and 179 controls, aged 20-66 years, participating in the Netherlands Study of Depression and Anxiety (NESDA). Diagnoses were assigned using the DSM-IV based Composite International Diagnostic Interview. Carotid intima-media thickness (CIMT) and plaque information were obtained using B-mode ultrasound imaging. Results. Overall, depressive and anxiety disorders were not associated with carotid atherosclerosis. However, age of depression onset was associated with CIMT (total: 0.01mm per 10 years, P=0.01; bifurcation: 0.02mm per 10 years, P=0.003) and plaque presence (OR = 1.35 per 10 years, 95% CI = 1.02-1.80, P=0.04). When compared with controls, late-onset (>= 40 years) depressed had an increased CIMT in the atherosclerosis progression-prone bifurcation segment (0.75 vs. 0.81 mm, P=0.004). Conclusions. These findings suggest a distinct pathophysiology of late-onset as compared with early-onset depression, including a vascular component.

Background: Arterial stiffness gains attention as a potential mechanism underlying the frequently found association between depression or anxiety and cardiovascular disease. However, observations regarding stiffness and psychopathology were often based on small samples. The current study aimed to examine whether subjects with a diagnosis of depressive or anxiety disorder showed increased stiffness and to explore associations between various psychiatric characteristics and arterial stiffness.Methods: The sample included 449 cases with DSM-IV based lifetime diagnoses of depressive and/or anxiety disorder and 169 control subjects. Subjects were participating in the Netherlands Study of Depression and Anxiety and were aged 20 to 66 years. Characteristics included comorbidity, subtype of disorder, symptom severity and duration, age of onset, and use of antidepressant medication. Arterial stiffness was measured by calibrated radial tonometry (heart rate normalized central augmentation index [AIx75]; in percentage) and carotid M-mode ultrasound (distensibility coefficient).Results: After adjustment for covariates, AIx75 was increased in current (1-month) depression or anxiety (15.7% vs. 13.3% in control subjects, p = .01). Disorder characteristics associated with AIx75 were depression and anxiety comorbidity (15.3%, p = .02), higher depression severity (beta = .10, p < .001) and anxiety severity (beta = .10, p < .001), and longer symptom duration (beta = .07, p = .01). No significant associations were found between distensibility coefficient and psychopathology.Conclusions: Current depressive or anxiety disorders were associated with a higher central augmentation index, a manifestation of early wave reflection because of arterial stiffness. Exposure to depression and anxiety may therefore enhance the development and progression of atherosclerosis and other cardiovascular conditions.

Objective: Liver fat is associated with dyslipidemia following a fat load. Previous studies demonstrated that alimentary fat is temporarily retained within enterocytes and mobilized by subsequently ingested nutrients. As this potentially contributes to cumulative postprandial hyperlipidemia, we assessed postprandial lipoprotein changes and their association with liver fat following 3 consecutive meals during a 24 h period in males with type 2 diabetes, and men with the metabolic syndrome (MetS).Methods: Plasma lipids were measured in 14 type 2 diabetic, 14 MetS and 14 healthy age-matched males, following a standardized breakfast (t = 0 h), lunch (t = 4 h) and diner (t = 8 h). Blood samples were collected before and at t = 2, 4, 6, 8, 12, 16, 20 and 24 h following breakfast. Liver fat was measured by proton magnetic resonance spectroscopy.Results: Type 2 diabetic (mean age 55 (4.2) years; HbA1c 7.2 (1.1)%) and MetS men had similar BMI, waist, blood pressure and triglycerides. 24 h-AUC triglycerides, ApoB, and cholesterol-rich-remnants, but not ApoB-48, differed significantly among groups (calculated by ANOVA, all P < 0.05). Liver fat was independently associated with 24 h-AUC triglycerides, ApoB and cholesterol-rich-remnants (r = 0.57, P < 0.001, r = 0.38, P = 0.017; r = 0.48, P = 0.002, respectively), but not with 24 h-AUC ApoB-48 (r = 0.22, P = 0.18).Conclusions: In type 2 diabetes and the MetS exposure to 3 consecutive meals produced exaggerated 24 h triglyceride, ApoB and cholesterol-rich-remnant concentrations, which were closely associated with liver fat. Instead, ApoB-48 peak was delayed in type 2 diabetes, but not related to liver fat. In addition to liver fat, other mechanisms, including local intestinal processes, determine atherogenic postprandial lipoprotein changes following 3 consecutive meals during 24 h. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Matrix metalloproteinases (MMPs) may play a pathophysiological role in the development of diabetic nephropathy (DN). We hypothesized that urinary MMP activity in patients with type 2 diabetes mellitus (T2DM) is related to a decline in renal function. We determined MMP-2, -8 and -9 activity in 24-h urine collections in relation to risk factors for DN in T2DM patients with (UA, n=27) and without albuminuria (NA, n=48) and controls (CO, n=28). MMP-8 and -9 levels were highest in UA patients (P<0.01). Of UA patients, 93% had at least one MMP increased, compared to 78% of NA patients and 46% of CO (P=0.001). Age, diabetes duration, BMI, systolic blood pressure, fasting plasma glucose, HbA1c and renal function were determinants of MMP-8 and -9 (P<0.05). In summary, MMP-8 and -9 are highest in T2DM UA patients. MMP-9, showed the strongest associations with clinical parameters related to DN.

Type 2 diabetes is associated with prolonged and exaggerated postprandial hyperglycemia and hypertriglyceridemia, endothelial dysfunction, and cardiovascular disease (CVD) (1–7). Endothelial dysfunction may link postprandial dysmetabolism to CVD (5–7). Since the postprandial state unveils the full scope of metabolic abnormalities in type 2 diabetes, previous studies (1) in fasting subjects may have underestimated the true risk. Currently, endothelial functions can only be estimated from indirect measurements, such as flow-mediated dilation (FMD) (6,8). Cell-derived microparticles are released by cells in response to stress. Increased numbers of microparticles of various cellular origin circulate in patients at risk of CVD (9,10). Recently, vascular-endothelial cadherin (CD144)-positive microparticles were demonstrated in type 2 diabetic patients with coronary artery disease and patients with end-stage renal disease (11,12). Since vascular-endothelial cadherin is exclusively expressed by endothelial cells, CD144-positive microparticles may be regarded as endothelium-derived microparticles (EMPs), directly reflecting endothelial damage. However, it is unknown whether circulating EMPs are cause or consequence of CVD, and whether their occurrence associates with CVD per se or, rather, with diabetes-related metabolic abnormalities. We hypothesized that in patients with uncomplicated type 2 diabetes, exposure to three consecutive high-fat mixed meals, given during a 24-h period, will disclose the full scope of their compromised metabolism and subsequent endothelial dysfunction, measured as FMD and circulating EMPs. After obtaining informed consent, 27 nonsmoking Caucasian male subjects ( n = 15 with uncomplicated type 2 diabetes and n = 12 healthy age-matched volunteers) were studied during a 24-h period. No drug use other than sulfonylureas and/or metformin was allowed. After an overnight fast, subjects received three consecutive, …