Carl Johan Behre

Gut metagenome in European women with normal, impaired and diabetic glucose control

Type 2 diabetes (T2D) is a result of complex gene–environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.

Human oral, gut, and plaque microbiota in patients with atherosclerosis

Periodontal disease has been associated with atherosclerosis, suggesting that bacteria from the oral cavity may contribute to the development of atherosclerosis and cardiovascular disease. Furthermore, the gut microbiota may affect obesity, which is associated with atherosclerosis. Using qPCR, we show that bacterial DNA was present in the atherosclerotic plaque and that the amount of DNA correlated with the amount of leukocytes in the atherosclerotic plaque. To investigate the microbial composition of atherosclerotic plaques and test the hypothesis that the oral or gut microbiota may contribute to atherosclerosis in humans, we used 454 pyrosequencing of 16S rRNA genes to survey the bacterial diversity of atherosclerotic plaque, oral, and gut samples of 15 patients with atherosclerosis, and oral and gut samples of healthy controls. We identified Chryseomonas in all atherosclerotic plaque samples, and Veillonella and Streptococcus in the majority. Interestingly, the combined abundances of Veillonella and Streptococcus in atherosclerotic plaques correlated with their abundance in the oral cavity. Moreover, several additional bacterial phylotypes were common to the atherosclerotic plaque and oral or gut samples within the same individual. Interestingly, several bacterial taxa in the oral cavity and the gut correlated with plasma cholesterol levels. Taken together, our findings suggest that bacteria from the oral cavity, and perhaps even the gut, may correlate with disease markers of atherosclerosis.

Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64-year-old women.

Abstract.  Fagerberg B, Kellis D, Bergström G, Behre CJ (Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden). Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64‐year‐old women. J Intern Med 2011; 269: 636–643.

Feasibility of bariatric surgery as a strategy for secondary prevention in cardiovascular disease: a report from the Swedish Obese Subjects trial.

Aims. Evaluation of bariatric surgery as secondary prevention in obese patients with ischemic heart disease (IHD). Methods. Analysis of data from 4047 subjects in the Swedish Obese Subjects (SOSs) study. Thirty-five patients with IHD are treated with bariatric surgery (n = 21) or conventional treatment (n = 14). Mean follow-up is 10.8 years. Results. Bariatric surgery resulted in sustained weight loss during the study period. After 2 years, the surgery group displayed significant reductions in cardiovascular risk factors, relief from cardiorespiratory symptoms, increments in physical activity, and improved quality of life. After 10 years, recovery from hypertension, diabetes, physical inactivity, and depression was still more common in the surgery group. There were no signs of increased cardiovascular morbidity or mortality in the surgery group. Conclusion. Bariatric surgery appears to be a safe and feasible treatment to achieve long-term weight loss and improvement in cardiovascular risk factors, symptoms, and quality of life in obese subjects with IHD.

Are serum adiponectin concentrations in a population sample of 64-year-old Caucasian women with varying glucose tolerance associated with ultrasound-assessed atherosclerosis?

Objective.  To examine whether serum adiponectin concentrations were associated with subclinical atherosclerosis assessed as intima media thickness (IMT) in the carotid arteries in Caucasian women with varying degrees of glucose tolerance.

Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome

Genetic and epigenetic factors may predispose women to polycystic ovary syndrome (PCOS), a common heritable disorder of unclear etiology. Here we investigated differences in genome-wide gene expression and DNA methylation in adipose tissue from 64 women with PCOS and 30 controls. In total, 1720 unique genes were differentially expressed (Q < 0.05). Six out of twenty selected genes with largest expression difference (CYP1B1, GPT), genes linked to PCOS (RAB5B) or type 2 diabetes (PPARG, SVEP1), and methylation (DMAP1) were replicated in a separate case-control study. In total, 63,213 sites (P < 0.05) and 440 sites (Q < 0.15) were differently methylated. Thirty differentially expressed genes had corresponding changes in 33 different DNA methylation sites. Moreover, a total number of 1913 pairs of differentially expressed “gene-CpG” probes were significantly correlated after correction for multiple testing and corresponded with 349 unique genes. In conclusion, we identified a large number of genes and pathways that are affected in adipose tissue from women with PCOS. We also identified specific DNA methylation pathways that may affect mRNA expression. Together, these novel findings show that women with PCOS have multiple transcriptional and epigenetic changes in adipose tissue that are relevant for development of the disease.

Moderate Intensities of Leisure-Time Physical Activity Are Associated With Lower Levels of High-Sensitivity C-Reactive Protein in Healthy Middle-Aged Men

Circulating C-reactive protein (CRP), reflective of systemic chronic low-grade inflammation, is a marker associated with cardiovascular disease (CVD). One of the mechanisms through which physical activity might promote cardiovascular health is by preventing changes in inflammation biomarkers, such as CRP. The present study examined the association of self-reported physical activity with an inflammation biomarker, high-sensitivity CRP (hs-CRP), in a population-based cohort of clinically healthy 58-year-old men. Compared with a sedentary lifestyle both moderate (1.81 [0.94-3.69] vs 1.28 [0.55-2.90] mg/L; P < .05) and vigorous physical activity (1.81 [0.94-3.69] vs 0.88 [0.42-1.81] mg/L; P < .001) were associated with decrease in hs-CRP levels. In summary, we identified an association between self-reported leisure time physical activity and hs-CRP in a cross-sectional study of healthy 58-year-old men, with decreased levels of CRP by increased intensities of physical activity.

The Lipocalins Retinol-Binding Protein-4, Lipocalin-2 and Lipocalin-Type Prostaglandin D2-Synthase Correlate with Markers of Inflammatory Activity, Alcohol Intake and Blood Lipids, But not with Insulin Sensitivity in Metabolically Healthy 58-year-Old Swedish Men

The lipocalins retinol-binding protein (RBP)-4, lipocalin-2 and lipocalin-type prostaglandin D-synthase (L-PGDS) have been suggested to mediate obesity-associated insulin resistance and other metabolic co-morbidities. The role of lipocalins is however controversial and it is unclear whether they have a physiological role in regulation of insulin sensitivity and metabolic function in clinically healthy humans. Therefore, we examined the correlations between serum levels of RBP-4, L-PGDS and lipocalin-2 and insulin sensitivity and other metabolic parameters in non-diabetic subjects selected to display variations in insulin sensitivity. 100 clinically healthy 58-year-old Swedish men were selected by stratified sampling among 818 screened subjects to represent quintiles of varying degrees of insulin sensitivity. Insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp method. Serum levels of lipocalins and cytokines were determined using antibody-based techniques. Serum lipids were measured by standardized laboratory methods. None of the measured lipocalins showed any correlations with insulin sensitivity. However, we found that lipocalin-2 and L-PGDS were correlated with each other, but not with RBP-4. Lipocalin-2 and L-PGDS were positively correlated with soluble TNF- receptors 1 and 2 and negatively with alcohol consumption and serum HDL. Further, lipocalin-2 was correlated with interleukin-6 whereas RBP-4 was negatively correlated with TNF-α. □These results suggest that RBP-4, lipocalin-2 and L-PGDS do not regulate insulin sensitivity in healthy men. Rather the expression levels of lipocalin-2 and L-PGDS, but not RBP-4, seemed to reflect inflammatory activity and were inversely correlated with alcohol intake and serum HDL levels.

The haptoglobin 2-2 genotype is associated with carotid atherosclerosis in 64-year old women with established diabetes

BACKGROUND Haptoglobin polymorphism generates three common human genotypes: Hp1-1, Hp2-1 and Hp2-2. Among subjects with diabetes, Hp2-2 is associated with an elevated risk to develop cardiovascular disease. The impact of haptoglobin genotype on subclinical carotid atherosclerosis is not known. We hypothesized that Hp2-2 was associated with increased occurrence of carotid atherosclerosis in subjects with diabetes. METHODS We studied a population-based sample of 64-year old women with diabetes (n=226), either established diabetes known before study entry (n=116) or new diabetes detected at study screening (n=110). Haptoglobin genotype was determined by PCR. Carotid atherosclerosis was assessed by ultrasound imaging. RESULTS In the entire diabetes cohort, no differences were observed in carotid intima-media thickness (IMT) or plaque prevalence between the genotype groups. However, among those with established diabetes, Hp2-2 was associated with higher plaque prevalence and larger carotid IMT compared with the Hp2-1 and Hp1-1 genotypes. Common cardiovascular risk factors did not differ between the genotype groups. CONCLUSIONS The Hp2-2 genotype was associated with increased occurrence of subclinical carotid atherosclerosis in 64-year old women with established diabetes. This association was not explained by traditional risk factors for cardiovascular disease. These results extend previous observations that Hp2-2 is associated with clinical cardiovascular disease in diabetes.

Central Nervous System Lipocalin‐Type Prostaglandin D2‐Synthase is Correlated with Orexigenic Neuropeptides, Visceral Adiposity and Markers of the Hypothalamic‐Pituitary‐Adrenal Axis in Obese Humans

Lipocalin‐type prostaglandin D2‐synthase (L‐PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L‐PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L‐PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3‐week dietary lead‐in followed by 12‐weeks of leptin or placebo treatment. At baseline, CSF L‐PGDS was positively correlated with neuropeptide Y (NPY) (ρ = 0.695, P < 0.001, n = 26) and galanin (ρ = 0.651, P < 0.001) as well as visceral adipose tissue (ρ = 0.415, P = 0.035). Furthermore, CSF L‐PGDS was inversely correlated with CSF leptin (ρ = −0.529, P = 0.005) and tended to correlate inversely with s.c. adipose tissue (ρ = −0.346, P = 0.084). As reported earlier, leptin treatment had no effect on weight loss and did not affect CSF L‐PGDS or NPY levels compared to placebo. After weight loss, the change of CSF L‐PGDS was significantly correlated with the change of CSF NPY levels (ρ = 0.604, P = 0.004, n = 21). Because of the correlation between baseline CSF L‐PGDS levels and visceral adipose tissue, we examined associations with hypothalamic‐pituitary‐adrenal (HPA) axis components. Baseline CSF L‐PGDS was correlated with corticotrophin‐releasing hormone (ρ = 0.764, P < 0.001) and β‐endorphin (ρ = 0.491, P < 0.001). By contrast, serum L‐PGDS was not correlated with any of the measured variables either at baseline or after treatment. In summary, CSF L‐PGDS was correlated with orexigenic neuropeptides, visceral fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L‐PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail.