Design and baseline data in the BAriatic surgery SUbstitution and Nutrition study (BASUN): a 10-year prospective cohort study.

BACKGROUND: There is still a lack of knowledge on long-term effects of surgical and non-surgical weight-lowering treatments. BASUN is a prospective study with 10 years of follow-up that will observe the effects and consequences of surgical and medical treatment of obesity. The aims are to cover areas where data on long-term outcomes are lacking, e.g., nutritional deficiencies, substance abuse, psychiatric health, as well as patient-reported outcomes. METHODS: BASUN is a cohort study that recruited study persons with obesity (BMI ≥ 35 kg/m2) referred to the Regional Obesity Centre of Region Västra Götaland. The interventions were Roux-en-Y gastric bypass (RYGB) or Sleeve gastrectomy (SG), or 12 months of structured, multi-professional medical treatment (MT), including very low energy diet, followed by diet and pharmaceutical treatment. The study is not randomized, but based on patients preferences and multidisciplinary assessments. The study persons are examined at baseline, 2, 5, and 10 years with blood tests, measurements and questionnaires. The recruitment period lasted from May 2015 to November 2017. RESULTS: One thousand one hundred twenty-seven patients were included (74% female). Three hundred eighty-two patients were accepted for medical treatment, 589 for surgical treatment (388 RYGB and 201 SG) and 156 patients left the study without treatment, leaving a final study population of 971 patients. There were slight differences between the treatment groups with regards to age and BMI. Pharmaceutical treatments, level of education, smoking and marital status were not significantly different between the groups. CONCLUSION: This study will follow 971 obese subjects in clinical practice treated with the best surgical or medical methods currently available. It has the potential to evaluate outcomes usually not reported in short-term studies, and to assist in identifying factors that are of importance for the choices of treatment. The main limitations are non-randomization and differences in baseline characteristics. The large number of participants and the length of the prospective follow-up are major strengths of the study. BASUN is designed to identify both early and late benefits and adverse events of treatment of obesity. TRIAL REGISTRATION: This trial was prospectively registered on March 03, 2015; NCT03152617.

Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture.

A single bout of low-frequency electroacupuncture (EA) causing muscle contractions increases whole-body glucose uptake in insulin-resistant rats. We explored the underlying mechanism of this finding and whether it can be translated into clinical settings. Changes in glucose infusion rate (GIR) were measured by euglycemic-hyperinsulinemic clamp during and after 45 min of low-frequency EA in 21 overweight/obese women with polycystic ovary syndrome (PCOS) and 21 controls matched for age, weight, and body mass index (experiment 1) and in rats receiving autonomic receptor blockers (experiment 2). GIR was higher after EA in controls and women with PCOS. Plasma serotonin levels and homovanillic acid, markers of vagal activity, decreased in both controls and patients with PCOS. Adipose tissue expression of pro-nerve growth factor (proNGF) decreased, and the mature NGF/proNGF ratio increased after EA in PCOS, but not in controls, suggesting increased sympathetic-driven adipose tissue metabolism. Administration of α-/ß-adrenergic receptor blockers in rats blocked the increase in GIR in response to EA. Muscarinic and dopamine receptor antagonist also blocked the response but with slower onset. In conclusion, a single bout of EA increases whole-body glucose uptake by activation of the sympathetic and partly the parasympathetic nervous systems, which could have important clinical implications for the treatment of insulin resistance.-Benrick, A., Kokosar, M., Hu, M., Larsson, M., Maliqueo, M., Marcondes, R. R., Soligo, M., Protto, V., Jerlhag, E., Sazonova, A., Behre, C. J., Højlund, K., Thorén, P., Stener-Victorin, E. Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture.

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.

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.

Low 25-OH vitamin D is associated with benign prostatic hyperplasia.

PURPOSE: We tested the hypothesis that low vitamin D is associated with benign prostatic hyperplasia. We also studied whether body composition, sex hormones, serum sex hormone-binding globulin, albumin corrected serum calcium, adiponectin and lipid status are associated with benign prostatic hyperplasia. MATERIALS AND METHODS: We investigated 184 representative, randomly selected men 72 to 76 years old enrolled in the Gothenburg arm of the Osteoporotic Fractures in Men Study (MrOS). Men with a history of prostate cancer, prostate operation or medication for benign prostatic hyperplasia were excluded from study, leaving 155 available for analysis. A cross-sectional study was performed in which benign prostatic hyperplasia measured by total prostate volume was related to clinical, anthropometric, endocrine and metabolic factors on univariate and multivariate analyses with regression models. RESULTS: Median prostate volume was 40 ml. In multivariate models only 25-OH vitamin D, albumin corrected serum calcium, serum sex hormone-binding globulin and high density lipoprotein cholesterol were significantly and inversely associated with large prostate glands. CONCLUSIONS: The current report adds 4 independent factors associated with benign prostatic hyperplasia, including low 25-OH vitamin D, serum calcium, sex hormone-binding globulin and high density lipoprotein cholesterol.

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.

Increasing leisure time physical activity is associated with less prevalence of the metabolic syndrome in healthy middle-aged men.

The metabolic syndrome (MetS) is characterized by a constellation of factors that confer an increased risk for cardiovascular morbidity and mortality. It is well-known that physical activity (PA) has a protective role on cardiovascular morbidity and mortality, mainly through its favorable effects on traditional risk factors such as body mass and blood pressure (BP). We assessed the prevalence of MetS in a population-based sample of 58-year-old men with respect to leisure-time PA and also to occupational PA. The results showed an inverse linear association (P < .05) between leisure time physical activity (LTPA) and MetS in this group. In conclusion, this study suggests that PA has an important role in controlling MetS.

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.

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.

Slightly elevated high-sensitivity C-reactive protein (hsCRP) concentrations are associated with carotid atherosclerosis in women with varying degrees of glucose tolerance.

We examined whether high-sensitivity C-reactive protein (hsCRP) ≥2.0 mg/L was associated with increased intima-media thickness (IMT), plaque burden, and plaque echolucency in carotid arteries. Women (n = 635) from a population sample of 64-year-old females with varying degrees of glucose tolerance underwent risk factor assessment, measurement of hsCRP, and ultrasound examinations of the carotid arteries. Participants with hsCRP levels ≥2.0 mg/L had elevated carotid bulb IMT independently of other cardiovascular risk factors compared with those with hsCRP <2.0 mg/L. The participants with plaques in the highhsCRP group had larger total plaque area compared to those with plaque in the lower hsCRP group. Plaque echolucency did not differ between groups. High-sensitivity CRP levels ≥2.0 mg/L were accompanied by elevated IMT in the carotid bulbs independently of other cardiovascular risk factors. Total plaque area was larger among women with plaques in the high hsCRP group versus the lower hsCRP group.

Ankle-brachial index should be measured in both the posterior and the anterior tibial arteries in studies of peripheral arterial disease.

Lower extremity peripheral artery disease (PAD) is a powerful predictor of cardiovascular events and mortality. The ankle-brachial index (ABI) is an objective and standard diagnostic method to diagnose PAD (an ABI ≤ 0.9 is considered pathological). The American Heart Association (AHA) and the American College of Cardiology (ACC) recommend using both the posterior and anterior tibial arteries when assessing ABI. We investigated whether there was a difference in the diagnosis of PAD if the ABI was measured in the posterior or the anterior tibial arteries. The results showed that among participants with ABI ≤0.9, between 30% and 40% would not get a PAD diagnosis if the ABI was measured in only 1 of the arteries. In conclusion, this study emphasizes the importance of measuring the ABI in both the posterior tibial and the anterior tibial arteries when diagnosing PAD.

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.

Albuminuria within the normal range and ultrasound-assessed atherosclerosis in the AIR study: a 9-year follow-up of 58-year-old clinically healthy men.

BACKGROUND: Microalbuminuria, traditionally defined as 30-300 mg urinary albumin/24 h, predicts renal impairment and cardiovascular disease. Studies suggest that also a far lower urinary albumin excretion (UAE) can predict clinical outcome. Intima media thickness (IMT) is an established estimate of atherosclerosis. In this study, we investigated the predictive value of UAE within the normal rate (UAE-n) for the progression of IMT in the carotid and femoral arteries. METHODS: We included 325 clinically healthy men with normoalbuminuria. Anthropometrics, urine and blood samples were taken and IMT in the carotid and femoral arteries were assessed by B-mode ultrasound at baseline and after 3 and 9 years. The annual progression rate of IMT (r-IMT) was calculated. RESULTS: UAE-n correlated with carotid IMT at baseline and after 3 and 9 years, but not with r-IMT. In a regression analysis, only HDL and baseline IMT remained as statistically significant co-variates to mean IMT at 9 years. IMT in the femoral artery and r-IMT at any time-point did not correlate to baseline UAE. CONCLUSION: UAE-n was associated with carotid IMT after 3 and 9 years but not r-IMT or with femoral artery IMT. Carotid IMT after 9 years' follow-up was independently related to baseline IMT and HDL cholesterol. In this cohort of 58-year-old men, our interpretation is that UAE-n is not associated with the increase in carotid and femoral artery IMT observed after 9 years.

C-reactive protein and tumor necrosis factor-alpha in relation to insulin-mediated glucose uptake, smoking and atherosclerosis.

OBJECTIVES: To examine the hypothesis that serum concentration of C-reactive protein (CRP) is inversely associated with insulin sensitivity and obesity, and that this may by mediated by tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6). MATERIAL AND METHODS: Cross-sectional, one-center study of a population-based sample of 58-year-old Swedish men (n = 98). Exclusion criteria were cardiovascular disease, clinical diabetes mellitus and/ or continuous cardiovascular medication. Glucose infusion-rate (euglycemic hyperinsulinemic clamp), adjusted for fat-free mass, which together with total body fat was measured by dual-energy X-ray absorptiometry. Serum concentrations of CRP, TNFalpha, soluble TNFalpha receptor 2 (sTNFAR2), IL-6 determined by ELISA. Ultrasound was used to measure intima-media thickness (IMT) in both common carotid arteries, carotid bulbs and in the right femoral artery. RESULTS: CRP was inversely associated with insulin sensitivity (r = -0.28, p < 0.01) and with total body fat (r = 0.31, p < 0.01), but not independently of the TNFalpha and sTNFAR2 product. Serum CRP, TNFalpha, sTNFAR2, but not IL-6, were associated with low insulin sensitivity, total body fat, abdominal obesity, hyperinsulinemia, hypertriglyceridemia, low HDL cholesterol and small LDL particles, i.e. the metabolic syndrome. These associations were independent of smoking and carotid and femoral artery IMT. CONCLUSIONS: Serum concentrations of CRP were related to insulin sensitivity and accompanying factors constituting the metabolic syndrome. The results indicate that this association may be mediated by adipose tissue and TNFalpha effects, the latter measured as the product of TNFalpha and sTNFAR2. This was a cross-sectional study and causality cannot be proven.

Dissociation between adipose tissue expression and serum levels of adiponectin during and after diet-induced weight loss in obese subjects with and without the metabolic syndrome.

The study aimed to examine if dysmetabolic subjects (MetS+) have lower adiponectin gene expression and lower circulating adiponectin levels than non-dysmetabolic obese subjects (MetS-) at baseline, if adiponectin expression and adiponectin concentration rise more in the dysmetabolic group during weight loss, and if v-SNARE Vti1a (vesicle transport soluble NSF attachment protein receptor vps10p tail interacting 1a) expression increases during the weight loss, as a mechanism for increased adiponectin secretion. Twenty-one obese MetS+ and 19 obese MetS- subjects underwent a very low-energy diet for 16 weeks followed by 2 weeks of refeeding. Abdominal subcutaneous adipose tissue biopsies and blood samples were taken before, during, and after dieting for DNA microarray, reverse transcriptase-polymerase chain reaction, and biochemical analyses. Serum adiponectin was also assessed in a sex- and age-matched healthy, nonobese reference group. Weight decreased by 26.3+/-9.8 kg in the MetS+ group and 28.2+/-8.4 kg in the MetS- group with concomitant reductions in insulin, hemoglobin A1c, and triglycerides that were more pronounced in the MetS+ group. Initially, the MetS+ subjects had lower serum adiponectin, but the differences disappeared at week 8, with a continuous increase in serum adiponectin throughout the study in both groups to a level that was higher than in the reference group. The expression of adiponectin and v-SNARE Vti1a did not differ between the groups or over time. In conclusion, obese subjects with the metabolic syndrome had lower circulating adiponectin than subjects without the syndrome. Weight loss increased serum levels of adiponectin without a parallel increase in adiponectin gene expression. The mechanisms involved in the regulation of adiponectin levels merits further investigation.

Alcohol consumption in relation to metabolic regulation, inflammation, and adiponectin in 64-year-old Caucasian women: a population-based study with a focus on impaired glucose regulation.

OBJECTIVE: The aims of this study were to examine alcohol drinking patterns in women with type 2 diabetes, impaired glucose tolerance (IGT), and normal glucose tolerance (NGT) and to investigate whether alcohol intake was associated with improved insulin sensitivity, decreased biomarkers of inflammation, and increased adiponectin levels and if these effects were limited to dysmetabolic women. RESEARCH DESIGN AND METHODS: From a cohort of 64-year-old Caucasian women, 209 with type 2 diabetes, 205 with IGT, and 186 with NGT were recruited. Alcohol consumption and medication use were assessed by questionnaires. Anthropometric data were collected, and blood glucose, insulin, HDL cholesterol, triglycerides, C-reactive protein, white blood cell count, and serum adiponectin were measured. RESULTS: Compared with the NGT group, alcohol consumption was lower in the IGT group and lowest in the diabetes group. Mean alcohol intakes of >9.2 and > or =3-9 g/day were positively associated with adiponectin and insulin sensitivity (homeostasis model assessment [HOMA]), respectively, independently of obesity, metabolic control, and other confounders. Alcohol intake correlated negatively with inflammatory markers, although this did not remain after adjustment for HOMA and waist circumference. The inverse associations between alcohol consumption and factors related to the metabolic syndrome such as HOMA, waist circumference, and inflammatory markers were more obvious among women with diabetes and IGT than in healthy women. CONCLUSIONS: In these women, moderate alcohol consumption showed beneficial associations with the prevalence of type 2 diabetes, IGT, insulin sensitivity, and serum adiponectin. There is a need to clarify whether adiponectin may be a mechanistic link and also to clarify the clinical implications of these observations.