Inflammatory markers, the tryptophan-kynurenine pathway, and vitamin B status after bariatric surgery.

OBJECTIVE: Obesity is associated with increased inflammation and insulin resistance. In conditions with chronic immune activation, low plasma vitamin B6-levels are described, as well as an increased kynurenine:tryptophan-ratio (KTR). We investigated circulating tryptophan, kynurenine and its metabolites, neopterin, B-vitamins, CRP, and HbA1c in individuals with obesity before and after bariatric surgery. METHODS: This longitudinal study included 37 patients with severe obesity, scheduled for bariatric surgery. Blood samples were taken at inclusion and at three months and one year postoperatively. RESULTS: We observed significant positive correlations between HbA1c and both 3-hydroxy-kynurenine and 3-hydroxyanthranilic acid at inclusion. After surgery, fasting glucose, HbA1C and triglycerides decreased, whereas HDL-cholesterol increased. Tryptophan, kynurenine and its metabolites, except for anthranilic acid, decreased during weight loss. The KTR and CRP decreased while vitamin B6 increased during the year following operation, indicating reduced inflammation (all p<0.05). CONCLUSIONS: In patients with obesity subjected to bariatric surgery, levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid seemed to be positively correlated to impaired glucose tolerance. One year following surgery, plasma levels of the kynurenine metabolites were substantially decreased, along with a metabolic improvement. The relation of circulating kynurenine pathway metabolites with biomarkers of metabolic impairment in patients with obesity needs further evaluation.

The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease.

AIMS/HYPOTHESIS: The tryptophan metabolite kynurenine has potent immune modulatory and vasoactive properties. Experimental data implicate kynurenine in obesity-related morbidities. Epidemiological studies are, however, sparse. We evaluated associations of the plasma and urine kynurenine:tryptophan ratio (KTR) to incident type 2 diabetes. METHODS: We followed 2519 individuals with coronary artery disease (CAD; 73.1% men) without diabetes at baseline for a median of 7.6 years, during which 173 (6.9%) new incidences of type 2 diabetes were identified. Multivariate Cox regression analyses were applied to investigate the prospective relationships of plasma and urine KTR with new onset type 2 diabetes. RESULTS: At inclusion, mean (SD) age was 61.3 (10.4) years, BMI was 25.9 (3.71) kg/m2 and median (interquartile range) HbA1c was 5.6% (5.0%-6.0%) (38 [31-42] mmol/mol). Plasma KTR was not significantly related to type 2 diabetes risk. By contrast, urine KTR showed a strong positive association. Comparing quartile 4 with quartile 1, the HRs (95% CIs) were 2.59 (1.56, 4.30) and 2.35 (1.39, 3.96) in the age- and sex-adjusted and multivariate models, respectively. CONCLUSIONS/INTERPRETATION: Urine KTR is a strong predictor of incident type 2 diabetes in individuals with CAD. Potential clinical implications and possible pathogenic roles of renal kynurenine excretion in type 2 diabetes development should be further elucidated.

Consistent ethnic specific differences in diabetes risk and vitamin D status in the National Health and Nutrition Examination Surveys.

Previous findings from the Third National Health and Nutrition Examination Survey (NHANES III), a representative sample of the US population carried out in 1988-1994, showed an inverse association between diabetes risk and serum concentrations of 25-hydroxyvitamin D (25(OH)D) in non-Hispanic whites and Mexican-Americans but not in non-Hispanic blacks. The study aim was to determine if this same pattern in ethnic variation occurred in more recent NHANES surveys. Cross-sectional data came from the NHANES carried out from 1988 to 1994 (NHANES III) and from 2001 to 2006 (NHANES 01-06). The analysis included 11,331 people (5641 non-Hispanic white, 2714 non-Hispanic black and 2976 Mexican American) without known diabetes mellitus, fasting for ≥8h and aged ≥20 years, with available measurements of 25(OH)D, fasting glucose, fasting insulin and body mass index (BMI). Adjusting for age, gender, BMI, leisure time physical activity and season, higher levels of 25(OH)D were associated with decreased fasting glucose, decreased fasting insulin, and decreased diabetes risk in both non-Hispanic whites and Mexican Americans for both surveys and when combined. When combining NHANES III and NHANES 01-06 the odds ratio (95% confidence interval) for having diabetes was 0.28 (0.19, 0.41) in the highest 25(OH)D quartile compared to the lowest quartile in non-Hispanic whites, and 0.13 (0.06, 0.28) in Mexican Americans (both p<0.0001); but 1.54 (0.62, 3.82) in non-Hispanic blacks, among whom 25(OH)D was not associated with fasting glucose, fasting insulin, or diabetes risk (p>0.05). There was a significant interaction between non-Hispanic whites and Mexican Americans combined, compared with non-Hispanic blacks, when 25(OH)D was regressed against fasting glucose (p=0.016) but not against fasting insulin (p>0.05). The major finding in both NHANES surveys of consistent inverse associations between serum 25(OH)D concentrations and diabetes risk in non-Hispanic whites and Mexican Americans, but not in non-Hispanic blacks, suggests this finding is unlikely due to chance.

Estradiol determines the effects of PTH on ERα-dependent transcription in MC3T3-E1 cells.

Bone remodeling is a continuous process regulated by several hormones such as estrogens and parathyroid hormone (PTH). Here we investigated the influence of PTH on estrogen receptor alpha (ERα)-dependent transcriptional activity in MC3T3-E1 osteoblasts. Cells that were transfected with an ER-responsive reporter plasmid and treated with PTH showed increased luciferase activity. However, in the presence of 17ß-estradiol, we observed that PTH inhibited ERα-mediated transcription. cAMP mimicked the effects by PTH, and the findings were confirmed in COS-1 cells transfected with expression vector encoding the catalytic subunit of cAMP-dependent protein kinase (PKA). Furthermore, PTH exhibited specific effects on the mRNA expression of the decoy receptor osteoprotegerin (OPG) and the receptor activator of NF kappa-B ligand (RANKL) in MC3T3-E1 osteoblasts. In the absence of 17ß-estradiol, PTH and cAMP enhanced the OPG/RANKL ratio, whereas, OPG/RANKL was suppressed when estradiol was present. In conclusion, our results indicate that the presence of estradiol determines whether PTH and cAMP stimulates or inhibits ERα-dependent activity and the OPG/RANKL mRNA expression in an osteoblastic cell line.

1,25-dihydroxyvitamin D and the vitamin D receptor gene polymorphism Apa1 influence bone mineral density in primary hyperparathyroidism.

OBJECTIVE: Parathyroid hormone (PTH) and vitamin D are the most important hormones regulating calcium metabolism. In primary hyperparathyroidism (PHPT) excessive amounts of PTH are produced. Bone turnover is enhanced, leading to reduced bone mineral density and elevated levels of serum calcium. The aim of this study was to investigate relations between serum levels of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and bone mineral density, as well as known genetic polymorphisms in the vitamin D receptor and enzymes metabolising vitamin D in patients with PHPT. DESIGN/SUBJECTS: We conducted a cross-sectional study of 52 patients with PHPT. RESULTS: Mean level of 25(OH)D was 58.2 nmol/L and median 1,25(OH)(2)D level was 157 pmol/L. Among our patients with PHPT 36.5% had 25(OH)D levels below 50 nmol/L. Serum 1,25(OH)(2)D was inversely correlated to bone mineral density in distal radius (p = 0.002), but not to bone mineral density at lumbar spine or femoral neck. The vitamin D receptor polymorphism Apa1 (rs7975232) was associated with bone mineral density in the lumbar spine. CONCLUSIONS: The results suggest that PHPT patients with high blood concentrations of 1,25(OH)(2)D may have the most deleterious skeletal effects. Randomized, prospective studies are necessary to elucidate whether vitamin D supplementation additionally increases serum 1,25(OH)(2)D and possibly enhances the adverse effects on the skeleton in patients with PHPT.

Serum level of under-carboxylated osteocalcin and bone mineral density in early menopausal Norwegian women.

PURPOSE: Serum level of under-carboxylated osteocalcin (ucOC) is considered a sensitive measure of vitamin K status, and ucOC levels are associated with bone mineral density (BMD) and fracture risk in elderly persons. The aim of this study was to assess the relationship between ucOC and BMD in early menopausal women. METHODS: The data reported here come from the enrollment in a double-blinded placebo-controlled randomized trial comprising 334 healthy Norwegian women between 50 and 60 years, 1-5 years after menopause, not using warfarin or medication known to affect bone metabolism. Total hip, femoral neck, lumbar spine, and total body BMD and serum level of ucOC and total osteocalcin were measured, and information of lifestyle was collected through questionnaires. The association between ucOC and BMD at all measurement sites was assessed by multiple regression analyses adjusting for possible confounding variables. RESULTS: The absolute serum level of ucOC was significantly and negatively associated with BMD at all measurements sites, both in univariate analyses (p < 0.01) and in multivariate analyses adjusting for years since menopause, smoking status and weight (p < 0.01). However, serum ucOC, expressed as percentage of the total osteocalcin level, was not associated with BMD at any site. CONCLUSIONS: Achievement of adequate vitamin K nutritional intake is important, but ucOC expressed as percentage of total osteocalcin levels as reflection of vitamin K status does not seem to play a central role in determining BMD levels in early menopausal women.

Physiological effects of combined thermal and electrical muscle stimulation (cTEMS) in healthy individuals: a pilot study.

OBJECTIVE: Adding superficial heat to electrical muscle stimulation may provide added effects. In this pilot study we investigated the effects on oxygen consumption of combined thermal and electrical muscle stimulation at different levels of heat and modes of electrical stimulation. DESIGN: An observational clinical pilot study. SUBJECTS: A total of 14 healthy persons aged 30-70 years. METHODS: Subjects were randomly assigned to stimulation with different electrical pulse types in random order. At 38.2°C and 40.7°C heat intensity we measured peak oxygen uptake, capillary lactate, catecholamines, growth hormone and hemodynamics at 20% of the maximum output (194 mA) and at each individual's maximal stimulation intensity. RESULTS: Multivariate analyses showed that electrical stimulation significantly increased peak oxygen uptake and the levels of lactate, catecholamine and growth hormone. Increasing the heat during electrical stimulation gave additional hemodynamic response and rise in growth hormone. We observed a dose-response relationship in peak oxygen uptake for increase in stimulation intensity. The highest oxygen uptake was observed with biphasic continuous stimulation at 7 Hz (p < 0.001). CONCLUSIONS: Biphasic low frequency electrical muscle stimulation elicited the highest oxygen uptake; higher stimulation intensity was not obtained by adding heat.

Primary hyperparathyroidism influences the expression of inflammatory and metabolic genes in adipose tissue.

BACKGROUND: Primary hyperparathyroidism (PHPT) is characterised by increased production of parathyroid hormone (PTH) resulting in elevated serum calcium levels. The influence on bone metabolism with altered bone resorption is the most studied clinical condition in PHPT. In addition to this, patients with PHPT are at increased risk of non-skeletal diseases, such as impaired insulin sensitivity, arterial hypertension and increased risk of death by cardiovascular diseases (CVD), possibly mediated by a chronic low-grade inflammation. The aim of this study was to investigate whether adipose tissue reflects the low-grade inflammation observed in PHPT patients. METHODOLOGY/PRINCIPAL FINDINGS: Subcutaneous fat tissue from the neck was sampled from 16 non-obese patients with PHPT and from 16 patients operated for benign thyroid diseases, serving as weight-matched controls. RNA was extracted and global gene expression was analysed with Illumina BeadArray Technology. We found 608 differentially expressed genes (q-value<0.05), of which 347 were up-regulated and 261 were down-regulated. Gene ontology analysis showed that PHPT patients expressed increased levels of genes involved in immunity and defense (e.g. matrix metallopeptidase 9, S100 calcium binding protein A8 and A9, CD14, folate receptor 2), and reduced levels of genes involved in metabolic processes. Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD.

Seasonal and age-related differences in serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone in patients from Western Norway.

OBJECTIVE: The aim of this study was to investigate the seasonal and age-related variation of vitamin D and PTH serum concentrations in a large general patient population in Western Norway. DESIGN: A retrospective study was conducted at the Hormone laboratory, Haukeland University Hospital, Bergen, Norway. All analyses of 25-hydroxyvitamin D (25(OH)D) (n = 8325), 1,25-dihydroxyvitamin D (1,25(OH)2D) (n = 4509) and PTH (n = 4203) requested from private practitioners from 2005 to 2008 were included. All three analytes were available in 1551 subjects. Subjects. Mean age of the study population was 49.8 years and 70.9% of the samples were from women. RESULTS: The highest concentrations of 25(OH)D and 1,25(OH)2D were observed in July-September. In April 43% of the studied population had 25(OH)D concentrations below 50 nmol/L. There was a positive correlation between 25(OH)D and 1,25(OH)2D (p < 0.001). The levels of 25(OH)D and PTH were negatively correlated (p < 0.001) while 1,25(OH)2D and PTH showed a weak positive correlation (p = 0.015). We observed higher concentrations of 25(OH)D (p = 0.003) and lower 1,25(OH)2D levels (p < 0.001) in the older age groups. PTH increased throughout the whole age span (p < 0.001). CONCLUSION: We observed a seasonal variation in 25(OH)D and 1,25(OH)2D with low serum concentrations during winter/early spring while PTH showed an inverse pattern. Higher levels of PTH in winter and the elderly may reflect an impaired vitamin D status that may affect calcium homeostasis and bone health.

Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone.

UNLABELLED: Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone. OBJECTIVE: To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105). MAIN OUTCOME MEASURES: Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity. RESULTS: Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine. CONCLUSIONS: BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.

Effect of exercise training on chromogranin A and relationship to N-ANP and inflammatory cytokines in patients with chronic heart failure.

Exercise training improves functional parameters in patients with congestive heart failure (CHF). The aim of this study was to establish whether exercise training influence the elevated CgA levels in CHF patients. Plasma CgA was determined at baseline and at peak exercise before and after 12 weeks of training in 25 men (mean age 67+/-8 years) with CHF (NYHA functional class II and III). Plasma Chromogranin A (CgA) was significantly elevated in CHF, however without change after the 12 week exercise period. A positive correlation was obtained for CgA versus N-ANP and CgA versus TNFalpha for the patients with poor survival, indicating that in these patients the elevated plasma CgA was more closely connected to the myocardial release of natriuretic peptides and the inflammatory response than to activation of the sympathoadrenergic system.