Author Correction: Effect of carnosine supplementation on the plasma lipidome in overweight and obese adults: a pilot randomised controlled trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Vitamin D supplementation increases adipokine concentrations in overweight or obese adults.

PURPOSE: Vitamin D regulates adipokine production in vitro; however, clinical trials have been inconclusive. We conducted secondary analyses of a randomized controlled trial to examine whether vitamin D supplementation improves adipokine concentrations in overweight/obese and vitamin D-deficient adults. METHODS: Sixty-five individuals with a BMI ≥ 25 kg/m2 and 25-hydroxyvitamin D (25(OH)D) ≤ 50 nmol/L were randomized to oral cholecalciferol (100,000 IU single bolus followed by 4,000 IU daily) or matching placebo for 16 weeks. We measured BMI, waist-to-hip ratio, % body fat (dual X-ray absorptiometry), serum 25(OH)D (chemiluminescent immunoassay) and total adiponectin, leptin, resistin, and adipsin concentrations (multiplex assay; flow cytometry). Sun exposure, physical activity, and diet were assessed using questionnaires. RESULTS: Fifty-four participants completed the study (35M/19F; mean age = 31.9 ± 8.5 years; BMI = 30.9 ± 4.4 kg/m2). After 16 weeks, vitamin D supplementation increased 25(OH)D concentrations compared with placebo (57.0 ± 21.3 versus 1.9 ± 15.1 nmol/L, p < 0.001). There were no differences between groups for changes in adiponectin, leptin, resistin, or adipsin in unadjusted analyses (all p > 0.05). After adjustment for baseline values, season, sun exposure, and dietary vitamin D intake, there was a greater increase in adiponectin (ß[95%CI] = 13.7[2.0, 25.5], p = 0.02) and leptin (ß[95%CI] = 22.3[3.8, 40.9], p = 0.02) in the vitamin D group compared with placebo. Results remained significant after additional adjustment for age, sex, and % body fat (p < 0.02). CONCLUSIONS: Vitamin D may increase adiponectin and leptin concentrations in overweight/obese and vitamin D-deficient adults. Further studies are needed to clarify the molecular interactions between vitamin D and adipokines and the clinical implications of these interactions in the context of obesity. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT02112721.

Carnosine supplementation reduces plasma soluble transferrin receptor in healthy overweight or obese individuals: a pilot randomised trial.

Abnormalities of iron homeostasis have been linked to insulin resistance, type 2 diabetes and cardiovascular disease. Carnosine, an over-the-counter food supplement with chelating properties, has been shown to decrease serum iron and improve glucose metabolism in diabetic rodents. We have previously demonstrated that carnosine supplementation prevented worsening of glucose metabolism in healthy overweight and obese middle-aged adults. Yet, the impact of carnosine on markers of iron metabolism in humans has not been investigated. We aimed to determine whether carnosine supplementation has an effect on iron parameters in overweight and obese, otherwise healthy adults. We included 26 participants, who were randomly allocated to receive 1 g carnosine (n = 14) or identical placebo (n = 12) twice daily for 12 weeks. Iron parameters including iron, ferritin, transferrin, soluble transferrin receptor, total iron binding capacity and iron saturation were measured in serum or plasma by standard commercial assays. Carnosine supplementation decreased plasma soluble transferrin receptor compared to placebo (mean change difference ± standard error: - 0.07 ± 0.03 mg/l, p = 0.04). None of the other iron parameters were different between carnosine and placebo groups. At follow-up, soluble transferrin receptor was associated inversely with urinary carnosine concentrations and positively with serum carnosinase-1 activity (both p < 0.02). Our findings suggest that carnosine may modulate iron metabolism in high-risk groups which could ameliorate insulin resistance and prevent type 2 diabetes. Larger human clinical trials are required to confirm our results.

Vitamin D supplementation improves waist-to-hip ratio and fasting blood glucose in vitamin D deficient, overweight or obese Asians: A pilot secondary analysis of a randomised controlled trial.

Recent trials do not support a role for vitamin D supplementation in prevention or treatment of type 2 diabetes mellitus, although effects may differ in Asian populations. In this pilot secondary analysis of a placebo-controlled randomised trial of overweight or obese individuals with low 25-hydroxyvitamin D (25(OH)D < 50 nmol/L), we examined whether vitamin D supplementation improved insulin sensitivity or body composition in participants of Asian ethnicity. Amongst 65 trial participants, 33 reported being of Asian descent (mean ± SD age 30 ± 7 years; 67% male). Participants were block randomised to receive vitamin D (n = 14; initial bolus dose of 2500 µg cholecalciferol followed by 100 µg cholecalciferol/d) or placebo (n = 19; identical capsules) for 16 weeks. Primary outcome was change in insulin sensitivity (M-value) assessed by hyperinsulinemic-euglycemic clamp. Secondary outcomes were changes in 25(OH)D (chemiluminescent immunoassay), fasting blood glucose (YSI Stat 2300), and body composition including waist-hip ratio and total body fat percentage (dual-energy X-ray absorptiometry). Questionnaires assessed sun-exposure habits, physical activity, and diet. After the 16-week intervention, 25(OH)D concentrations increased significantly in the vitamin D group with no change in placebo (61.4 ± 21.1 vs -0.4 ± 12.7 nmol/L; P < 0.01). Vitamin D group participants demonstrated significant improvements in waist-hip ratio (-0.02 ± 0.03 vs 0.00 ± 0.02; P < 0.01) and fasting blood glucose (-0.1 ± 0.2 vs 0.2 ± 04 mmol/L; P < 0.04) compared with the placebo group, but changes in insulin sensitivity and other body composition measures did not differ significantly between groups (all P > 0.05). In conclusion, vitamin D supplementation improved waist-hip ratio and fasting blood glucose in overweight and obese Asian-Australians with low vitamin D concentrations. Further research is required to determine whether vitamin D supplementation is potentially more effective in specific ethnic groups.

Vitamin D supplementation may improve back pain disability in vitamin D deficient and overweight or obese adults.

Back pain is currently the greatest cause of disability worldwide, and there are very limited therapeutic options available. Vitamin D deficiency and obesity are both risk factors for back pain. The few randomised controlled trials examining the effects of vitamin D supplementation on back pain have methodological limitations and largely include non-vitamin D deficient participants. Thus, the aim of this study was to determine whether vitamin D supplementation improves back pain symptoms in vitamin D deficient and overweight or obese, otherwise healthy adults. Sixty-five overweight or obese adults (BMI ≥ 25 kg/m2) with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] concentrations ≤50 nmol/L) were randomised to a bolus oral dose of 100,000 IU followed by 4000 IU cholecalciferol/day or matching placebo for 16 weeks. We measured 25(OH)D concentrations (chemiluminescent immunoassays) and self-reported back pain (Chronic Pain Grade Questionnaire) before and after the intervention. Lifestyle habits including sun exposure, physical activity, and diet were collected using questionnaires. Fifty-four participants completed the study, of which 49 had complete data for back pain and were included in the present analyses (31 M/18 F; mean ± SD age: 31.8 ± 8.9 years; BMI: 31.1 ± 4.5 kg/m2). After the 16-week intervention, 25(OH)D levels increased significantly with vitamin D supplementation compared with placebo (55.7 ± 20.9 versus 3.9 ± 14.4 nmol/L, respectively, p < 0.001). There were no significant differences between vitamin D and placebo groups in change in back pain intensity or disability scores (all p > 0.05). However, in those with 25(OH)D concentrations <30 nmol/L at baseline (n = 20), there was a significantly greater reduction in back pain disability scores in the vitamin D group compared with placebo, after adjusting for important covariates known to affect vitamin D status and/or back pain (b [95%CI] = -11.6 [-22.4, -0.8], p = 0.04). Our findings suggest that vitamin D supplementation in overweight or obese and markedly vitamin D deficient adults (25(OH)D <30 nmol/L) may improve back pain disability. Although treating severe vitamin D deficiency is recommended for optimising bone health, this study suggests it may also improve back pain. Hence, testing for vitamin D deficiency in those with back pain who are overweight or obese may be warranted.

Carnosine Supplementation Improves Serum Resistin Concentrations in Overweight or Obese Otherwise Healthy Adults: A Pilot Randomized Trial.

Adipokines play an important role in the regulation of glucose metabolism. We have previously shown that carnosine supplementation in overweight or obese non-diabetic individuals improves glucose metabolism but does not change adiponectin concentrations. However, its effect on other adipokines has not been investigated. Herein we further determined the effect of carnosine supplementation on serum adipsin, resistin and leptin. Twenty-two overweight or obese otherwise healthy adults were randomly assigned to receive either 2 g of carnosine (n = 13) or identically looking placebo (n = 9) for 12 weeks. Serum adipsin, leptin and resistin were analyzed using a bead-based multiplex assay. Carnosine supplementation decreased serum resistin concentrations compared to placebo (mean change from baseline: -35 ± 83 carnosine vs. 35 ± 55 ng/mL placebo, p = 0.04). There was a trend for a reduction in serum leptin concentrations after carnosine supplementation (-76 ± 165 ng/mL carnosine vs. 20 ± 28 ng/mL placebo, p = 0.06). The changes in leptin and resistin concentrations were inversely related to the change in concentration for urinary carnosine (r = -0.72, p = 0.0002; r = -0.67, p = 0.0009, respectively), carnosine-propanal (r = -0.56, p = 0.005; r = -0.63, p = 0.001, respectively) and carnosine-propanol (r = -0.61, p = 0.002; r = -0.60, p = 0.002, respectively). There were no differences between groups in change in adipsin concentrations. Our findings show carnosine supplementation may normalize some, but not all, of the serum adipokine concentrations involved in glucose metabolism, in overweight and obese individuals. Further clinical trials with larger samples are needed to confirm these results.

Erratum: Higher glomerular filtration rate is related to insulin resistance but not to obesity in a predominantly obese non-diabetic cohort.

This corrects the article DOI: 10.1038/srep45522.

Adipsin Concentrations Are Associated with Back Pain Independently of Adiposity in Overweight or Obese Adults.

Objective: To compare cardiometabolic risk factors including cytokine and adipokine concentrations between individuals with and without back pain. Methods: In 62 overweight/obese adults (BMI ≥ 25 kg/m2; 23F/39M), we collected data on: self-reported back pain; anthropometry [BMI, waist circumference, body composition (dual energy X-ray absorptiometry-DEXA)]; metabolic parameters [fasting glucose; insulin sensitivity (hyperinsulinaemic-euglycaemic clamps)]; cardiovascular parameters (blood pressure, lipids); serum inflammation markers [high-sensitivity C-reactive protein (hsCRP; immunoturbidimetric-assay), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10 (multiplex-assay)]; and adipokines [leptin, adipsin, resistin, and adiponectin (multiplex-assay)]. Results: Participants who reported having back pain in the past month (n = 24; 39%) had higher BMI (mean ± SD = 33.8 ± 6.3 vs. 30.2 ± 4.1 kg/m2, p = 0.008), fat-mass (39.9 ± 12.3 vs. 33.9 ± 9.8%, p = 0.04), and waist circumference (109.6 ± 16.8 vs. 101.0 ± 9.3 cm, p = 0.01) compared to those without back pain (n = 38; 61%). No differences were observed in cardiometabolic parameters, inflammatory markers, or adiponectin or resistin concentrations. Those reporting back pain had higher adipsin concentrations compared to those without back pain [median (IQR) = 744 (472-2,804) vs. 721 (515-867) ng/ml, p = 0.03], with a trend for higher leptin [5.5 (1.5-24.3) vs. 2.3 (1.5-6.7) ng/ml, p = 0.05], both of which persisted after adjustment for age and sex. Adipsin remained associated with back pain independently of adiposity (BMI, waist, fat-mass, or total %body fat; all p ≤ 0.03). Conclusions: Greater obesity, and higher adipsin and leptin concentrations were observed in those who reported back pain in the past month compared to those without back pain, and adipsin was associated with back pain independently of adiposity. Larger studies are needed to determine if adipsin could be a novel therapeutic target for prevention and/or treatment of back pain.

Vitamin D and symptoms of depression in overweight or obese adults: A cross-sectional study and randomized placebo-controlled trial.

Recent evidence suggests that vitamin D deficiency may contribute to increased risk of depression. However, previous studies are limited by variability in participant characteristics including vitamin D deficiency status and presence of existing diseases, use of low doses of vitamin D supplementation for short durations, and use of co-interventions or psychotropic drugs. We examined whether 25-hydroxyvitamin D (25(OH)D) concentrations were associated with symptoms of depression, as well as whether vitamin D supplementation reduced symptoms of depression in overweight or obese and vitamin D-deficient, but otherwise healthy adults. Cross-sectional analyses were performed on baseline data from 63 (39M/24F) overweight or obese (body mass index (BMI) ≥25kg/m2) and vitamin D-deficient (25(OH)D ≤50 nmol/l) adults (mean age=31.3±8.5), without clinical depression. Participants were randomized to either a bolus oral dose of 100,000 IU followed by 4000 IU daily of cholecalciferol, or matching placebo for 16 weeks. Interventional analyses were performed on data from 48 participants (30M/18F) who completed the trial. We measured serum 25(OH)D concentrations; anthropometry: BMI, waist-to-hip ratio (WHR), % body fat (dual X-ray absorptiometry); and depressive symptoms using the Beck Depression Inventory (BDI) before and after intervention. Data on dietary vitamin D intake (3-day food record), physical activity (international physical activity questionnaire), and sun exposure habits were collected using questionnaires. At baseline, mean 25(OH)D concentration was 32.9±11.3 nmol/l and total BDI score was 6.6±6.3 (range=0-33). There were no associations between 25(OH)D concentrations and total BDI scores or BDI subscales (all p>0.1). After the 16-week intervention, 25(OH)D concentrations increased in the vitamin D group compared to placebo (56.0±20.8 versus 2.7±13.9 nmol/L, respectively; p <0.0001). Change in total BDI scores did not differ between vitamin D and placebo groups (-2.0±4.5 versus -1.5±2.9, respectively; p=0.7). There were no differences in BDI subscales between groups (both p>0.1). Results remained non-significant after adjusting for multiple covariates including sun exposure, physical activity, and dietary vitamin D intake (all p>0.1). Our findings suggest that vitamin D deficiency may not be related to increased risk of depression in individuals without clinically significant depression and that the use of vitamin D supplementation may not be warranted for reducing depressive symptoms in this population. Further large-scale studies are needed to establish whether vitamin D supplementation may be beneficial for improving depressive symptoms in other population groups, including in those with existing depressive or psychiatric disorders.

Serum 25-hydroxyvitamin D concentrations are associated with nuclear factor kappa-B activity but not with inflammatory markers in healthy normoglycemic adults.

Vitamin D has been reported to have anti-inflammatory properties in in vitro and animal studies, which are thought to occur via inhibition of the nuclear factor kappa-B (NFκB) pathway. However, the association between vitamin D and in vivo NFκB activity in humans has not previously been reported. The aim of the present study was to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and NFκB activity in peripheral blood mononuclear cells (PBMCs) as well as plasma inflammatory markers in healthy individuals. We hypothesized that 25(OH)D concentrations would be negatively associated with NFκB activity and pro-inflammatory markers downstream of NFκB, and positively associated with anti-inflammatory markers. We measured circulating 25(OH)D (chemiluminescent immunoassay); anthropometry: body mass index (BMI), waist-to-hip ratio (WHR), and % body fat (dual X-ray absorptiometry); plasma pro- and anti-inflammatory markers: high sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and IL-10 (ELISA); and NFκB activity in PBMCs (DNA-binding assay). Forty-nine participants were included in the study (21M/28F; age=31.6±10.2years (mean±SD); BMI=28.4±4.6kg/m2; % body fat=30.2±9.3%). Mean 25(OH)D concentration was 48.2±24.5 nmol/l. There were no differences in 25(OH)D concentrations between genders and no association between 25(OH)D concentrations and age, BMI, or % body fat (all p>0.1). Serum 25(OH)D concentrations were positively associated with NFκB activity in PBMCs (r=0.48, p=0.0008) but not with any of the pro- or anti-inflammatory markers measured (all p>0.1). After adjusting for age, sex, and % body fat, 25(OH)D concentrations remained positively associated with NFκB activity in PBMCs (ß=0.55, p<0.0001). Although in-vitro studies suggest that vitamin D inhibits NFκB activity, our novel cross-sectional data from a cohort of healthy individuals suggest that vitamin D may regulate rather than inhibit the NFκB pathway. Large-scale intervention and mechanistic studies are needed to further investigate the effects of vitamin D on NFκB activity in vivo in humans.

Effect of vitamin D supplementation on inflammation and nuclear factor kappa-B activity in overweight/obese adults: a randomized placebo-controlled trial.

In-vitro studies suggest that vitamin D reduces inflammation by inhibiting nuclear factor kappa-B (NFκB) activity. Yet, no trials have examined the effects of vitamin D supplementation on NFκB activity in-vivo in humans. We conducted a double-blind randomized trial (RCT) examining effects of vitamin D supplementation on inflammatory markers and NFκB activity in peripheral blood mononuclear cells (PBMCs). Sixty-five overweight/obese, vitamin D-deficient (25-hydroxyvitamin D [25(OH)D] ≤ 50 nmol/L) adults were randomized to a single 100,000 IU bolus followed by 4,000 IU daily cholecalciferol or matching placebo for 16 weeks. We measured BMI, % body fat, serum 25(OH)D, high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), interferon-gamma (IFN-γ), several interleukins, and NFκB activity in PBMCs. Fifty-four participants completed the study. Serum 25(OH)D concentrations increased with vitamin D supplementation compared to placebo (p < 0.001). Vitamin D and placebo groups did not differ in any inflammatory markers or NFκB activity (all p > 0.05). Results remained non-significant after adjustment for age, sex, and % body fat, and after further adjustment for sun exposure, physical activity, and dietary vitamin D intake. Although in-vitro studies report anti-inflammatory effects of vitamin D, our RCT data show no effect of vitamin D supplementation on inflammatory markers or NFκB activity in-vivo in humans.

Disparity in the micronutrient content of diets high or low in advanced glycation end products (AGEs) does not explain changes in insulin sensitivity.

We have previously shown that an isoenergetic low advanced glycation end products (AGEs) diet matched for macronutrient content improved insulin sensitivity compared to high AGE diet. Here, we evaluated the differences in micronutrient intake of these two dietary patterns and if they could explain differences in insulin sensitivity. Participants consumed the intervention diets each for 2 weeks with 4 weeks of habitual dietary intake (washout) in-between. Dietary analysis revealed that the high AGE diet contained greater levels of retinol equivalents (RE) (478.9 + 151.3 µg/day versus 329.0 + 170.0 µg/day; p < .006), vitamin A (806.3 + 223.5 (µg RE)/day versus 649.1 + 235.8 (µg RE)/day; p < .05) and thiamine (2.3 + 0.6 mg/day versus 1.6 + 0.4 mg/day; p = .014) compared to the low AGE diet. The changes in polyunsaturated fat, retinol, vitamin A and thiamine did not correlate with changes in insulin sensitivity (all p > .1) therefore are unlikely to explain observed changes in insulin sensitivity. (clinicaltrials.gov:NCT00422253).

Higher glomerular filtration rate is related to insulin resistance but not to obesity in a predominantly obese non-diabetic cohort.

Glomerular hyperfiltration has been associated with obesity, insulin resistance, and systolic blood pressure (SBP). However, previous studies are limited by confounders such as pre-existing diabetes or hypertension, or have used indirect measures of adiposity and insulin sensitivity (IS). Therefore, we examined the relationship between estimated glomerular filtration rate (eGFR) and IS measured by the hyperinsulinaemic euglycaemic clamp in a healthy population on no medications. We performed oral glucose tolerance test (OGTT) and measured % body fat (DEXA), BMI, blood pressure and M-value (hyperinsulinaemic euglycaemic clamp) in 104 individuals (44 females and 60 males). The majority of the study population (n = 89, 85.6%) were classified on their BMI as overweight/obese. eGFR was related to age, BMI, M-value (IS), 2-hour glucose levels post OGTT and white blood cell count (WBC) (all p < 0.05); but not to SBP (p = 0.1) or fasting glucose levels (p = 0.2). After adjustment for gender, BMI, SBP and WBC, the inverse association between eGFR and M-value (p = 0.001), and 2-hour glucose post OGTT (p = 0.02) persisted. In conclusion, although eGFR has been associated with BMI and blood pressure in previous studies, in our healthy population, eGFR was more closely related to markers of glucose metabolism (IS and 2-hour glucose post OGTT) than to BMI and blood pressure.

25-hydroxyvitamin D is associated with adiposity and cardiometabolic risk factors in a predominantly vitamin D-deficient and overweight/obese but otherwise healthy cohort.

Vitamin D deficiency has reached epidemic proportions worldwide and has recently been linked to cardiometabolic risk factors including obesity, insulin resistance, hypertension, dyslipidemia, as well as type 2 diabetes and cardiovascular disease. The objective of this study was to examine the associations between circulating 25-hydrovitamin D (25(OH)D) levels and cardiometabolic risk factors using direct measures of adiposity, glucose intolerance, and insulin resistance, as well as lipids, blood pressure, and plasma markers of inflammation. We measured circulating 25(OH)D, physical activity (International Physical Activity Questionnaire- IPAQ), anthropometry (body mass index (BMI), waist-to-hip ratio (WHR), % body fat (dual energy X-ray absorptiometry)), metabolic parameters (fasting and 2-h plasma glucose levels during oral glucose tolerance test; insulin sensitivity (M, hyperinsulinaemic-euglycaemic clamp), and cardiovascular and inflammatory profiles (blood pressure (BP), pulse pressure (PP), mean arterial pressure (MAP), plasma lipid levels, white blood cell count (WBC), and plasma high-sensitivity C-reactive protein levels (hsCRP)) in 111 healthy, non-diabetic adults (66 males/45 females; age 31.1±9.2years; % body fat 36.0±10.2%). Mean 25(OH)D was 39.8±19.8 nmol/L with no difference between genders (p=0.4). On univariate analysis, 25(OH)D was associated with% body fat (r=-0.27; p=0.005), 2-h glucose (r=-0.21; p=0.03), PP (r=0.26; p=0.006), and insulin sensitivity (r=0.20, p=0.04), but not with age, BMI, WHR, fasting glucose, BP, MAP, lipids, or inflammatory markers (all p>0.05). After adjusting for age and sex, 25(OH)D remained associated with% body fat (ß=-0.12%; p=0.003), 2-h glucose (ß=-0.13mmol/L; p=0.02), PP (ß=0.12mmHg; p=0.009), and insulin sensitivity (ß=0.22mg/kg/min; p=0.03), and became associated with fasting glucose (ß=-0.04mmol/L; p=0.04) and hsCRP (ß=-0.51mg/L; p=0.04). After adjusting for age, sex, and % body fat, 25(OH)D was no longer associated with insulin sensitivity, 2-h glucose, or hsCRP, but remained associated with fasting glucose (ß=-0.05mmol/L; p=0.03) and PP (ß=0.10mmHg; p=0.03). 25(OH)D remained associated with fasting glucose (ß=-0.06mmol/L; p=0.02) after hsCRP and physical activity were added to the model with % body fat, age, and sex. ​These cross-sectional data suggest that associations between vitamin D and cardiometabolic risk among healthy, non-diabetic adults are largely mediated by adiposity. Large-scale intervention and mechanistic studies are needed to further investigate whether vitamin D has an independent role in the prevention and/or management of cardiometabolic risk and disease.

Serum 25-hydroxyvitamin D concentration is not associated with glomerular filtration rate in a predominantly obese otherwise healthy population.

Evidence from observational studies indicates a role for vitamin D in kidney function and progression to chronic kidney disease. Findings from animal studies have proposed underlying mechanisms including increased activation of the renin-angiotensin system, increased blood pressure, insulin resistance and chronic low-grade inflammation. However, human studies are limited by confounders arising from heterogeneous samples of participants. We examined the relationship between 25(OH)D and estimated glomerular filtration rate (eGFR) in a predominantly obese otherwise healthy and drug-naive population with no history of chronic kidney disease (CKD). One hundred and twenty one non-diabetic (75g oral glucose tolerance test; OGTT) volunteers (70 males and 51 females), aged 18-57 years participated in the study. Median 25(OH)D level was 37nmol/L with no difference by sex. Twenty six participants (21.5%) had 25(OH)D <25 nmol/L, 75 participants (62%) had 25(OH)D of 25-49.99nmol/L, and 20 participants (16.5%) had 25(OH)D ≥50nmol/L. In univariate analysis, 25(OH)D was related negatively to percent body fat and 2-h glucose level post OGTT. Mean (SD) eGFR was 113.1 (14.9)mL/min/1.73m2, and in the multivariable analysis, it was related to age, sex, percent body fat and 2-h glucose level post OGTT, but not to 25(OH)D. Furthermore, there was no relationship between eGFR and 25(OH)D across BMI categories. Our data suggest that measuring 25(OH)D in predominantly obese otherwise healthy individuals with no history of CKD may not be beneficial in early recognition of kidney disease.

The complex immunological and inflammatory network of adipose tissue in obesity.

A number of approaches have been utilized in the prevention, management, and treatment of obesity, including, surgery, medication, diet, exercise, and overall lifestyle changes. Despite these interventions, the prevalence of obesity and the various disorders related to it is growing. In obesity, there is a constant state of chronic low-grade inflammation which is characterized by activation and infiltration of pro-inflammatory immune cells and a dysregulated production of high levels of pro-inflammatory cytokines. This pro-inflammatory milieu contributes to insulin resistance, type-2 diabetes, cardiovascular disease, and other related co-morbidities. The roles of the innate (macrophages, neutrophils, eosinophils, mast cells, NK cells, MAIT cells) and the adaptive (CD4 T cells, CD8 T cells, regulatory T cells, and B cells) immune responses and the roles of adipokines and cytokines in adipose tissue inflammation and obesity are discussed. An understanding of the crosstalk between the immune system and adipocytes may shed light in better treatment modalities for obesity and obesity-related diseases.

Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans.

BACKGROUND: Carnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists. METHODS AND RESULTS: Samples of vastus lateralis muscle were obtained by needle biopsy. We measured muscle carnosine levels (high-performance liquid chromatography), % body fat (bioimpedance), abdominal subcutaneous and visceral adiposity (magnetic resonance imaging), insulin sensitivity (euglycaemic hyperinsulinemic clamp), resting energy expenditure (REE, indirect calorimetry), free-living ambulatory physical activity (accelerometers) and lipid profile in 36 sedentary non-vegetarian middle aged men (45±7 years) with varying degrees of adiposity and glucose tolerance. Muscle carnosine content was positively related to % body fat (r = 0.35, p = 0.04) and subcutaneous (r = 0.38, p = 0.02) but not visceral fat (r = 0.17, p = 0.33). Muscle carnosine content was inversely associated with insulin sensitivity (r = -0.44, p = 0.008), REE (r = -0.58, p<0.001) and HDL-cholesterol levels (r = -0.34, p = 0.048). Insulin sensitivity and physical activity were the best predictors of muscle carnosine content after adjustment for adiposity. CONCLUSION: Our data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease.

Vitamin D supplementation for the prevention of type 2 diabetes in overweight adults: study protocol for a randomized controlled trial.

BACKGROUND: Despite Australia's sunny climate, low vitamin D levels are increasingly prevalent. Sun exposure is limited by long working hours, an increase in time spent indoors, and sun protection practices, and there is limited dietary vitamin D fortification. While the importance of vitamin D for bone mineralization is well known, its role as a protective agent against chronic diseases, such as type 2 diabetes and cardiovascular disease, is less understood. Observational and limited intervention studies suggest that vitamin D might improve insulin sensitivity and secretion, mainly via its anti-inflammatory properties, thereby decreasing the risk of development and progression of type 2 diabetes. The primary aim of this trial is to investigate whether improved plasma concentrations of 25-hydroxyvitamin D (25(OH)D), obtained through vitamin D supplementation, will increase insulin sensitivity and insulin secretion. A secondary aim is to determine whether these relationships are mediated by a reduction in underlying subclinical inflammation associated with obesity. METHODS/DESIGN: Fifty overweight but otherwise healthy nondiabetic adults between 18 and 60 years old, with low vitamin D levels (25(OH)D < 50 nmol/l), will be randomly assigned to intervention or placebo. At baseline, participants will undergo a medical review and anthropometric measurements, including dual X-ray absorptiometry, an intravenous glucose tolerance test, muscle and fat biopsies, a hyperinsulinemic euglycemic clamp, and questionnaires assessing diet, physical activity, sun exposure, back and knee pain, and depression. The intervention group will receive a first dose of 100,000 IU followed by 4,000 IU vitamin D (cholecalciferol) daily, while the placebo group will receive apparently identical capsules, both for a period of 16 weeks. All measurements will be repeated at follow-up, with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion for the intervention group compared with the placebo group. Secondary outcome measures will compare changes in anthropometry, cardiovascular risk factors, and inflammatory markers. DISCUSSION: The trial will provide much needed clinical evidence on the impact of vitamin D supplementation on insulin resistance and secretion and its underlying mechanisms, which are relevant for the prevention and management of type 2 diabetes. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02112721 .

Advanced glycation end products (AGEs) are cross-sectionally associated with insulin secretion in healthy subjects.

It has been postulated that chronic exposure to high levels of advanced glycation end products (AGEs), in particular from dietary sources, can impair insulin secretion. In the present study, we investigated the cross-sectional relationship between AGEs and acute insulin secretion during an intravenous glucose tolerance test (IVGTT) and following a 75 g oral glucose tolerance test (OGTT) in healthy humans. We report the cross-sectional association between circulating AGE concentrations and insulin secretory function in healthy humans (17 F: 27 M, aged 30 ± 10 years) with a wide range of BMI (24.6-31.0 kg/m(2)). Higher circulating concentrations of AGEs were related to increased first phase insulin secretion during IVGTT (r = 0.43; p < 0.05) and lower 2-h glucose concentrations during OGTT (r = -0.31; p < 0.05). In addition, fasting (r = -0.36; p < 0.05) and 2-h glucose concentrations were negatively related to circulating levels of soluble receptor for AGE (RAGE) isoforms (r = -0.39; p < 0.01). In conclusion, in healthy humans, we show a cross-sectional association between advanced glycation end products and acute insulin secretion during glucose tolerance testing.

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure.

BACKGROUND: High levels of circulating advanced glycation end products (AGEs) can initiate chronic low-grade activation of the immune system (CLAIS) with each of these factors independently associated with cardiovascular (CV) morbidity and mortality. Therefore, our objective was to characterize the relationship between serum AGEs, CLAIS and other risk factors for CV disease in normotensive non-diabetic individuals. METHODS: We measured body mass index (BMI), waist-to-hip ratio (WHR), blood pressure, lipid and glucose profile in 44 non-diabetic volunteers (17 female, 27 males). Carboxymethyl-lysine (CML) was measured by ELISA as a marker for circulating AGEs and NF-κB p65 activity as an inflammatory marker by DNA-binding in peripheral blood mononuclear cells lysates (PBMC). RESULTS: Plasma CML concentrations were related to diastolic blood pressure (r=-0.51, p<0.01) independently of age, sex, BMI and WHR (p<0.05). Diastolic blood pressure was also related to NF-κB activity in PBMC (r=0.47, p<0.01) before and after adjustment for age, sex, BMI and WHR (p<0.05). Plasma CML concentrations were related to the pulse pressure before (r=0.42; p<0.05) and after adjustment for age, sex, BMI and waist (p<0.05). Neither CML nor NF-κB activity were related to systolic blood pressure (both p=ns). Plasma CML concentrations were not associated with plasma lipid or glucose concentrations (all p=ns). CONCLUSIONS: Plasma AGE levels and NF-κB activity in PBMC were independent determinants of diastolic and pulse pressure in healthy normotensive individuals. This association suggests a role for AGEs in the etiology of hypertension, possibly via the initiation of CLAIS and aortic stiffening.