Carnosine supplementation improves glucose control in adults with pre-diabetes and type 2 diabetes: A randomised controlled trial.

BACKGROUND AND AIMS: Type 2 diabetes (T2DM) is a major cause of morbidity and mortality globally. Carnosine, a naturally occurring dipeptide, has anti-inflammatory, antioxidant, and anti-glycating effects, with preliminary evidence suggesting it may improve important chronic disease risk factors in adults with cardiometabolic conditions. METHODS AND RESULTS: In this randomised controlled trial, 43 adults (30%F) living with prediabetes or T2DM consumed carnosine (2 g) or a matching placebo daily for 14 weeks to evaluate its effect on glucose metabolism assessed via a 2-h 75 g oral glucose tolerance test. Secondary outcomes included body composition analysis by dual energy x-ray absorptiometry (DEXA), calf muscle density by pQCT, and anthropometry. Carnosine supplementation decreased blood glucose at 90 min (-1.31 mmol/L; p = 0.02) and 120 min (-1.60 mmol/L, p = 0.02) and total glucose area under the curve (-3.30 mmol/L; p = 0.04) following an oral glucose tolerance test. There were no additional changes in secondary outcomes. The carnosine group results remained significant before and after adjustment for age, sex, and change in weight (all>0.05), and in further sensitivity analyses accounting for missing data. There were no significant changes in insulin levels. CONCLUSION: This study provides preliminary support for larger trials evaluating carnosine as a potential treatment for prediabetes and the initial stages of T2DM. Likely mechanisms may include changes to hepatic glucose output explaining the observed reduction in blood glucose without changes in insulin secretion following carnosine supplementation.

Carnosine Did Not Affect Vascular and Metabolic Outcomes in Patients with Prediabetes and Type 2 Diabetes: A 14-Week Randomized Controlled Trial.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in patients with prediabetes and type 2 diabetes mellitus (T2DM). Carnosine has been suggested as a potential approach to reduce ASCVD risk factors. However, there is a paucity of human data. Hence, we performed a 14-week double-blind randomized placebo-controlled trial to determine whether carnosine compared with placebo improves vascular and metabolic outcomes in individuals with prediabetes and T2DM. In total, 49 patients with prediabetes and T2DM with good glycemic control were randomly assigned either to receive 2 g/day carnosine or matching placebo. We evaluated endothelial dysfunction, arterial stiffness, lipid parameters, blood pressure, heart rate, hepatic and renal outcomes before and after the intervention. Carnosine supplementation had no effect on heart rate, peripheral and central blood pressure, endothelial function (logarithm of reactive hyperemia (LnRHI)), arterial stiffness (carotid femoral pulse wave velocity (CF PWV)), lipid parameters, liver fibroscan indicators, liver transient elastography, liver function tests, and renal outcomes compared to placebo. In conclusion, carnosine supplementation did not improve cardiovascular and cardiometabolic risk factors in adults with prediabetes and T2DM with good glycemic control. Therefore, it is improbable that carnosine supplementation would be a viable approach to mitigating the ASCVD risk in these populations. The trial was registered at clinicaltrials.gov (NCT02917928).

Implementation of non-pharmacological interventions for the treatment of hypertension in primary care: a narrative review of effectiveness, cost-effectiveness, barriers, and facilitators.

BACKGROUND: The current guidelines for the prevention, detection, evaluation, and management of hypertension recommend six types of non-pharmacological interventions: alcohol reduction, salt intake reduction, increased potassium intake, physical activity, weight loss, and heart-healthy diets. However, the non-pharmacological interventions are still not widely used in primary care. In this paper, we, therefore, reviewed and summarised the evidence on the effectiveness, cost-effectiveness, barriers, and facilitators of non-pharmacological interventions for the treatment of hypertension in primary care. METHODS: A thorough literature search was conducted in Embase, Google Scholar, and PubMed databases, to identify the most recent reviews or, in their absence, primary studies on alcohol reduction, salt intake reduction, potassium supplementation, physical activity, weight reduction, heart-healthy diets, and other non-pharmacological interventions for the treatment of hypertension in primary care. RESULTS: Alcohol reduction is a non-pharmacological intervention for the treatment of hypertension in primary care with proven effectiveness, feasibility, and acceptability. Interventions for sodium intake reduction, physical activity, and weight reduction are effective but there is insufficient evidence regarding their feasibility and acceptability in primary care settings. Evidence on the effectiveness of potassium intake and heart-healthy diets is limited and inconsistent. There is a lack of evidence on the cost-effectiveness of non-pharmacological interventions in the treatment of hypertension. The most common barriers to deliver such interventions related to healthcare providers include a lack of time, knowledge, self-confidence, resources, clear guidelines, and financial incentives. The most common barriers related to patients include a lack of motivation and educational resources. Less evidence is available on facilitators of implementing non-pharmacological interventions in primary care. Besides, facilitators differed by different types of interventions. CONCLUSIONS: Available evidence suggests that more pragmatic, clinically feasible, and logistically simple interventions are required for sodium intake reduction, physical activity, and weight reduction in primary care settings. Future studies should provide further evidence on the effectiveness of weight control, potassium intake, and heart-healthy diets. More research is also needed on cost-effectiveness and facilitators of all types of effective non-pharmacological interventions for the treatment of hypertension in primary care.

Yoga for hypertensive patients: a study on barriers and facilitators of its implementation in primary care.

BACKGROUND: International guidelines for hypertension treatment recommend the use of yoga, particularly among low-risk patients. However, evidence is lacking on the implementation potential of health-worker-led yoga interventions in low-resource, primary care settings. OBJECTIVE: To assess barriers to and facilitators of the implementation of a yoga intervention for hypertensive patients in primary care in Nepal. METHODS: The study was conducted using focus group discussions, in-depth interviews, key informant interviews, and telephone interviews. Data were collected from the 'Yoga and Hypertension' (YoH) trial participants, YoH intervention implementers, and officials from the Ministry of Health and Population in Nepal. RESULTS: Most YoH trial participants stated that: (1) it was easy to learn yoga during a five-day training period and practise it for three months at home; (2) practising yoga improved their health; and (3) group yoga sessions in a community centre would help them practise yoga more regularly. Most YoH intervention implementers stated that: (1) they were highly motivated to implement the intervention; (2) the cost of implementation was acceptable; (3) they did not need additional staff to effectively implement the intervention; (4) providing remuneration to the staff involved in the intervention would increase their motivation; and (5) the yoga programme was 'simple and easy to follow' and 'easily performed by participants of any age'. The government officials stated that: (1) yoga is considered as a key health promotional activity in Nepal; and (2) the integration of the yoga intervention into the existing health care programme would not be too challenging, because the existing personnel and other resources can be utilised. CONCLUSION: While there is a good potential that a yoga intervention can be implemented in primary care, capacity development for health workers and the involvement of community yoga centres in the delivery of the interventions may be required to facilitate this implementation.

Nutritional Interventions for COVID-19: A Role for Carnosine?

As COVID-19 continues to take an enormous toll on global health, the effort to find effective preventive and treatment strategies has been unparalleled in recent history [...].

Effects of a health worker-led 3-month yoga intervention on blood pressure of hypertensive patients: a randomised controlled multicentre trial in the primary care setting.

BACKGROUND: Hypertension control remains a major challenge globally. A recent systematic review suggested that yoga has beneficial effects on reducing blood pressure. However, the role of yoga in hypertension management in primary health care has received little attention, and no studies have evaluated the impact of a yoga program fully delivered by health care staff on hypertension. This study, therefore, assessed the effects of a health worker-led yoga intervention on blood pressure reduction among hypertensives patients in the primary care setting. METHODS: This was a multicentric, two-arm, randomised trial conducted among hypertensive patients in seven Ayurveda Health Centres in Nepal between March 2017 and June 2018. One hundred and twenty-one participants who were on or without medications were randomised to intervention (n = 61) and wait-list control (n = 60) groups using stratified block randomisation. Participants in the intervention arm received an intervention consisting of an initial five-day structured yoga training at the centres and then a further home-based practice of yoga for five days a week for the following 90 days. Both intervention and control groups also participated in a 2-h health education session. The primary outcome of this trial was systolic blood pressure at 90-day follow-up. Data were analysed on an intention-to-treat basis using linear mixed-effects regression models. RESULTS: We included all 121 study participants (intervention/control = 61/60) in the primary analysis (52.1% males; mean ± SD age = 47.8 ± 10.8 years). The difference in systolic blood pressure between the intervention group and the control group was - 7.66 mmHg (95% CI: - 10.4, - 4.93). For diastolic blood pressure, the difference was - 3.86 mmHg (95% CI: - 6.65, - 1.06). No adverse events were reported by the participants. CONCLUSIONS: A yoga program for hypertensive patients consisting of a five-day training in health centres and 90 days of practice at home is effective for reducing blood pressure. Significant benefits for hypertensive patients could be expected if such programmes would become a part of the standard treatment practice. TRIAL REGISTRATION: This trial was prospectively registered with the Clinical Trial Registry of India [ CTRI/2017/02/007822 ] on 10/02/2017.

Polyphenol Rich Sugar Cane Extract Inhibits Bacterial Growth.

Plants that are primarily used as a food source commonly have undervalued biological properties beyond the basic supply of nutrients. One important example of this are the antimicrobial properties of plants. Inclusion of natural and food grade antimicrobial ingredients in recipes to prevent food spoilage and disease transmission, or in cosmetic products to prevent transient and pathogenic bacteria would have world-wide public health implications. A patented natural polyphenol rich sugar cane extract (PRSE), is marketed as a high anti-oxidant and polyphenol ingredient, but its anti-microbial activity has not been reported previously. We determined the anti-bacterial properties of PRSE on common human pathogens relating to a range of diseases including food poisoning, tooth decay, acne and severe skin infections using disc/well diffusion experiments. Our findings indicate that PRSE is an efficient antimicrobial, which could be included at differing dosages to target a range of food borne and environmental pathogens.

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.

Effect of 16-weeks vitamin D replacement on calcium-phosphate homeostasis in overweight and obese adults.

This randomised placebo-controlled trial aimed to determine the effect of 16-weeks cholecalciferol supplementation on calcium-phosphate homeostasis and bone mineral density (BMD) in overweight and obese adults. Fifty-four vitamin D-deficient (25OHD<50 nmol/L), overweight and obese adults (mean age 32 ± 8.5 years) were included in the trial. Participants were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 weeks. Before and after the intervention, serum calcium, phosphate, 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (iPTH) and C-terminal plasma fibroblast growth factor-23 (cFGF-23) concentrations were measured. Whole-body BMD was assessed using dual-energy X-ray absorptiometry (DXA) and diet and sun exposure were assessed using self-administered questionnaires. There were no significant differences in baseline characteristics between the vitamin D and placebo group. After 16-weeks of vitamin D supplementation, mean changes in 25(OH)D concentration were higher in the vitamin D group (57 nmol/L 95% CI 49, 65) compared with placebo (2 nmol/L 95% CI -4, 8), P < 0.001. Additionally, iPTH concentrations declined in the vitamin D group (-1.19 pmol/L 95% CI -1.9, -0.47) compared with placebo (0.14 pmol/L 95% CI -0.49, 0.77), P = 0.006. There were no significant differences in calcium, phosphate, iPTH and cFGF-23 concentrations and whole-body BMD between vitamin D and placebo at follow-up. Inverse correlations were observed between mean change in serum iPTH and cFGF-23 in the vitamin D group only (r=-0.41, P = 0.029). In individuals with greater vitamin D deficiency at baseline (25(OH)D < 30 nmol/L), there was a significant increase in mean whole-body BMD (0.01 g/cm2, 95% CI 0.001, 0.025) however, the mean change in BMD was not different between vitamin D and placebo groups in this sub-group analysis. We conclude that cholecalciferol supplementation for 16 weeks increases serum 25(OH)D concentrations and reduces iPTH concentrations in overweight and obese, but otherwise healthy adults with vitamin D deficiency, and has no effect on calcium, phosphate and iFGF-23 concentrations and whole-body BMD.

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.

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.

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.

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.

The relationship between 25-hydroxyvitamin D concentration and liver enzymes in overweight or obese adults: Cross-sectional and interventional outcomes.

Vitamin D deficiency is prevalent in individuals with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. However, there is limited and inconsistent data on the effect of vitamin D supplementation on liver function. Hepatic enzymes have been used as surrogate markers for NAFLD and have been associated with metabolic syndrome. We examined the relationships between 25-hydroxyvitamin D (25(OH)D) and γ-glutamyl transferase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP) in 120 drug-naïve individuals with no history of liver disease. In addition, the effect of vitamin D supplementation (100,000 loading dose of cholecalciferol followed by 4000IU daily for 16 weeks) on hepatic enzymes was investigated in a subgroup of 54 vitamin D-deficient overweight or obese individuals (28 randomised to cholecalciferol and 26 to placebo). Hepatic enzymes, anthropometric parameters, lipid profile, insulin sensitivity (hyperinsulinaemic-euglycaemic clamp, M value) and high sensitivity C-reactive protein (hs-CRP) were measured before and after the intervention. In the cross-sectional study, levels of GGT and ALT were higher in men compared to women (both p=0.001). There were no significant differences in GGT, ALT and ALP between vitamin D categories (25(OH)D<25nmol/L, 25-50nmol/L, and >50nmol/L) and no relationships were found between the three enzymes and 25(OH)D before and after adjustment for age, sex, BMI, WHR, and insulin sensitivity (all p>0.5). In the randomised trial, 25(OH)D concentrations increased in the vitamin D group (mean change 57.0±21.3nmol/L) compared to the placebo group (mean change 1.9±15.1nmol/L). Mean changes in GGT, ALT and ALP were not significantly different between vitamin D and placebo groups (all p>0.2). Change in 25(OH)D concentration was not correlated with changes in GGT, ALT and ALP before and after adjustments for age and sex (all p>0.1). In summary, 25(OH)D concentrations were not related to hepatic enzymes in drug-naive adults with no history of liver disease, and vitamin D supplementation had no effect on the serum levels of hepatic enzymes in vitamin D-deficient and overweight or obese, otherwise healthy individuals. Hence, vitamin D supplementation is unlikely to prevent incident NAFLD.

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.

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

Carnosine has been shown to reduce oxidation and glycation of low density lipoprotein hence improving dyslipidaemia in rodents. The effect of carnosine on human plasma lipidome has thus far not been investigated. We aimed to determine whether carnosine supplementation improves the plasma lipidome in overweight and obese individuals. Lipid analysis was performed by liquid chromatography mass spectrometry in 24 overweight and obese adults: 13 were randomly assigned to 2 g carnosine daily and 11 to placebo, and treated for 12 weeks. Carnosine supplementation maintained trihexosylceramide (0.01 ± 0.19 vs -0.28 ± 0.34 nmol/ml, p = 0.04), phosphatidylcholine (77 ± 167 vs -81 ± 196 nmol/ml, p = 0.01) and free cholesterol (20 ± 80 vs -69 ± 80 nmol/ml, p = 0.006) levels compared to placebo. Trihexosylceramide was inversely related with fasting insulin (r = -0.6, p = 0.002), insulin resistance (r = -0.6, p = 0.003), insulin secretion (r = -0.4, p = 0.05) and serum carnosinase 1 activity (r = -0.3, p = 0.05). Both phosphatidylcholine and free cholesterol did not correlate with any cardiometabolic parameters. Our data suggest that carnosine may have beneficial effects on the plasma lipidome. Future larger clinical trials are needed to confirm this.

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.

Does supplementation with carnosine improve cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes? study protocol for a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Carnosine, an over-the-counter food supplement, has a promising potential for the prevention and treatment of chronic diseases such as type 2 diabetes (T2DM), cardiovascular and neurodegenerative diseases through its anti-inflammatory, antiglycation, antioxidative and chelating effects. We have previously shown that supplementation with carnosine preserves insulin sensitivity and secretion in non-diabetic overweight and obese individuals. The effect of carnosine on cardiometabolic risk and related cognitive outcomes in patients with pre-diabetes and T2DM has thus far not been studied. We therefore aim to investigate whether supplementation with carnosine improves cardiometabolic health and cognitive function in patients with pre-diabetes and T2DM. METHODS AND ANALYSIS: We will employ a parallel design randomised controlled trial. Fifty participants with pre-diabetes (impaired fasting glycaemia and impaired glucose tolerance) and T2DM (with HbA1c level < 8%) aged between 18 to 70 years will be randomly assigned to the intervention or control group. At baseline, participants will undergo a medical review and series of tests including anthropometric measurements (body mass index, a dual X-ray absorptiometry and peripheral quantitative computed tomography scan), an oral glucose tolerance test, cardiovascular measurements (central blood pressure, endothelial function and arterial stiffness), cognitive function, physical activity measurement, heart rate variability and liver fibroscan as well as questionnaires to assess dietary habits, sleep quality, depression and quality of life. The intervention group will receive 2 g of carnosine daily in two divided doses while the control group will receive identical placebo capsules for 14 weeks. All baseline measurements will be repeated at the end of the intervention. The change in glycaemic, cardiovascular and cognitive parameters as well as other measures will be compared between the groups. ETHICS AND DISSEMINATION: This study is approved by the Human Research Ethics Committee of Monash Health and Monash University, Australia. The findings will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION: NCT02917928; Pre-results.

Effect of dietary advanced glycation end products on inflammation and cardiovascular risks in healthy overweight adults: a randomised crossover trial.

Diets high in advanced glycation end products (AGEs) are thought to be detrimental to cardiovascular health. However, there remains uncertainty about the beneficial effect of a low AGE diet on cardiovascular risk factors and inflammatory markers in overweight individuals. We thus performed a randomised, double blind, crossover trial to determine whether consumption of low AGE diets reduce inflammation and cardiovascular risks in overweight and obese otherwise healthy adults. All participants (n = 20) consumed low and high AGE diets alternately for two weeks and separated by a four week washout period. Low AGE diets did not change systolic (p = 0.2) and diastolic blood pressure (p = 0.3), mean arterial pressure (p = 0.8) and pulse pressure (p = 0.2) compared to high AGE diets. Change in total cholesterol (p = 0.3), low-density lipoprotein (p = 0.7), high-density lipoprotein (p = 0.2), and triglycerides (p = 0.4) also did not differ and there was no difference in inflammatory markers: interleukin-6 (p = 0.6), monocyte chemoattractant protein-1 (p = 0.9), tumour necrosis factor α (p = 0.2), C-reactive protein (p = 0.6) and nuclear factor kappa beta (p = 0.2). These findings indicate that consumption of low AGE diets for two weeks did not improve the inflammatory and cardiovascular profiles of overweight and obese adults.

Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: a randomized placebo-controlled trial.

Background: Vitamin D supplementation has been proposed as a potential strategy to prevent type 2 diabetes. Existing clinical trials have been limited by short duration, low doses of vitamin D, variability in participants' vitamin D-deficiency status, and the use of surrogate measures of body composition, insulin sensitivity, and insulin secretion.Objective: To address existing knowledge gaps, we conducted a double-blind, randomized, placebo-controlled trial to investigate whether vitamin D supplementation that is provided in a sufficient dose and duration to vitamin D-deficient individuals would improve insulin sensitivity or secretion as measured with the use of gold-standard methods. We hypothesized that vitamin D supplementation would improve insulin sensitivity and secretion compared with placebo.Design: Sixty-five overweight or obese, vitamin D-deficient (25-hydroxyvitamin D [25(OH)D] concentration ≤50 nmol/L) adults were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 wk. Before and after the intervention, participants received gold-standard assessments of body composition (via dual X-ray absorptiometry), insulin sensitivity (via hyperinsulinemic-euglycemic clamps), and insulin secretion [via intravenous-glucose-tolerance tests (IVGTTs)].Results: Fifty-four participants completed the study [35 men and 19 women; mean ± SD age: 31.9 ± 8.5 y; body mass index (in kg/m2): 30.9 ± 4.4]. 25(OH)D increased with vitamin D supplementation compared with placebo (57.0 ± 21.3 compared with 1.9 ± 15.1 nmol/L, respectively; P = 0.02). Vitamin D and placebo groups did not differ in change in insulin sensitivity (0.02 ± 2.0 compared with -0.03 ± 2.8 mg · kg-1 · min-1, respectively; P = 0.9) or first-phase insulin secretion (-21 ± 212 compared with 24 ± 184 mU/L, respectively; P = 0.9). Results remained nonsignificant after adjustment for age, sex, percentage of body fat, sun exposure, physical activity, and dietary vitamin D intake (P > 0.1).Conclusions: Vitamin D supplementation does not improve insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults, despite using high-dose vitamin D supplementation and robust endpoint measures. Therefore, it is unlikely that vitamin D supplementation would be an effective strategy for reducing diabetes risk even in vitamin D-deficient populations. This trial was registered at clinicaltrials.gov as NCT02112721.