Anti-inflammatory effects of oral supplementation with curcumin: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Chronic inflammation is a major contributor to the development of noncommunicable diseases. Curcumin, a bioactive polyphenol from turmeric, is a well-known anti-inflammatory agent in preclinical research. Clinical evidence remains inconclusive because of discrepancies regarding optimal dosage, duration, and formulation of curcumin. OBJECTIVE: The aim of this systematic review, conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and checklist, was to evaluate the efficacy of curcumin supplementation on systemic inflammatory mediators, comparing dose, duration, and bioavailability status of interventions. DATA SOURCES: The Medline, CINAHL, EMBASE, Scopus, and Cochrane literature databases were searched from 1980 to May-end 2019. Randomized controlled trials investigating effects of dietary curcumin on inflammatory mediators in humans not receiving anti-inflammatory treatment were eligible for inclusion. Two authors independently assessed titles and abstracts of identified articles for potential eligibility and respective, retrieved, full-text articles; disagreements were resolved by a third author. Evidence quality was critically appraised using the Quality Criteria Checklist for Primary Research. DATA EXTRACTION: Thirty-two trials (N = 2,038 participants) were included and 28 were meta-analyzed using a random-effects model; effect sizes were expressed as Hedges' g (95%CI). DATA ANALYSIS: Pooled data (reported here as weighted mean difference [WMD]; 95%CI) showed a reduction in C-reactive protein (-1.55 mg/L; -1.81 to -1.30), interleukin-6 (-1.69 pg/mL, -2.56 to -0.82), tumor necrosis factor α (-3.13 pg/mL; -4.62 to -1.64), IL-8 (-0.54 pg/mL; -0.82 to -0.28), monocyte chemoattractant protein-1 (-2.48 pg/mL; -3.96 to -1.00), and an increase in IL-10 (0.49 pg/mL; 0.10 to 0.88), with no effect on intracellular adhesion molecule-1. CONCLUSION: These findings provide evidence for the anti-inflammatory effects of curcumin and support further investigation to confirm dose, duration, and formulation to optimize anti-inflammatory effects in humans with chronic inflammation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42019148682.

Docosahexaenoic Acid-Rich Fish Oil Supplementation Reduces Kinase Associated with Insulin Resistance in Overweight and Obese Midlife Adults.

Targeting kinases linked to insulin resistance (IR) and inflammation may help in reducing the risk of type 2 diabetes (T2D) and Alzheimer's disease (AD) in its early stages. This study aimed to determine whether DHA-rich fish oil supplementation reduces glycogen synthase kinase (GSK-3), which is linked to both IR and AD. Baseline and post-intervention plasma samples from 58 adults with abdominal obesity (Age: 51.7 ± 1.7 years, BMI: 31.9 ± 0.8 kg/m2) were analysed for outcome measures. Participants were allocated to 2 g DHA-rich fish oil capsules (860 mg DHA + 120 mg EPA) (n = 31) or placebo capsules (n = 27) per day for 12 weeks. Compared to placebo, DHA-rich fish oil significantly reduced GSK-3ß by -2.3 ± 0.3 ng/mL. An inverse correlation (p < 0.05) was found between baseline insulin and IR and their changes following intervention only in participants with C-reactive protein levels higher than 2.4 mg/L. DHA-rich fish oil reduces GSK-3 and IR, suggesting a potential role of long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) in ameliorating AD risk.

Long-chain omega-3 polyunsaturated fatty acids and cognitive decline in non-demented adults: a systematic review and meta-analysis.

CONTEXT: Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) are widely considered as nootropic agents that may be beneficial in reversing cognitive impairment. OBJECTIVE: The present systematic review of randomized controlled trials was conducted to determine the changes in cognitive function after intervention with LCn-3PUFA supplementation in non-demented adults, including those with mild cognitive impairment. DATA SOURCES: Five databases (MEDLINE, CINAHL, Scopus, EMBASE, and the Cochrane Library) were searched systematically along with reference lists of selected articles. STUDY SELECTION: Studies were eligible for inclusion if they measured the effect of LCn-3PUFA supplementation on cognition in non-demented adults. DATA EXTRACTION: A total of 787 records were screened, of which 25 studies were eligible for inclusion. Treatment effects were summarized as global cognitive function for primary outcome and measured using the Mini-Mental State Examination and individual cognitive domains for secondary outcome. The pooled effect sizes were estimated using Hedge's g and random-effects modeling. DATA ANALYSIS: Results from randomized controlled trials indicate that LCn-3PUFAs have no effect on global cognitive function (Hedge's g = 0.02; 95% confidence interval, -0.12 to 0.154), and among the specific cognitive domains, only memory function showed a mild benefit (Hedge's g = 0.31; P = 0.003; z = 2.945). CONCLUSION: The existing literature suggests that LCn-3PUFA supplementation could provide a mild benefit in improving memory function in non-demented older adults. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42017078664.

Association between plasma phospholipid omega-3 polyunsaturated fatty acids and type 2 diabetes is sex dependent: The Hunter Community Study.

BACKGROUND & AIMS: Chronic inflammation drives the development of insulin resistance and type 2 diabetes. Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) eicosapentaenoic acid (EPA, c20:5n-3) and docosahexaenoic acid (DHA, c22:6n-3) may protect against type 2 diabetes development. The aim of this current study is to determine whether LCn-3PUFA status is associated with type 2 diabetes in the Hunter Community Study. METHODS: Men and women aged 55-85 years were randomly selected from the electoral roll and invited to participate. Participants were included in the current study if they had plasma phospholipid fatty acid composition data available and diabetes status could be determined. LCn-3PUFA status was determined by fatty acid composition of plasma phospholipids (EPA + DHA, %,w/w). Diabetes was determined according to World Health Organisation criteria. Insulin was measured in n = 251 participants and HOMA-IR calculated. RESULTS: In total, n = 2092 (diabetes: n = 249) participants were included. After adjusting for confounders of diabetes, LCn-3PUFA status was inversely associated with diabetes in overweight/obese females (OR [95%CI]: 0.90 [0.80, 1.00], p = 0.045) but not males (p-interactionsex = 0.041). Overweight/obese females with diabetes had significantly lower levels of DHA than those without diabetes (mean difference [95%CI]: -0.53 [-0.87, -0.20], p = 0.002), with no difference in EPA. LCn-3PUFA was inversely associated with HOMA-IR (r = -0.175, p = 0.005). CONCLUSIONS: This study provides further evidence of a sex-dependent association between LCn-3PUFA and type 2 diabetes. Causal pathways between LCn-3PUFA and type 2 diabetes merits delineation.

Modulation of Circulating Trimethylamine N-Oxide Concentrations by Dietary Supplements and Pharmacological Agents: A Systematic Review.

Discovery of the association of plasma/serum trimethylamine N-oxide (TMAO) concentrations with atherosclerosis has sparked immense interest in exploring TMAO as a predictor of cardiovascular disease risk. A spectrum of antibiotics and other therapeutic strategies have been employed to test their potential to modulate TMAO concentrations, assuming the gut microbiome to be the key source of TMAO. The aim of this systematic review was to determine whether dietary supplements or pharmacological agents affect TMAO concentrations in adults. Six databases were searched (Medline, EMBASE, CINAHL, Scopus, ProQuest, and PubMed) for randomized and nonrandomized controlled trials. Searches were limited to the English language and to studies in adults. Thirteen eligible trials were identified, including 6 studies on dietary supplements and 7 on pharmacological agents. Whereas intervention studies involving dietary supplements were mostly randomized controlled trials, those involving pharmacological agents appeared opportunistic and varied greatly in study design and duration. Different interventional products were tested, and the studies lacked the consistency to reliably synthesize any evidence for the modifiability of TMAO concentrations by dietary supplements or pharmacological agents. Choline and l-carnitine are conditionally essential nutrients, and carefully designed placebo-controlled randomized trials specifically aimed at reducing the synthesis of microflora-dependent TMAO production from choline-containing precursors by pro- and/or prebiotics, antibiotics, or other pharmaceutical agents may be the way forward for future research.

Curcumin alleviates postprandial glycaemic response in healthy subjects: A cross-over, randomized controlled study.

In the current study, we aimed to evaluate the effects of a single dose of curcumin and/or fish oil on postprandial glycaemic parameters in healthy individuals. This was a randomised, placebo-controlled and crossover study. Sixteen (n = 16) volunteers were randomised to receive placebo, curcumin (180 mg) tablets, fish oil (1.2 g long chain omega-3 polyunsaturated fatty acids) capsules and curcumin + fish oil prior to a standard meal on 4 test days separated by a week. Blood glucose, serum insulin and triglycerides were measured at intervals between 0-120 min. Difference between the treatments was measured using two-way repeated measures analysis of variance and pair-wise comparisons using Wilcoxon signed-rank or paired t-test as appropriate. Postprandial glucose concentrations were significantly lower in the curcumin (60.6%, P = 0.0007) and curcumin + fishoil group (51%, P = 0.002) groups at 60 min from baseline. Compared with placebo, area under the curve (AUC) for change in blood glucose concentration was reduced by curcumin (36%, P = 0.003) and curcumin + fishoil (30%, 0.004), but not fish oil alone (p = 0.105). Both curcumin (P = 0.01) and curcumin + fishoil (P = 0.03) treatments significantly lowered postprandial insulin (AUC) by 26% in comparison with placebo. Curcumin, but not fish oil, reduces postprandial glycaemic response and insulin demand for glucose control.

Differential effects of medium- and long-chain saturated fatty acids on blood lipid profile: a systematic review and meta-analysis.

Background: Medium-chain saturated fatty acids (MCFAs) may affect circulating lipids and lipoproteins differently than long-chain saturated fatty acids (LCSFAs), but the results from human intervention trials have been equivocal. Objective: The aim of this study was to determine whether MCFAs and LCSFAs have differential impacts on blood lipids and lipoproteins. Design: Five databases were searched (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus) until April 2018, and published clinical trials investigating the differential effects of dietary MCFAs and LCSFAs on blood lipids were included. Searches were limited to the English language and to studies with adults aged >18 y. Where possible, studies were pooled for meta-analysis using RevMan 5.2. The principle summary measure was the mean difference between groups calculated using the random-effects model. Results: Eleven eligible crossover and 1 parallel trial were identified with a total of 299 participants [weighted mean ± SD age: 38 ± 3 y; weighted mean ± SD body mass index (kg/m2): 24 ± 2]. All studies were pooled for the meta-analysis. Diets enriched with MCFAs led to significantly higher high-density lipoprotein (HDL) cholesterol concentrations than diets enriched with LCSFAs (0.11 mmol/L; 95% CI: 0.07, 0.15 mmol/L) with no effect on triglyceride, low-density lipoprotein (LDL) cholesterol, and total cholesterol concentrations. Consumption of diets rich in MCFAs significantly increased apolipoprotein A-I (apoA-I) concentrations compared with diets rich in LCSFAs (0.08 g/L; 95% CI: 0.02, 0.14 g/L). There was no evidence of statistical heterogeneity for HDL cholesterol, apoA-I, and triglyceride concentrations; however, significant heterogeneity was observed for the total cholesterol (I2 = 49%) and LDL cholesterol analysis (I2 = 58%). Conclusion: The findings of this research demonstrate a differential effect of MCFAs and LCSFAs on HDL cholesterol concentrations. Further investigations are warranted to elucidate the mechanism by which the lipid profile is altered. This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42017078277.

Science behind the cardio-metabolic benefits of omega-3 polyunsaturated fatty acids: biochemical effects vs. clinical outcomes.

Lower incidence of cardiovascular disease (CVD) in the Greenland Inuit, Northern Canada and Japan has been attributed to their consumption of seafood rich in long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA). While a large majority of pre-clinical and intervention trials have demonstrated heart health benefits of LCn-3PUFA, some studies have shown no effects or even negative effects. LCn-3PUFA have been shown to favourably modulate blood lipid levels, particularly a reduction in circulating levels of triglycerides. High density lipoprotein-cholesterol (HDL-C) levels are elevated following dietary supplementation with LCn-3PUFA. Although LCn-3PUFA have been shown to increase low-density lipoprotein-cholesterol (LDL-C) levels, the increase is primarily in the large-buoyant particles that are less atherogenic than small-dense LDL particles. The anti-inflammatory effects of LCn-3PUFA have been clearly outlined with inhibition of NFkB mediated cytokine production being the main mechanism. In addition, reduction in adhesion molecules (intercellular adhesion molecule, ICAM and vascular cell adhesion molecule 1, VCAM-1) and leukotriene production have also been demonstrated following LCn-3PUFA supplementation. Anti-aggregatory effects of LCn-3PUFA have been a subject of controversy, however, recent studies showing sex-specific effects on platelet aggregation have helped resolve the effects on hyperactive platelets. Improvements in endothelium function, blood flow and blood pressure after LCn-3PUFA supplementation add to the mechanistic explanation on their cardio-protective effects. Modulation of adipose tissue secretions including pro-inflammatory mediators and adipokines by LCn-3PUFA has re-ignited interest in their cardiovascular health benefits. The aim of this narrative review is to filter out the reasons for possible disparity between cohort, mechanistic, pre-clinical and clinical studies. The focus of the article is to provide possible explanation for the observed controversies surrounding heart health benefits of LCn-3PUFA.

InsuTAG: A novel physiologically relevant predictor for insulin resistance and metabolic syndrome.

The aim of this study was to investigate whether a novel physiologically relevant marker, InsuTAG (fasting insulin × fasting triglycerides) can predict insulin resistance (IR) and metabolic syndrome (MetS). Data of 618 participants from the Retirement Health and Lifestyle Study (RHLS) were evaluated for the current study. IR was defined by homeostatic model assessment (HOMA-IR) scores. Pearson correlations were used to examine the associations of InsuTAG with HOMA-IR and other markers. Predictions of IR from InsuTAG were evaluated using multiple regression models. Receiver operating characteristic curves (ROC) were constructed to measure the sensitivity and specificity of InsuTAG values and to determine the optimum cut-off point for prediction of IR. InsuTAG was positively correlated with HOMA-IR (r = 0.86; p < 0.0001). InsuTAG is a strong predictor of IR accounting for 65.0% of the variation in HOMA-IR values after adjusting for potential confounders. Areas under the ROC curve showed that InsuTAG (0.93) has higher value than other known lipid markers for predicting IR, with a sensitivity and specificity of 84.15% and 86.88%. Prevalence of MetS was significantly (p < 0.0001) higher in subjects with InsuTAG values greater than optimal cut-off value of 11.2. Thus, InsuTAG appears to be a potential feasible marker of IR and metabolic syndrome.

Curcumin and long-chain Omega-3 polyunsaturated fatty acids for Prevention of type 2 Diabetes (COP-D): study protocol for a randomised controlled trial.

BACKGROUND: Lifestyle interventions, including increase in physical activity and dietary counselling, have shown the ability to prevent type 2 diabetes (T2D) in high-risk state individuals, but the prevalence is still skyrocketing in Australia, in line with global prevalence. Currently, no medicines are approved by the Therapeutic Goods Administration in Australia for the management of prediabetes. Therefore, there is a need of developing a safer, biologically efficacious and cost-effective alternative for delaying the transition of individual health state from prediabetes into T2D. In the current trial we propose to evaluate the effects of curcumin and/or long-chain omega-3 polyunsaturated fatty acids on improving glycosylated haemoglobin as a primary outcome, along with secondary outcomes of glycaemic indices, lipid profile and inflammatory parameters. METHODS/DESIGN: Eighty individuals diagnosed with prediabetes, aged between 30 and 70 years, will be randomly assigned to double placebo, curcumin alone, fish oil alone or double active groups according to a computer-generated randomisation sequence for 12 weeks. At baseline and post-intervention visits participants will be asked to provide blood samples and undergo body composition measurements. A blood sample is used for estimating glycaemic profiles, lipid profiles and inflammatory parameters (C-reactive protein, whole blood cell count, adiponectin, leptin, interleukin-6). The interim visit includes review on compliance with supplements based on capsule log and capsule count, adverse events and anthropometric measurements. In addition to these procedures, participants provide self-reported questionnaires on dietary intake (using a 3-day food record), a physical activity questionnaire and medical history. DISCUSSION: This trial aims to determine whether curcumin and/or long-chain omega-3 polyunsaturated fatty acids affect surrogate markers of glycaemic control which is relevant to delaying T2D. To date 38 participants completed the trial. No changes have been made to the clinical protocol post recruitment. If successful, this trial will provide considerable evidence for performing a larger trial to investigate whether this combination can be administered for preventing or delaying the onset of T2D in high-risk individuals. TRIAL REGISTRATION: ACTRN12615000559516 , registered on 29 May 2015).

Do ω-3 PUFAs affect insulin resistance in a sex-specific manner? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Evidence has suggested that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) improve obesity-induced insulin resistance (IR); however, results from human intervention trials have been equivocal. Recently it has been reported that n-3 PUFA status is inversely associated with type 2 diabetes in women but not in men, suggesting a sex-dependent effect. OBJECTIVE: We aimed to determine whether n-3 PUFA interventions affect IR in a sex-dependent manner. DESIGN: Five databases were searched (Medline, EMBASE, CINAHL, Scopus, and Pre-Medline) for randomized controlled trials. Searches were limited to the English language and to studies with adults aged >18 y. When possible, studies were pooled for a meta-analysis. The principle summary measure was the standardized mean difference (SMD) between groups. RESULTS: Thirty-one eligible trials were identified with a total of 1848 participants [men: 45.1%; weighted mean ± SD age: 52.5 ± 8.2 y; weighted body mass index (in kg/m2): 28.8 ± 3.0]. Seven studies were conducted in women, 4 studies were conducted in men, and the remaining studies pooled men and women together. Twenty-six trials were pooled for the meta-analysis (men: n = 2; women: n = 6). With all studies (n = 26) pooled, there was no effect of n-3 PUFA on IR at the group level (SMD: 0.089; 95% CI: -0.105, 0.283; P = 0.367). In trials of ≥6 wk, a significant improvement in IR was seen in women (SMD: -0.266; 95% CI: -0.524, -0.007; P = 0.045) but not in men (SMD: 0.619; 95% CI: -0.583, 1.820; P = 0.313). CONCLUSIONS: With this analysis, we provide preliminary evidence of a sex-dependent response of IR to an n-3 PUFA intervention. Additional studies are needed to confirm sex-dependent associations and to elucidate the potential mechanisms that are involved. This trial was registered at www.crd.york.ac.uk/PROSPERO/ as CRD42015017940.

Sex-dependent association between erythrocyte n-3 PUFA and type 2 diabetes in older overweight people.

The association between n-3 PUFA intake and type 2 diabetes (T2D) is unclear, and studies relating objective biomarkers of n-3 PUFA consumption to diabetic status remain limited. The aim of this study was to determine whether erythrocyte n-3 PUFA levels (n-3 index; n-3I) are associated with T2D in a cohort of older adults (n 608). To achieve this, the n-3I (erythrocyte %EPA+%DHA) was determined by GC and associated with fasting blood glucose; HbA1c; and plasma insulin. Insulin resistance (IR) was assessed using the homeostatic model assessment of insulin resistance (HOMA--IR). OR for T2D were calculated for each quartile of n-3I. In all, eighty-two type 2 diabetic (46·3 % female; 76·7 (sd 5·9) years) and 466 non-diabetic (57·9 % female; 77·8 (sd 7·1) years) individuals were included in the analysis. In overweight/obese (BMI≥27 kg/m2), the prevalence of T2D decreased across ascending n-3I quartiles: 1·0 (reference), 0·82 (95 % CI 0·31, 2·18), 0·56 (95 % CI 0·21, 1·52) and 0·22 (95 % CI 0·06, 0·82) (P trend=0·015). A similar but non-significant trend was seen in overweight men. After adjusting for BMI, no associations were found between n-3I and fasting blood glucose, HbA1c, insulin or HOMA-IR. In conclusion, higher erythrocyte n-3 PUFA status may be protective against the development of T2D in overweight women. Further research is warranted to determine whether dietary interventions that improve n-3 PUFA status can improve measures of IR, and to further elucidate sex-dependent differences.