Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aß) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aß, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the ß-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aß, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Elevated plasma sclerostin is associated with high brain amyloid-ß load in cognitively normal older adults.

Osteoporosis and Alzheimer's disease (AD) mainly affect older individuals, and the possibility of an underlying link contributing to their shared epidemiological features has rarely been investigated. In the current study, we investigated the association between levels of plasma sclerostin (SOST), a protein primarily produced by bone, and brain amyloid-beta (Aß) load, a pathological hallmark of AD. The study enrolled participants meeting a set of screening inclusion and exclusion criteria and were stratified into Aß- (n = 65) and Aß+ (n = 35) according to their brain Aß load assessed using Aß-PET (positron emission tomography) imaging. Plasma SOST levels, apolipoprotein E gene (APOE) genotype and several putative AD blood-biomarkers including Aß40, Aß42, Aß42/Aß40, neurofilament light (NFL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and phosphorylated tau (p-tau181 and p-tau231) were detected and compared. It was found that plasma SOST levels were significantly higher in the Aß+ group (71.49 ± 25.00 pmol/L) compared with the Aß- group (56.51 ± 22.14 pmol/L) (P < 0.01). Moreover, Spearman's correlation analysis showed that plasma SOST concentrations were positively correlated with brain Aß load (ρ = 0.321, P = 0.001). Importantly, plasma SOST combined with Aß42/Aß40 ratio significantly increased the area under the curve (AUC) when compared with using Aß42/Aß40 ratio alone (AUC = 0.768 vs 0.669, P = 0.027). In conclusion, plasma SOST levels are elevated in cognitively unimpaired older adults at high risk of AD and SOST could complement existing plasma biomarkers to assist in the detection of preclinical AD.

Plasma Trimethylamine N-Oxide Levels Are Associated with Poor Kidney Function in People with Type 2 Diabetes.

Previous studies have linked elevated plasma trimethylamine N-oxide (TMAO) levels to poor renal function. The relationship between TMAO and chronic kidney disease (CKD) in type 2 diabetes (T2D) is still unclear. We investigated the association between plasma TMAO levels and CKD in patients with T2D. A cross-sectional study of 133 patients with T2D with or without CKD has been conducted. Blood biomarkers of kidney function, diabetes, and inflammation were assessed in the study participants. Plasma TMAO levels were quantified using UPLC-MS/MS. People with T2D and CKD exhibited significantly higher plasma TMAO levels [10.16 (5.86-17.45) µmol/L] than those without CKD [4.69 (2.62-7.76) µmol/L] (p = 0.002). Participants in the highest quartile of TMAO levels (>8.38 µmol/L) presented relatively elevated serum creatinine levels and a higher number of people with CKD than those in the lower quartiles. TMAO levels were significantly correlated with kidney function biomarkers, including estimated glomerular filtration rate and urinary albumin to creatinine ratio. The association between TMAO and CKD was evident (p < 0.0001) and remained significant after adjusting for risk factors of kidney disease, including age, gender, body mass index, duration of diabetes, and smoking. These findings suggest the association between plasma TMAO and CKD in patients with T2D.

Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer's Disease.

BACKGROUND: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. OBJECTIVE: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. METHODS: Plasma GFAP and Aß were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aß-PET imaging, comprising 54 healthy control (13 Aß-PET+ and 41 Aß-PET-), 11 mild cognitively impaired (3 Aß-PET+ and 8 Aß-PET-) and 6 probable AD (5 Aß-PET+ and 1 Aß-PET-) individuals. Linear regressions were used to assess associations of interest. RESULTS: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aß deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aß (plasma Aß42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aß (Aß-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. CONCLUSION: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aß load.

Plasma Aß42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort.

INTRODUCTION: Plasma amyloid beta (Aß)1-42/Aß1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking. METHODS: Plasma Aß1-42, Aß1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aß-PET (positron emission tomography)-negative cognitively unimpaired (CU Aß-, n = 81) and mild cognitive impairment (MCI Aß-, n = 26) participants were compared with Aß-PET-positive participants across the AD continuum (CU Aß+, n = 39; MCI Aß+, n = 33; AD Aß+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aß-PET load were assessed over a 7 to 10-year duration. RESULTS: Lower plasma Aß1-42/Aß1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aß+, MCI Aß+, and AD Aß+, whereas elevated plasma NfL was observed in MCI Aß+ and AD Aß+, compared with CU Aß- and MCI Aß-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aß-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aß1-42/Aß1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aß-/+ status across the AD continuum. Longitudinally, plasma Aß1-42/Aß1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aß1-42/Aß1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aß1-42/Aß1-40, and higher p-tau181 and GFAP were associated with increased Aß-PET load prospectively. DISCUSSION: These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aß-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aß-/+ status across the AD continuum, a panel of biomarkers may have superior Aß-/+ status predictive capability across the AD continuum. HIGHLIGHTS: Area under the curve (AUC) of p-tau181 ≥ AUC of Aß42/40, GFAP, NfL in predicting PET Aß-/+ status (Aß-/+).  AUC of Aß42/40+p-tau181+GFAP panel ≥ AUC of Aß42/40/p-tau181/GFAP/NfL for Aß-/+.  Longitudinally, Aß42/40, p-tau181, and GFAP were altered in MCI versus CU.  Longitudinally, GFAP and NfL were altered in AD versus CU.  Aß42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline.  Aß42/40, p-tau181, and GFAP are associated with increased PET Aß load prospectively.

Bioactive Yoghurt Containing Curcumin and Chlorogenic Acid Reduces Inflammation in Postmenopausal Women.

Menopause is marked by a gradual and permanent decrease of estrogen from the ovaries, leading to metabolic and physiological changes in the body. Combined with increased body mass index, postmenopausal women have elevated systemic inflammation and metabolic disturbances leading to increased risk of developing chronic diseases. A bioactive coconut yoghurt containing curcumin and chlorogenic acid was developed with the potential to target inflammatory processes. In this randomized crossover study, healthy postmenopausal women with a BMI of 25-40 were recruited to consume 125 g of either the bioactive or placebo yoghurt. Blood samples were collected at baseline, 30 min, and 1, 2, 3 and 4 h postprandially. Plasma inflammatory markers (TNFα and IL6) and metabolic markers (triglycerides, insulin and glucose) were measured. Participants had significantly lower plasma TNFα Cmax after consumption of the bioactive yoghurt compared to placebo (mean difference = 0.3 pg/mL; p = 0.04). Additionally, plasma TNFα was significantly lower postprandially compared to baseline after consumption of the bioactive yogurt but not the placebo. No differences were observed in the metabolic markers measured. Conclusions: The bioactive yoghurt fortified with curcumin and chlorogenic acid has the potential to reduce inflammatory mediators; however, a larger and longer-term study is required to confirm these findings.

Plasma high-density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume.

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data.

Association of Plasma Neurofilament Light Chain With Glycaemic Control and Insulin Resistance in Middle-Aged Adults.

Aims: This study aimed to determine the association of plasma neurofilament light (NfL), a marker of neurodegeneration, with diabetes status and glycaemic parameters in people with normal glycaemia (NG), pre-diabetes (PD) and type 2 diabetes (T2D). Methods: Clinical and descriptive data for the diagnostic groups, NG (n=30), PD (n=48) and T2D (n=29), aged between 40 and 75 years were included in this cross-sectional analysis. Plasma NfL levels were analyzed using the ultra-sensitive single-molecule array (Simoa) platform. Results: A positive correlation was evident between plasma NfL and fasting glucose (r = 0.2824; p = 0.0032). Plasma NfL levels were not correlated with fasting insulin and insulin resistance. Plasma Nfl levels were significantly different across the diabetes groups (T2D >PD >NG, p=0.0046). Post-hoc analysis indicated significantly higher plasma NfL levels in the T2D [12.4 (5.21) pg/mL] group than in the PD [10.2 (4.13) pg/mL] and NG [8.37 (5.65) pg/mL] groups. The relationship between diabetes status and NfL remained significant after adjusting for age, sex, BMI, HOMA-IR and physical activity (adjusted r2 = 0.271, p = 0.035). Conclusions: These results show biomarker evidence of neurodegeneration in adults at risk or with T2D. Larger sample size and longitudinal analysis are required to better understand the application of NfL in people with risk and overt T2D.

Association between Plasma Trimethylamine N-Oxide Levels and Type 2 Diabetes: A Case Control Study.

Animal and human studies have reported conflicting results on the relationship between circulating trimethylamine N-oxide (TMAO) levels and risk of Type 2 diabetes (T2D). This study aimed to compare plasma TMAO levels in people with or without T2D and explore the association of TMAO and T2D. A prospective case-control study of 297 participants, 164 healthy controls and 133 patients with T2D, was conducted. TMAO levels were quantified by UPLC-MS/MS. Comorbidities, dietary patterns, physical activity, and blood biomarkers were assessed. Median (IQR) plasma TMAO levels were significantly higher in diabetes cases (4.95 (2.84−8.35) µmol/L) compared to healthy controls (3.07 (2.05−4.82) µmol/L) (p < 0.001). The association between TMAO and T2D was significant in the non-adjusted Model 1 (p < 0.001) and after adjusting for confounders of diabetes including age, BMI, and level of education in Model 2 (p = 0.04). When the association was further adjusted for physical activity and diet in Model 3, plasma TMAO levels at only the highest quartile (>6.40 µmol/L) were associated with the risk of diabetes (OR = 3.36, 95% CI [1.26, 9.04], p = 0.02). The results presented suggest an association between plasma TMAO levels and T2D. A significant correlation was found between red meat consumption and increased levels of TMAO in T2D patients. A longitudinal study is warranted to further evaluate the correlation between TMAO and T2D.

Significance of Postprandial Insulin and Triglycerides to Evaluate the Metabolic Response of Composite Meals Differing in Nutrient Composition - A Randomized Cross-Over Trial.

Background and aims: GlucoTRIG, based on postprandial plasma insulin and triglyceride concentrations, has been recently developed as a novel index to determine the postprandial metabolic response to the meals. This study aimed to test GlucoTRIG as a measure for ranking composite meals for their metabolic effects. Methods: In a randomized cross-over trial, healthy adult volunteers (both males and females; n = 10 for each meal) consumed three is caloric (2000 kj) test meals (meal 1, meal 2, meal 3) of varying macronutrient composition. Postmeal consumption, venous blood samples were collected to determine plasma insulin and plasma triglycerides for estimating the GlucoTRIG value using (Triglycerides180min × Insulin180min) - (Triglycerides0min × Insulin0min). Results: The GlucoTRIG values differed significantly (p = 0.0085) across meals. The statistical significance remains even after adjusting for confounding variables such as baseline diet, insulin, and triglycerides. The meal (M3) with a high fiber, low total fat content and containing less refined foods (fruits, beans, vegetables, plain yogurt) exhibited a significantly (p = 0.007) lower GlucoTRIG value (10 ± 7.7) compared to the other two meals, M1 (77 ± 19.8) and M2 (38 ± 12.1) which contained low processed foods, and were relatively high in fat and low in fiber meals. No statistically significant differences were observed between M1 and M2 meal. Conclusions: GlucoTRIG is a physiologically based index that may be useful to rank composite meals for reducing the risk of metabolic diseases. Further research focusing on the application of GlucoTRIG to foods, meals, and diets is warranted.ACTRN12619000973112 (Australian New Zealand Clinical Trials Registry, ANZCTR).

Association of Islet Amyloid Polypeptide to C-Peptide Ratio With Cystic Fibrosis-Related Diabetes: A Prospective Cross-sectional Study.

OBJECTIVES: Early detection of cystic fibrosis (CF) related diabetes (CFRD) improves health outcomes and reduces CF-related mortality. The study aims to evaluate the ratio of islet amyloid polypeptide (IAPP) to C-peptide in CF patients with diabetes and without diabetes. METHODS: Cross-sectional analysis was carried out in a prospective cohort of 33 participants (CF [n = 16] and CFRD [n = 18]). We examined the association of plasma IAPP:C-peptide ratio with clinical information, including glycated hemoglobin, and lung function markers. RESULTS: The median (interquartile range) IAPP:C-peptide ratio was significantly (P = 0.004) higher in people with CFRD (4.8 [4.5]) compared with participants without CFRD (12.1 [19.7]). The ratio of IAPP to C-peptide significantly accounted for a 38% variation in the diabetes status in patients with CF (r2 = 0.399, P < 0.001). Islet amyloid polypeptide is strongly correlated with serum ferritin levels (r = 0.683, P = 0.005) and forced expiratory volume in CFRD, but not in nondiabetic participants with CF. CONCLUSIONS: Islet amyloid polypeptide:C-peptide ratio could be a potential marker of CFRD in adults with CF. Further research requires validation of this marker in longitudinal cohort studies to confirm the capability of IAPP:C-peptide to predict CFRD.

Biophysical evidence to support and extend the vitamin D-folate hypothesis as a paradigm for the evolution of human skin pigmentation.

OBJECTIVE: To test the "vitamin D-folate hypothesis for the evolution of human skin pigmentation." METHODS: Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n = 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n = 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. RESULTS: Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). UV-wavelength exhibits a dose-response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. Three dietary antioxidants (vitamins C, E, and ß-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3 . CONCLUSION: New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.

Postprandial lipaemia following consumption of a meal enriched with medium chain saturated and/or long chain omega-3 polyunsaturated fatty acids. A randomised cross-over study.

BACKGROUND & AIMS: Postprandial lipaemic response has emerged as a risk factor for cardiovascular disease. Dietary fats such as medium-chain saturated fatty acids (MCSFA) and long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) are known to reduce postprandial lipaemic responses. The combination of the two could potentially have complementary and/or synergistic effects for optimising cardiovascular health. This study aims to investigate the effects of MCSFA (coconut oil) with or without LCn-3PUFA (fish oil) inclusion in the test meal on postprandial blood lipids in healthy adults. METHODS: In a randomised, double-blinded, placebo-controlled, 2 × 2 factorial cross-over study, participants (n = 15) were randomised to receive four standardised isocaloric test meals. Test meals include: placebo [PL, containing no fish oil (0 g EPA & DHA) or coconut oil (0 g MCSFA)], fish oil [FO, 6 g fish oil (3.85 g EPA & DHA), containing no coconut oil (0 g MCSFA)], coconut oil [CO, 18.65 g coconut oil (15 g MCSFA), containing no fish oil (0 g EPA & DHA)] and coconut oil + fish oil [COFO, 18.65 g coconut oil (15 g MCSFA) + 6 g fish oil (3.85 g EPA & DHA)]; all providing a total fat content of 33.5 g. Participants received all four treatments on four separate test days with at least 3 days washout in between. Blood parameters were measured by finger pricks at 7 timepoints between 0 and 300min. The primary outcome of this study was the change in postprandial triglycerides (TG) concentrations with secondary outcomes as total cholesterol, high-density lipoprotein cholesterol and blood glucose concentrations. RESULTS: TG area under the curve (AUC) (mmol/L/min) was significantly lower for FO (383.67, p = 0.0125) and COFO (299.12, p = 0.0186) in comparison to PL (409.17) only. TG incremental area under the curve (iAUC) (mmol/L/min) was significantly lower with COFO (59.67) in comparison to CO (99.86), (p = 0.0480). Compared to PL, the change in absolute TG concentrations (mmol/L) from baseline to post TG peak time (180min) after FO were significantly less at 240min (0.39 vs 0.15), 270min (0.2 vs 0.1), and 300min (0.28 vs 0.06), and after COFO was significantly less at 300min (0.28 vs 0.16) (p < 0.05). No significant differences in postprandial AUC and iAUC for any other blood parameters were reported. CONCLUSIONS: Our study demonstrated that LCn-3PUFA with or without MCSFA but not MCSFA alone are effective in reducing postprandial TG in healthy individuals.

Dietary supplementation with docosahexaenoic acid rich fish oil increases circulating levels of testosterone in overweight and obese men.

Pre-clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs), in particular, docosahexaenoic acid (DHA) have been shown to affect testosterone synthesis in males. This study is a secondary analysis of a randomized controlled trial which determined the effect of a DHA-enriched fish oil supplement on insulin resistance. The aim of the current study was to determine whether testosterone levels change in response to a DHA-enriched fish oil intervention. Overweight and obese men and women without diabetes were recruited to the study. Participants were stratified by sex and randomly allocated to intervention (860 mg DHA + 120 g EPA/day; FO) or an isocaloric control (corn oil; CO) for 12 weeks. A fasted blood sample was collected pre- and post-intervention. Fatty acid composition of erythrocyte membranes was measured using gas chromatography. Total testosterone and metabolic parameters were measured by an accredited commercial pathology laboratory. Sixty-one participants (CO/FO: n = 29/32) were included in the current analysis (male: n = 22, 36.07%).  DHA-enriched fish oil supplementation increased total testosterone levels in males after adjusting for baseline levels, age and BMI. There was no treatment effect in females. Changes in testosterone levels in males were positively associated with changes to omega-3 PUFAs EPA and DHA and inversely correlated with omega-6 PUFA, arachidonic acid and dihomo-gamma-linolenic acid content in erythrocyte membranes, and was associated with beneficial changes to fasting insulin and HOMA-IR across the course of the study. DHA-enriched fish oil supplementation increases testosterone levels in overweight and obese men. Further research is warranted to substantiate these findings with a larger sample size and a longer follow-up period.

Chlorogenic Acid Potentiates the Anti-Inflammatory Activity of Curcumin in LPS-Stimulated THP-1 Cells.

The anti-inflammatory effects of curcumin are well documented. However, the bioavailability of curcumin is a major barrier to its biological efficacy. Low-dose combination of complimentary bioactives appears to be an attractive strategy for limiting barriers to efficacy of bioactive compounds. In this study, the anti-inflammatory potential of curcumin in combination with chlorogenic acid (CGA), was investigated using human THP-1 macrophages stimulated with lipopolysaccharide (LPS). Curcumin alone suppressed TNF-α production in a dose-dependent manner with a decrease in cell viability at higher doses. Although treatment with CGA alone had no effect on TNF-α production, it however enhanced cell viability and co-administration with curcumin at a 1:1 ratio caused a synergistic reduction in TNF-α production with no impact on cell viability. Furthermore, an qRT-PCR analysis of NF-κB pathway components and inflammatory biomarkers indicated that CGA alone was not effective in reducing the mRNA expression of any of the tested inflammatory marker genes, except TLR-4. However, co-administration of CGA with curcumin, potentiated the anti-inflammatory effects of curcumin. Curcumin and CGA together reduced the mRNA expression of pro-inflammatory cytokines [TNF-α (~88%) and IL-6 (~99%)], and COX-2 (~92%), possibly by suppression of NF-κB (~78%), IκB-ß-kinase (~60%) and TLR-4 receptor (~72%) at the mRNA level. Overall, co-administration with CGA improved the inflammation-lowering effects of curcumin in THP-1 cells.

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.

Independent and Interactive Influences of Environmental UVR, Vitamin D Levels, and Folate Variant MTHFD1-rs2236225 on Homocysteine Levels.

Elevated homocysteine (Hcy) levels are a risk factor for vascular diseases. Recently, increases in ultraviolet radiation (UVR) have been linked to decreased Hcy levels. This relationship may be mediated by the status of UVR-responsive vitamins, vitamin D and folate, and/or genetic variants influencing their levels; however, this has yet to be examined. Therefore, the independent and interactive influences of environmental UVR, vitamin D and folate levels and related genetic variants on Hcy levels were examined in an elderly Australian cohort (n = 619). Red blood cell folate, 25-hydroxyvitamin D (25(OH)D), and plasma Hcy levels were determined, and genotyping for 21 folate and vitamin D-related variants was performed. Erythemal dose rate accumulated over six-weeks (6W-EDR) and four-months (4M-EDR) prior to clinics were calculated as a measure of environmental UVR. Multivariate analyses found interactions between 6W-EDR and 25(OH)D levels (pinteraction = 0.002), and 4M-EDR and MTHFD1-rs2236225 (pinteraction = 0.006) in predicting Hcy levels. The association between 6W-EDR and Hcy levels was found only in subjects within lower 25(OH)D quartiles (<33.26 ng/mL), with the association between 4M-EDR and Hcy occurring only in subjects carrying the MTHFD1-rs2236225 variant. 4M-EDR, 6W-EDR, and MTHFD1-rs2236225 were also independent predictors of Hcy. Findings highlight nutrient-environment and gene-environment interactions that could influence the risk of Hcy-related outcomes.

GlucoTRIG: a novel tool to determine the nutritional quality of foods and meals in general population.

BACKGROUND: This study aimed to develop a novel criterion, GlucoTRIG, to rank meals for healthiness, that considers both glycaemic (serum insulin) and lipaemic (serum triglycerides) responses. METHODS: Healthy volunteers (n = 10) were recruited with the aim of deriving a standard GlucoTRIG value for a reference meal. Volunteers consumed the reference meal (2 regular slices of wholemeal bread; 250 mL chocolate flavoured milk; 7 g butter and 11 g peanut butter) comprising of carbohydrate, fat and protein (41, 40 and 16% energy respectively) on three different occasions with a minimum washout period of 3 days. The GlucoTRIG value was determined as the difference between the product of insulin and triglyceride obtained from venous blood samples at baseline and the product of insulin and triglyceride at 180 min. RESULTS: There were no significant differences in the participants' dietary intakes and their metabolic parameters between three visits (P > 0.005). The GlucoTRIG value obtained from three mean values of the reference meal was found to be 19 ± 3.5. There were no significant (P = 0.2303) differences observed between the GlucoTRIG values for the three visits. CONCLUSION: GlucoTRIG, consisting of both glycaemic and lipaemic responses, may be a physiologically relevant tool to rank foods and meals for reducing the risk of metabolic diseases. TRIAL REGISTRATION: ACTRN12619000973112.

Dietary Supplementation with Curcumin Reduce Circulating Levels of Glycogen Synthase Kinase-3ß and Islet Amyloid Polypeptide in Adults with High Risk of Type 2 Diabetes and Alzheimer's Disease.

Dietary supplementation with curcumin has been previously reported to have beneficial effects in people with insulin resistance, type 2 diabetes (T2D) and Alzheimer's disease (AD). This study investigated the effects of dietary supplementation with curcumin on key peptides implicated in insulin resistance in individuals with high risk of developing T2D. Plasma samples from participants recruited for a randomised controlled trial with curcumin (180 mg/day) for 12 weeks were analysed for circulating glycogen synthase kinase-3 ß (GSK-3ß) and islet amyloid polypeptide (IAPP). Outcome measures were determined using ELISA kits. The homeostasis model for assessment of insulin resistance (HOMA-IR) was measured as parameters of glycaemic control. Curcumin supplementation significantly reduced circulating GSK-3ß (-2.4 ± 0.4 ng/mL vs. -0.3 ± 0.6, p = 0.0068) and IAPP (-2.0 ± 0.7 ng/mL vs. 0.4 ± 0.6, p = 0.0163) levels compared with the placebo group. Curcumin supplementation significantly reduced insulin resistance (-0.3 ± 0.1 vs. 0.01 ± 0.05, p = 0.0142) compared with placebo group. Dietary supplementation with curcumin reduced circulating levels of IAPP and GSK-3ß, thus suggesting a novel mechanism through which curcumin could potentially be used for alleviating insulin resistance related markers for reducing the risk of T2D and AD.

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.