Search

Background: Substantial evidence supports the relationship between peripheral insulin resistance (IR) and the development of Alzheimer's disease (AD)-dementia. However, the mechanisms explaining these associations are only partly understood. We aimed to identify a metabolic signature of IR associated with the progression from mild cognitive impairment (MCI) to AD-dementia., Methods: This is a case-control study on 400 MCI subjects, free of type 2 diabetes, within the ACE cohort, including individuals ATN + and ATN-. After a median of 2.1 years of follow-up, 142 subjects converted to AD-dementia. IR was assessed using the homeostasis model assessment for insulin resistance (HOMA-IR). A targeted multiplatform approach profiled over 600 plasma metabolites. Elastic net penalized linear regression with 10-fold cross-validation was employed to select those metabolites associated with HOMA-IR. The prediction ability of the signature was assessed using support vector machine and performance metrics. The metabolic signature was associated with AD-dementia risk using a multivariable Cox regression model. Using counterfactual-based mediation analysis, we investigated the mediation role of the metabolic signature between HOMA-IR and AD-dementia. The metabolic pathways in which the metabolites were involved were identified using MetaboAnalyst., Results: The metabolic signature comprised 18 metabolites correlated with HOMA-IR. After adjustments by confounders, the signature was associated with increased AD-dementia risk (HR = 1.234; 95% CI = 1.019-1.494; p < .05). The metabolic signature mediated 35% of the total effect of HOMA-IR on AD-dementia risk. Significant metabolic pathways were related to glycerophospholipid and tyrosine metabolism., Conclusions: We have identified a blood-based metabolic signature that reflects IR and may enhance our understanding of the biological mechanisms through which IR affects AD-dementia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Few studies have examined the associations of trimethylamine-N-oxide (TMAO) and its precursors (choline, betaine, dimethylglycine, and L-carnitine) with the risk of atrial fibrillation (AF) and heart failure (HF). This study sought to investigate these associations., Methods: Prospective associations of these metabolites with incident AF and HF were examined among participants at high cardiovascular risk in the PREDIMED study (PREvención con DIeta MEDiterránea) after follow-up for about 10 years. Two nested case-control studies were conducted, including 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma levels of TMAO and its precursors were semi-quantitatively profiled with liquid chromatography tandem mass spectrometry. Odds ratios were estimated with multivariable conditional logistic regression models., Results: After adjustment for classical risk factors and accounting for multiple testing, participants in the highest quartile vs. the lowest quartile of baseline choline and betaine levels had a higher risk of AF [OR (95% CI): 1.85 (1.30-2.63) and 1.57 (1.09-2.24), respectively]. The corresponding OR for AF for extreme quartiles of dimethylglycine was 1.39 (0.99-1.96). One SD increase in log-transformed dimethylglycine was positively associated with AF risk (OR, 1.17; 1.03-1.33). The corresponding ORs for HF for extreme quartiles of choline, betaine, and dimethylglycine were 2.51 (1.57-4.03), 1.65 (1.00-2.71) and 1.65 (1.04-2.61), respectively. TMAO and L-carnitine levels were not associated with AF or HF., Conclusions: Our findings support the role of the choline metabolic pathway in the pathogenesis of AF and HF., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Insulin resistance is a complex metabolic disorder and is often associated with type 2 diabetes (T2D)., Objectives: The aim of this study was to test whether baseline metabolites can additionally improve the prediction of insulin resistance beyond classical risk factors. Furthermore, we examined whether a multimetabolite model predicting insulin resistance in nondiabetics can also predict incident T2D., Methods: We used a case-cohort study nested within the Prevención con Dieta Mediterránea (PREDIMED) trial in subsets of 700, 500, and 256 participants without T2D at baseline and 1 and 3 y. Fasting plasma metabolites were semiquantitatively profiled with liquid chromatography-tandem mass spectrometry. We assessed associations between metabolite concentrations and the homeostasis model of insulin resistance (HOMA-IR) through the use of elastic net regression analysis. We subsequently examined associations between the baseline HOMA-IR-related multimetabolite model and T2D incidence through the use of weighted Cox proportional hazard models., Results: We identified a set of baseline metabolites associated with HOMA-IR. One-year changes in metabolites were also significantly associated with HOMA-IR. The area under the curve was significantly greater for the model containing the classical risk factors and metabolites together compared with classical risk factors alone at baseline [0.81 (95% CI: 0.79, 0.84) compared with 0.69 (95% CI: 0.66, 0.73)] and during a 1-y period [0.69 (95% CI: 0.66, 0.72) compared with 0.57 (95% CI: 0.53, 0.62)]. The variance in HOMA-IR explained by the combination of metabolites and classical risk factors was also higher in all time periods. The estimated HRs for incident T2D in the multimetabolite score (model 3) predicting high HOMA-IR (median value or higher) or HOMA-IR (continuous) at baseline were 2.00 (95% CI: 1.58, 2.55) and 2.24 (95% CI: 1.72, 2.90), respectively, after adjustment for T2D risk factors., Conclusions: The multimetabolite model identified in our study notably improved the predictive ability for HOMA-IR beyond classical risk factors and significantly predicted the risk of T2D., (© 2019 American Society for Nutrition.)

Studies examining associations between purine metabolites and type 2 diabetes (T2D) are limited. We prospectively examined associations between plasma levels of purine metabolites with T2D risk and the modifying effects of transcription factor-7-like-2 (TCF7L2) rs7903146 polymorphism on these associations. This is a case-cohort design study within the PREDIMED study, with 251 incident T2D cases and a random sample of 694 participants (641 non-cases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 years). Metabolites were semi-quantitatively profiled with LC-MS/MS. Cox regression analysis revealed that high plasma allantoin levels, including allantoin-to-uric acid ratio and high xanthine-to-hypoxanthine ratio were inversely and positively associated with T2D risk, respectively, independently of classical risk factors. Elevated plasma xanthine and inosine levels were associated with a higher T2D risk in homozygous carriers of the TCF7L2-rs7903146 T-allele. The potential mechanisms linking the aforementioned purine metabolites and T2D risk must be also further investigated.

Background & Aims: Limited prospective studies have examined the association between legumes consumption and mortality, whereas scarce, if at all, previous studies have evaluated such associations taking into consideration specific grain legumes. We aimed to investigate the association between total legumes consumption and grain legumes species (dry beans, chickpeas, lentils, and fresh peas) with all-cause, cardiovascular disease (CVD), cancer and other-cause mortality among elderly Mediterranean individuals at high CVD risk., Methods: We prospectively assessed 7216 participants from the PREvención con DIeta MEDiterránea study. Dietary intake was assessed at baseline and yearly during follow-up by using a validated food frequency questionnaire., Results: During a median follow-up of 6.0 years, 425 total deaths, 103 CVD deaths, 169 cancer deaths and 153 due to other-causes deaths occurred. Hazard ratios (HRs) [95% confidence interval (CI)] of CVD mortality were 1.52 (1.02-2.89) (P-trend = 0.034) and 2.23 (1.32-3.78) (P-trend = 0.002) for the 3rd tertile of total legumes and dry beans consumption, respectively, compared with the 1st tertile. When comparing extreme tertiles, higher total legumes and lentils consumption was associated with 49% (HR: 0.51; 95% CI: 0.31-0.84; P-trend = 0.009) and 37% (HR: 0.63; 95% CI: 0.40-0.98; P-trend = 0.049) lower risk of cancer mortality. Similar associations were observed for CVD death in males and for cancer death in males, obese and diabetic participants., Conclusions: These findings support the benefits of legumes consumption for cancer mortality prevention which may be counterbalanced by their higher risk for CVD mortality., Trial Registration: The trial is registered at http://www.controlled-trials.com (ISRCTN35739639). Registration date: 5th October 2005., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims/hypothesis: Branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with type 2 diabetes. However, repeated measurements of BCAA/AAA and their interactions with dietary interventions have not been evaluated. We investigated the associations between baseline and changes at 1 year in BCAA/AAA with type 2 diabetes in the context of a Mediterranean diet (MedDiet) trial., Methods: We included 251 participants with incident type 2 diabetes and a random sample of 694 participants (641 participants without type 2 diabetes and 53 overlapping cases) in a case-cohort study nested within the PREvención con DIeta MEDiterránea (PREDIMED) trial. Participants were randomised to a MedDiet+extra-virgin olive oil (n = 273), a MedDiet+nuts (n = 324) or a control diet (n = 295). We used LC-MS/MS to measure plasma levels of amino acids. Type 2 diabetes was a pre-specified secondary outcome of the PREDIMED trial., Results: Elevated plasma levels of individual BCAAs/AAAs were associated with higher type 2 diabetes risk after a median follow-up of 3.8 years: multivariable HR for the highest vs lowest quartile ranged from 1.32 for phenylalanine ([95% CI 0.90, 1.92], p for trend = 0.015) to 3.29 for leucine ([95% CI 2.03, 5.34], p for trend<0.001). Increases in BCAA score at 1 year were associated with higher type 2 diabetes risk in the control group with HR per SD = 1.61 (95% CI 1.02, 2.54), but not in the MedDiet groups (p for interaction <0.001). The MedDiet+extra-virgin olive oil significantly reduced BCAA levels after 1 year of intervention (p = 0.005 vs the control group)., Conclusions/interpretation: Our results support that higher baseline BCAAs and their increases at 1 year were associated with higher type 2 diabetes risk. A Mediterranean diet rich in extra-virgin olive oil significantly reduced the levels of BCAA and attenuated the positive association between plasma BCAA levels and type 2 diabetes incidence. Clinical trial number: SRCTN35739639 ( www.controlled-trials.com ).

Background: The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial., Objective: The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease., Design: This is a case-cohort design study within the Prevención con Dieta Mediterránea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) species, phosphocholine, α-glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method., Results: After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and α-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen, and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acid LPC plasmalogen concentrations had a lower T2D risk than the reference quartile., Conclusion: Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated. This trial is registered at http://www.controlled-trials.com as ISRCTN35739639.

Objective: To investigate all the important factors contributing to the development of metabolic syndrome (MetS) as well as to explore the changes of these factors, over time, by comparing adolescent populations of rural areas of Heraklion, Crete, for the years 2011 and 1989., Design: This study was carried out within two rural areas of the Heraklion region in Crete, Greece. The 1989 study was conducted in the village of Agia Varvara and the respective 2011 study within the municipality of Minoa Pediados. The study population consisted of 150 high school students (97 girls and 69 boys) in 1989 and 66 (30 girls and 36 boys) elementary (6th grade) and high school students in 2011, aged from 12 to 14 years old. Anthropometric, blood pressure and biochemical information was obtained., Results: Of the MetS risk factors studied, only obesity incidence was found higher in 2011 compared to 1989 (obese adolescents 1.3% in 1989 versus 21.2% in 2011, p<0.001). On the other hand, hypertension levels were higher in 1989 compared to 2011 (46.7% versus 6.3%, respectively, p<0.001). In addition, glucose and LDL-C levels were lower in 2011., Conclusions: The present study supports the fact that there are significant changes in metabolic risk factors through time in adolescent populations of Crete, mainly due to the rise in obesity levels as well as to the decrease in hypertension, total cholesterol and LDL- cholesterol, as observed from the comparison of the years 1989 and 2011.

Purpose: The aim of this study was to investigate the most important factors that determine lipid peroxidation in obese patients with obstructive sleep apnoea syndrome (OSAS)., Methods: Twenty-one obese patients with OSAS based on overnight attended polysomnography were included. Thiobarbituric acid reactive substances (TBARS) were measured in serum. Anthropometric measurements were carried out. Dietary habits were assessed by a standardised food frequency questionnaire., Results: Spearman's correlation analysis showed significant positive correlations between TBARS and apnoea-hypopnoea index and desaturations/hour while negative between TBARS and mean/lowest oxygen saturation. The most significant predicting factor in the multiple linear regression model was lowest oxygen saturation., Conclusions: This study has revealed an independent association between lowest oxygen saturation and TBARS levels after controlling for age, gender, diet and obesity in predominantly male patients with moderate to severe OSAS.

Objective: To identify the cardiovascular disease (CVD) risk-factor status and dietary habits of the surviving elderly participants of the initial Seven Countries Study (SCS) cohort and newly recruited middle-aged men from the same villages., Design: Our total cohort of remaining survivors of the SCS consisted of 27 men aged 90 years old and over, while a younger cross-sectional study of 85 men between 53 and 73 years of age of the same catchment area were also examined. Biochemical, anthropometric, dietetic and lifestyle CVD risk factors information was obtained., Results: It was found that being overweight and having systolic blood pressure higher than the recommended were highly prevalent (>75%) among both age groups as well as abdominal obesity (about 50%). Hypercholesterolemia was highly prevalent in the younger population (68.8%), while smoking rates were relatively low among elderly. The daily meat consumption of SCS participants had doubled, from 35g in the 1960s to 76g among the SCS survivors in 2010 (p=0.002), while daily fruit and vegetable consumption had dropped from 656g to 266g (p<0.001). The younger participants also had increased dietary meat (130g/day) (p<0.001) and decreased fruits-vegetables intake (412g/day) (p<0.001) compared to 50 years ago. However, the younger population and elderly subjects showed higher fish intake (91g/day and 38g/day respectively, p<0.001) compared to 1960 and favorable olive oil consumption. In regard to nutrient intake, the majority of the subjects did not meet the recommendations for CVD prevention., Conclusions: The study population is at increased risk for the development of CVD, while current dietary habits of the SCS survivors partially differed from those of 50 years ago.

Purpose: The aim of our study was to examine the possible effect of the Mediterranean diet on thiobarbituric acid reacting substances (TBARS) in obese patients with obstructive sleep apnoea/hypopnoea syndrome (OSAHS) who are under continuous positive airway pressure treatment., Methods: Nine hundred patients were evaluated during a 1-year period (November 2008-October 2009), and 21 obese patients who met the inclusion criteria, with moderate to severe OSAHS based on overnight attended polysomnography, were included in the study. After randomisation, 11 followed the Mediterranean diet and 10 a prudent diet for a 6-month period. TBARS were measured in serum., Results: TBARS levels decreased notably in both groups (p < 0.05), but no difference was observed between them (p > 0.05). There were significant differences in other characteristics. The Mediterranean diet group showed a greater reduction in weight (-10.8 ± 3.8), body mass index (-3.9 ± 1.6), waist circumference (-9.9 ± 3.0) and percentage of body fat (-4.7 ± 2.3) compared with the other group (-6.9 ± 3.1, -2.5 ± 1.0, -5.3 ± 2.6 and -2.2 ± 1.5, respectively; p < 0.05)., Conclusions: Our results showed that the Mediterranean diet did not reduce the TBARS more than the prudent diet.

We aimed to evaluate the effect of the Mediterranean diet (MD) compared with a prudent diet (PD) combined with physical activity on obese obstructive sleep apnoea syndrome (OSAS) patients who were treated with continuous positive airway pressure. 900 patients were evaluated and 40 obese patients (body mass index ≥ 30.0 kg · m(-2)) who met the inclusion criteria, with moderate-to-severe OSAS (apnoea-hypopnoea index (AHI) >15 events · h(-1) and Epworth Sleepiness Scale score >10) based on overnight attended polysomnography, were included in the study. After randomisation, 20 patients followed the MD and 20 a PD for a 6-month period. All patients were counselled to increase their physical activity. Concerning sleep parameters, only AHI during rapid eye movement (REM) sleep was reduced to a statistically significant degree, by mean ± SD 18.4 ± 17.6 events · h(-1) in the MD group and by 2.6 ± 23.7 events · h(-1) in the PD group (p<0.05). The MD group also showed a greater reduction in waist circumference (WC) (-8.7 ± 3.6 cm), WC/height ratio (-0.04 ± 0.02 cm · m(-1)) and WC/hip ratio (-0.04 ± 0.03 cm · cm(-1)), compared with the other group (-2.6 ± 1.7 events · h(-1), -5.7 ± 3.8 cm, -0.03 ± 0.02 cm · m(-1) and 0.02 ± 0.02 cm · cm(-1), respectively; p<0.05). Our results showed that the MD combined with physical activity for a 6-month period was effective in reducing the AHI during REM sleep without any statistically significant effect in the other sleep parameters, compared with a PD in obese adults with moderate-to-severe OSAS.

Biomarkers of Polyunsaturated Fatty Acids (PUFAs) have been related to depressive symptoms in healthy adults. It is also known that depression is high prevalent in Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) and obesity. The aim of our study was to examine a possible association between PUFAs of the n-6 and n-3 families and depressive symptoms in obese OSAHS patients. Sixty three patients with OSAHS based on overnight attended polysomnography were included. Gluteal adipose tissue biopsies were performed in all participants. Fatty acids were analyzed by gas chromatography. Depressive symptoms were assessed by the Zung Self-rating Depression Scale. The majority of participants had grade II obesity (BMI: 36.2±4.3 kg/m(2)) and moderate to severe OSAHS. Mild depressive symptoms were found to affect 27.8% of the studied patients. No link between symptoms of depression and individual n-6 and/or n-3 PUFAs of gluteal adipose tissue was detected. However, multiple linear regression analysis showed a positive correlation between depressive symptoms and 20:3n-6/18:3n-6 ratio, and a negative association with age and n-6/n-3 ratio. The possible influence of OSAHS and obesity in depression development and the quiescent nature of gluteal adipose tissue may account for the absence of any significant relations between n-6 and/or n-3 PUFAs and depressive symptoms in our sample. The positive relationship between symptoms of depression and the particular fatty acid ratio probably indicates an increase in prostaglandins family although this needs further research., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To assess the long-term effectiveness of a school-based health education intervention program 10 years after its initiation., Method: In 1992 the total population of first grade students from three counties of Crete participated in the study. Over 1000 students were randomly selected for initial and periodic evaluation. Biochemical and behavioural parameters (anthropometric, lipoproteins, blood pressure, physical activity, dietary record and health habits) were measured. Re-evaluation of the program was performed at 3, 6 and 10 years after its initiation., Results: Ten years after the initiation of the program, the results showed that BMI had increased significantly less (p<0.001) and performance in the shuttle run test was significantly better (p<0.001) in the intervention group as compared to the control group. The reduction in total cholesterol noted in both groups was significantly greater in the intervention group than in the control group (p<0.001). The incidence of smoking was also significantly lower in the intervention group (intervention group 7%, control group 13%, p<0.005)., Conclusion: This program appears to improve children's health and decrease risk factors for chronic diseases. If these positive effects are maintained in the forthcoming decades, the risk of chronic diseases may well be reduced., (Copyright © 2010 Elsevier Inc. All rights reserved.)