Association of Atherogenic Index of Plasma with Cardiometabolic Risk Factors and Markers in Lean 14-to-20-Year-Old Individuals: A Cross-Sectional Study.

Cardiometabolic risk factors at a young age pose a significant risk for developing atherosclerotic cardiovascular disease in adulthood. Atherogenic dyslipidemia is highly associated with obesity and metabolic syndrome already in young age. It remains unclear whether cardiometabolic risk factors associate with the atherogenic index of plasma (AIP = log (TAG/HDL-C) in lean subjects with low atherogenic risk. As both the AIP and markers of cardiometabolic risk are continuous variables, we expected their association to be linear before the manifestation of obesity and atherogenic dyslipidemia. We analyzed the prevalence of increased atherogenic risk (AIP ≥ 0.11) in 2012 lean 14-to-20-year-old subjects (55% females) and the trends of cardiometabolic risk factors across the quartiles (Q) of AIP in a subgroup of 1947 (56% females) subjects with low atherogenic risk (AIP < 0.11). The prevalence of AIP ≥ 0.11 reached 3.6% in females and 8.5% in males. HDL-C, non-HDL-C, triglycerides, and the continuous metabolic syndrome score showed a stepwise worsening across the AIP quartiles in both sexes. Measures of obesity and insulin resistance were worse in Q4 vs. Q1 groups, and leukocyte counts were higher in Q4 and Q3 vs. Q1. Females in Q4 presented with a higher C-reactive protein and lower adiponectin, estradiol, and testosterone levels. The multivariate regression model selected non-HDL-C, QUICKI, and erythrocyte counts as significant predictors of AIP in males; and non-HDL-C and C-reactive protein in females. A question arises whether the lean individuals on the upper edge of low atherogenic risk are prone to earlier manifestation of metabolic syndrome and shift to the higher AIP risk group.

Association of Inflammatory and Oxidative Status Markers with Metabolic Syndrome and Its Components in 40-to-45-Year-Old Females: A Cross-Sectional Study.

Oxidative stress and sterile inflammation play roles in the induction and maintenance of metabolic syndrome (MetS). This study cohort included 170 females aged 40 to 45 years who were categorized according to the presentation of MetS components (e.g., central obesity, insulin resistance, atherogenic dyslipidemia, and elevated systolic blood pressure) as controls not presenting a single component (n = 43), those with pre-MetS displaying one to two components (n = 70), and females manifesting MetS, e.g., ≥3 components (n = 53). We analyzed the trends of seventeen oxidative and nine inflammatory status markers across three clinical categories. A multivariate regression of selected oxidative status and inflammatory markers on the components of MetS was performed. Markers of oxidative damage (malondialdehyde and advanced-glycation-end-products-associated fluorescence of plasma) were similar across the groups. Healthy controls displayed lower uricemia and higher bilirubinemia than females with MetS; and lower leukocyte counts, concentrations of C-reactive protein, interleukine-6, and higher levels of carotenoids/lipids and soluble receptors for advanced glycation end-products than those with pre-MetS and MetS. In multivariate regression models, levels of C-reactive protein, uric acid, and interleukine-6 were consistently associated with MetS components, although the impacts of single markers differed. Our data suggest that a proinflammatory imbalance precedes the manifestation of MetS, while an imbalance of oxidative status accompanies overt MetS. Further studies are needed to elucidate whether determining markers beyond traditional ones could help improve the prognosis of subjects at an early stage of MetS.

Association of α-Dicarbonyls and Advanced Glycation End Products with Insulin Resistance in Non-Diabetic Young Subjects: A Case-Control Study.

α-Dicarbonyls and advanced glycation end products (AGEs) may contribute to the pathogenesis of insulin resistance by a variety of mechanisms. To investigate whether young insulin-resistant subjects present markers of increased dicarbonyl stress, we determined serum α-dicarbonyls-methylglyoxal, glyoxal, 3-deoxyglucosone; their derived free- and protein-bound, and urinary AGEs using the UPLC/MS-MS method; soluble receptors for AGEs (sRAGE), and cardiometabolic risk markers in 142 (49% females) insulin resistant (Quantitative Insulin Sensitivity Check Index (QUICKI) ≤ 0.319) and 167 (47% females) age-, and waist-to-height ratio-matched insulin-sensitive controls aged 16-to-22 years. The between-group comparison was performed using the two-factor (sex, presence/absence of insulin resistance) analysis of variance; multiple regression via the orthogonal projection to latent structures model. In comparison with their insulin-sensitive peers, young healthy insulin-resistant individuals without diabetes manifest alterations throughout the α-dicarbonyls-AGEs-sRAGE axis, dominated by higher 3-deoxyglucosone levels. Variables of α-dicarbonyls-AGEs-sRAGE axis were associated with insulin sensitivity independently from cardiometabolic risk markers, and sex-specifically. Cleaved RAGE associates with QUICKI only in males; while multiple α-dicarbonyls and AGEs independently associate with QUICKI particularly in females, who displayed a more advantageous cardiometabolic profile compared with males. Further studies are needed to elucidate whether interventions alleviating dicarbonyl stress ameliorate insulin resistance.

Lean insulin-resistant young adults display increased cardiometabolic risk: A retrospective cross-sectional study.

AIM: We investigated whether lean insulin-resistant individuals manifest increased cardiometabolic risk. METHODS: 2,341 (51.8% females) healthy 16-23-year-old subjects were categorized as lean or overweight/obese; and insulin-sensitive or insulin-resistant, and compared. RESULTS: In both sexes, lean insulin-sensitive and insulin-resistant subjects displayed similar measures of obesity (e.g., males, waist-to-height ratio: lean insulin-sensitive: 0.42 ± 0.03, lean insulin-resistant: 0.43 ± 0.03, overweight/obese insulin-sensitive: 0.49 ± 0.05, overweight/obese insulin-resistant: 0.53 ± 0.06). Lean insulin-sensitive individuals were more insulin-sensitive compared with their overweight/obese peers; insulin-resistant groups presented similar insulin-sensitivity (males, the Quantitative insulin-sensitivity check index (QUICKI): lean insulin-sensitive: 0.354 ± 0.022, lean insulin-resistant: 0.304 ± 0.013, overweight/obese insulin-sensitive: 0.343 ± 0.019, overweight/obese insulin-resistant: 0.299 ± 0.015). The two-factor analysis of variance indicated an independent effect of insulin sensitivity, overweight/obesity, and their interaction on the continuous metabolic syndrome score (p < 0.001, all; males, lean insulin-sensitive: 1.87 ± 0.35, lean insulin-resistant: 2.14 ± 0.42, overweight/obese insulin-sensitive: 2.15 ± 0.40, overweight/obese insulin-resistant: 2.75 ± 0.69). C-reactive protein, leukocyte count, and glomerular filtration rate in both sexes; uric acid, asymmetric dimethyl-arginine, and soluble vascular adhesion protein-1 in males; and soluble receptor for advanced glycation end-products in females were independently associated with insulin resistance. Among phenotypes associated with low QUICKI, the distribution of insulin-resistant individuals was random. CONCLUSION: Later clinical consequences of insulin resistance in lean subjects remain to be elucidated in longitudinal studies.

Elevated blood pressure-associated cardiometabolic risk factors and biomarkers in 16-23 years old students with or without metabolic abnormalities.

In obesity, cardiometabolic risk markers show worsening trends with increasing blood pressure (BP). We assumed that risk markers show similar trends across BP categories (normotension, high normal BP, hypertension) in metabolic abnormalities-free subjects (without obesity, insulin resistance, atherogenic dyslipidemia, hyperuricemia, microinflammation) and those presenting them. Data from 2547 (48.1% males) subjects aged 16-23 years were analyzed. The prevalence of males increased across BP categories. Forty-seven percent of individuals with elevated BP were metabolic abnormalities-free. Among 1461 metabolic abnormalities-free subjects, 9% had high normal BP, and 4% hypertension; among 1086 individuals presenting metabolic abnormalities, the prevalence reached 13% and 6%, respectively, (p < 0.001). Both groups displayed similar BP values in corresponding BP categories and significant trends in markers of adiposity, insulin resistance, HDL-cholesterol, atherogenic index of plasma, uric acid, adiponectinemia, and antioxidant capacity of plasma across BP categories. In metabolic abnormalities-free individuals, also significant trends in soluble receptors for advanced glycation end products were revealed. Continuous metabolic syndrome score, a measure of cardiometabolic risk, increased across BP categories regardless of presence or absence of metabolic abnormalities. Multivariate regression models selected male gender, fat-free mass, and uric acid as significant independent predictors for determining BP. Our data emphasize that having a BP outside the normal range significantly worsens risk for cardiometabolic disease in young individuals even if the thresholds for any of the risk factors are not exceeded. Longitudinal studies are needed to assess whether in patients with elevated BP the prognosis of adverse outcomes differs between those presenting and not presenting metabolic abnormalities.

Sex Differences in Association of Elevated Blood Pressure with Variables Characterizing Cardiometabolic Risk in Young Subjects with or Without Metabolic Abnormalities.

Males present higher blood pressure (BP) values, higher prevalence of elevated BP, and a different prevalence of cardiometabolic risk factors when compared with females. We assumed that the trends of risk markers across BP categories (normotension, high normal BP, and hypertension) differ in young males and females, and between subjects without metabolic abnormalities (without obesity, insulin resistance, atherogenic dyslipidemia, hyperuricemia, or microinflammation) and those presenting them. Data from 2543 subjects (48% males) aged from 16 to 23 years were analyzed. The findings showed that 15% of males and 4% of females presented high normal BP while 9% and 1%, respectively, had hypertension. In males, variables characterizing obesity status, insulin sensitivity, atherogenic dyslipidemia, uric acid, adiponectin, a soluble receptor for advanced glycation end-products, and leukocyte counts showed worsening trends across BP categories. Females presented significant trends only for obesity measures, LDL-cholesterol, and non-HDL-cholesterol. Across BP categories, trends of variables characterizing cardiometabolic risk differed among abnormalities-free and presenting males. The multivariate model selected measures of central obesity, atherogenic dyslipidemia, insulin resistance, and uric acid as significant predictors of BP in both genders, and C-reactive protein in females. Sex differences in measures of cardiovascular health in juveniles may remain undiscovered unless two sexes are analyzed separately. These differences may have implications for sex-specific disease risk in adulthood.

Estimation of the proportion of metabolic syndrome-free subjects on high cardiometabolic risk using two continuous cardiometabolic risk scores: a cross-sectional study in 16- to 20-year-old individuals.

In contrast to the dichotomous classification of metabolic syndrome, continuous metabolic syndrome scores enable to assess cardiometabolic burden in metabolic syndrome-free individuals. Using receiver operating characteristics analysis, discrimination power of continuous metabolic syndrome score calculated from population-based Z-scores or individual measures corrected to the accepted international standards for presence/absence of metabolic syndrome was assessed. Calculated cutoff values were used to estimate the proportions of metabolic syndrome-free subjects presenting high cardiometabolic risk. Clinical data were collected from 2331 (52% females) 16- to 20-year-old subjects. Receiver operating characteristics analyses showed an acceptable performance of both scores to classify metabolic syndrome presence: area under the curve (97-98%), sensitivity (95-100%), and specificity (86-96%). Compared with the prevalence of metabolic syndrome, proportions of metabolic syndrome-free subjects on high cardiometabolic risk, e.g., presenting continuous scores ≥ cutoff points, were about 3-fold higher in males, and 4-fold higher in females. Both scores correlated significantly with markers of cardiometabolic risk.Conclusion: Continuous cardiometabolic syndrome scores are practical tools to evaluate cardiometabolic risk in subjects not presenting metabolic syndrome. Accuracy, simplicity, and ability to classify metabolic syndrome-free subjects on high cardiometabolic risk make continuous metabolic syndrome score derived from international standards convenient for use in research and clinical practice. What is Known: • Dichotomous classification of metabolic syndrome is simple but not suitable for assessment of cardiometabolic burden in metabolic syndrome-free subjects. This prompted implementation of continuous scores, which are generally sample-specific. Score based on internationally accepted standards allows for comparison between populations and studies. • The performance of different continuous metabolic syndrome scores to assess the prevalence of metabolic syndrome-free subjects presenting high cardiometabolic burden has not been compared yet. What is New: • We compared the discrimination power of sample-specific Z-score-derived continuous metabolic syndrome score and that calculated based on internationally accepted standards for presence or absence of metabolic syndrome in young subjects. • The prevalence of metabolic syndrome-free subjects presenting high cardiometabolic risk was estimated using the cutoff points of continuous metabolic syndrome scores derived from the analyses of receiver operating characteristic curves.

Maternal Consumption of a Diet Rich in Maillard Reaction Products Accelerates Neurodevelopment in F1 and Sex-Dependently Affects Behavioral Phenotype in F2 Rat Offspring.

Thermal processing of foods at temperatures > 100 °C introduces considerable amounts of advanced glycation end-products (AGEs) into the diet. Maternal dietary exposure might affect the offspring early development and behavioral phenotype in later life. In a rat model, we examined the influence of maternal (F0) dietary challenge with AGEs-rich diet (AGE-RD) during puberty, pregnancy and lactation on early development, a manifestation of physiological reflexes, and behavioral phenotype of F1 and F2 offspring. Mean postnatal day of auditory conduit and eye opening, or incisor eruption was not affected by F0 diet significantly. F1 AGE-RD offspring outperformed their control counterparts in hind limb placing, in grasp tests and surface righting; grandsons of AGE-RD dams outperformed their control counterparts in hind limb placing and granddaughters in surface righting. In a Morris water maze, female AGE-RD F1 and F2 offspring presented better working memory compared with a control group of female offspring. Furthermore, male F2 AGE-RD offspring manifested anxiolysis-like behavior in a light dark test. Mean grooming time in response to sucrose splash did not differ between dietary groups. Our findings indicate that long-term maternal intake of AGE-RD intergenerationally and sex-specifically affects development and behavioral traits of offspring which have never come into direct contact with AGE-RD.

Gender-associated differences in the prevalence of central obesity using waist circumference and waist-to-height ratio, and that of general obesity, in Slovak adults.

OBJECTIVES: Central obesity represents an increased risk to develop cardiovascular diseases. Guidelines of international societies suggest estimating central obesity by measuring waist circumference (WC). Robust statistical data in literature provide evidence on the superiority of waist-to-height ratio (WHtR) over WC and body mass index (BMI) for detecting cardiometabolic risk in both genders. Based on measurements of weight, height and waist circumference we compared the prevalence of central obesity using both the above mentioned criteria in the apparently healthy Slovak adults, and compared the prevalence of central obesity to that of general obesity (BMI). METHODS: Data collected from 5,184 individuals (45% males) aged ≥18 years in four cross-sectional studies carried out between the years 2009-2012 were subjected to secondary analysis. RESULTS: Waist circumference underestimated central obesity in males and overestimated in females: 37.3% of males and 41.8% of females presented central obesity according to WC, 54.2% males and 34.9% females according to WHtR. 17.3% of males centrally obese according to WC present WHtR < 0.5; while 7.8% of females centrally obese according to their WHtR do not display increased WC. The frequency of central obesity increased with age. According to BMI, the prevalence of overweight was 39% in males and 22% in females; that of obesity was 17% and 15%, respectively. CONCLUSION: The prevalence of central obesity estimated using WC vs. WHtR differs significantly in Slovak adults. WHtR is considered superior for detection of the risk of future development of cardiovascular afflictions. Thus, further studies addressing the gender-associated discordance of central obesity measures are required to determine whether our results are consistent across geographical regions and ethnic groups.

The effects of a maternal advanced glycation end product-rich diet on somatic features, reflex ontogeny and metabolic parameters of offspring mice.

Maternal exposure to a Western type diet during pregnancy might predispose the offspring to manifestation of metabolic and behavioral disturbances in later life. The Western type diet contains large amounts of advanced glycation end products (AGEs). In humans and experimental rodents, the intake of an AGE-rich diet (AGE-RD) negatively affected glucose homeostasis, and initiated the production of reactive oxygen species. Rats consuming the AGE-RD presented changes in behavior. It remains unclear whether maternal intake of the AGE-RD might affect developmental plasticity in offspring. We examined early somatic (weight, incisor eruption, ear unfolding, and eye opening) and neuromotor development, oxidative status, insulin sensitivity (HOMA index) and locomotor activity assessed in PhenoTyper cages in the offspring of mice fed during pregnancy with either the AGE-RD (25% bread crusts/75% control chow) or control chow. Until weaning, the somatic development of offspring did not differ between the two dietary groups. The AGE-RD offspring manifested physiological reflexes (auditory startle, eye lid, ear twitch and righting reflexes) earlier. As young adults, the male offspring of the AGE-RD dams were heavier and less insulin sensitive compared with their control counterparts. The AGE-RD offspring showed higher locomotor activity during the active phase. Our data indicate that the maternal AGE-RD during pregnancy might accelerate the maturation of reflexes in offspring, predispose the male progeny to weight gain and affect their glucose homeostasis. These effects manifest without the direct consumption of the AGE-RD by offspring. Further work is needed to determine the mechanisms by which the maternal AGE-RD affects neurobehavioral pathways in offspring, as well as sex differences in adverse metabolic responses.

Gender Differences in Cardiometabolic Risk Factors in Metabolically Healthy Normal Weight Adults with Central Obesity.

We investigated whether metabolically healthy normal weight adults with central obesity display worse cardiometabolic profile compared with their centrally lean counterparts. This retrospective, cross-sectional study, comprised 1 135 subjects (64% females) aged 18-to-81 years, presenting ≤2 components of metabolic syndrome. They were classified as centrally lean (waist-to-height ratio (WHtR)<0.5 and waist circumference<80 cm in females and<94 cm in males) or presenting central obesity (WHtR ≥0.5, regardless of waist circumference). Data on blood pressure, glucose homeostasis, lipid profile, renal function, high-sensitive C-reactive protein (hsCRP), uric acid, adiponectin, leptin, and soluble receptor for advanced glycation end products were compared between the groups, separately in males and females. 5.7% of males and 6.9% of females presented WHtR ≥0.5. Compared with centrally lean subjects, those with central obesity had higher BMI-adjusted fasting plasma glucose (p<0.001), and leptin levels (p<0.05); females also presented higher blood pressure (p<0.001), while males had higher hsCRP concentrations (p=0.021). These changes associated with significantly higher BMI-adjusted odds to present fasting plasma glucose >5.6 mmol/l in both genders, higher odds to present hsCRP >3 mg/l in males, and those to present elevated blood pressure in females. Our analysis suggests that in metabolically healthy normal weight subjects WHtR ≥0.5 might indicate "early increased health risk".

Sex differences and sex hormones in anxiety-like behavior of aging rats.

Sex differences in the prevalence of affective disorders might be attributable to different sex hormone milieu. The effects of short-term sex hormone deficiency on behavior, especially on anxiety have been studied in numerous animal experiments, mainly on young adult rats and mice. However, sex differences in aged animals and the effects of long-term hypogonadism are understudied. The aim of our study was to analyze sex differences in anxiety-like behavior in aged rats and to prove whether they can be attributed to endogenous sex hormone production in males. A battery of tests was performed to assess anxiety-like behavior in aged female, male and gonadectomized male rats castrated before puberty. In addition, the aged gonadectomized male rats were treated with a single injection of estradiol or testosterone or supplemented with estradiol for two-weeks. Female rats displayed a less anxious behavior than male rats in most of the conducted behavioral tests except the light-dark box. Long-term androgen deficiency decreased the sex difference in anxiety either partially (open field, PhenoTyper cage) or completely (elevated plus maze). Neither single injection of sex hormones, nor two-week supplementation of estradiol in gonadectomized aged male rats significantly affected their anxiety-like behavior in the elevated plus maze. In conclusion, our results confirm sex differences in anxiety in aged rats likely mediated by endogenous testosterone production in males. Whether long-term supplementation with exogenous sex hormones could affect anxiety-like behavior in elderly individuals remains to be elucidated.

Association between metabolically healthy central obesity in women and levels of soluble receptor for advanced glycation end products, soluble vascular adhesion protein-1, and the activity of semicarbazide-sensitive amine oxidase.

AIM: To determine the levels of circulating soluble receptor for advanced glycation end products (sRAGE), as a biomarker of risk of metabolic syndrome and cardiovascular disease development in centrally obese (CO) women considered metabolically healthy (COH) in comparison with those metabolically unhealthy (COU). METHODS: 47 lean healthy, 17 COH (presenting waist-to-height ratio ≥0.5 but not elevated blood pressure, atherogenic lipid profile, and insulin resistance), and 50 COU (CO presenting ≥2 risk factors) women aged 40-45 years were included. Anthropometric characteristics, blood chemistry and hematology data, adipokines, markers of inflammation, sRAGE, soluble vascular adhesion protein-1 (sVAP-1), and the activity of semicarbazide sensitive amine oxidase (SSAO) were determined. RESULTS: Central obesity associated with low sRAGE levels (lean healthy: 1503±633 pg/mL; COH: 1103±339 pg/mL, P<0.05; COU: 1106±367 ng/mL, P<0.0.1), hyperleptinemia, and elevated markers of inflammation irrespective of the presence or absence of cardiometabolic risk factors. COU women presented high adiponectin levels. SVAP-1 concentrations and the activity of SSAO were similar in all 3 groups. CONCLUSION: COH women present abnormalities in non-standard markers of cardiometabolic risk (sRAGE, leptin, high sensitive C-reactive protein), supporting the view that there is no healthy pattern of obesity. The clinical impact of our findings for future prognosis of metabolically healthy obese subjects remains to be elucidated in longitudinal studies.

Sex-dependent effects of letrozole on anxiety in middle-aged rats.

Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men.

Correlation among soluble receptors for advanced glycation end-products, soluble vascular adhesion protein-1/semicarbazide-sensitive amine oxidase (sVAP-1) and cardiometabolic risk markers in apparently healthy adolescents: a cross-sectional study.

In non-diabetics, low levels of soluble receptor for advanced glycations end products (sRAGE) associate with an increased risk of development of diabetes, cardiovascular afflictions, or death. The majority of studies in non-diabetics report an inverse relationship between measures of obesity, cardiometabolic risk factors and sRAGE and/or endogenous secretory RAGE (esRAGE) levels. To elucidate whether this inconsistency is related to the metabolically healthy obese phenotype, or a different impact of the risk factors in presence and absence of obesity, we analyzed data from 2206 apparently healthy adolescents (51 % girls) aged 15-to-19 years. The association of sRAGE levels with soluble vascular adhesion protein-1/semicarbazide sensitive amine oxidase (sVAP-1/SSAO) was also investigated. Centrally obese, including metabolically healthy, adolescents present significantly lower sRAGE and esRAGE, but not sVAP-1, levels in comparison with their lean counterparts. An increasing number of cardiometabolic risk factors did not associate with significant changes in sRAGE, esRAGE or sVAP-1 levels either in lean or in obese subjects. In multivariate analyses, WHtR, hsCRP, markers of glucose homeostasis, renal function, adiponectin, and sVAP-1 associated significantly with sRAGE and esRAGE. SVAP-1 correlated significantly with glycemia, adiponectin, hsCRP, and sRAGE. Thus, in adolescents, a decline in sRAGE and esRAGE precedes the development of metabolic syndrome. When combined, standard and non-standard cardiometabolic risk factors explain only minor proportion in a variability of sRAGE and esRAGE (8 %-11 %); or sVAP-1 (12 %-20 %). Elucidation of pathogenetic mechanisms underlying early decline in sRAGE and esRAGE levels in obese adolescents and their clinical impact with regard to future cardiometabolic health requires further studies.