Circadian Gene Variants: Effects in Overweight and Obese Pregnant Women.

Obesity and overweight are common and complex conditions influenced by multiple genetic and environmental factors. Several genetic variants located in the genes involved in clock systems and fat taste perception can affect metabolic health. In particular, the polymorphisms in CLOCK and BMAL1 genes were reported to be significantly related to cardiovascular disease, metabolic syndrome, sleep reduction, and evening preference. Moreover, genetic variants in the CD36 gene have been shown to be involved in lipid metabolism, regulation of fat intake, and body weight regulation. The aim of this study is to evaluate, for the first time, the association between variants in some candidate genes (namely, BMAL1 rs7950226 (G>A), CLOCK rs1801260 (A>G), CLOCK rs4864548 (G>A), CLOCK rs3736544 (G>A), CD36 rs1984112 (A>G), CD36 rs1761667 (G>A)) and overweight/obesity (OB) in pregnant women. A total of 163 normal-weight (NW) and 128 OB participants were included. A significant correlation was observed between A-allele in CLOCK rs4864548 and an increased risk of obesity (OR: 1.97; 95% CI 1.22-3.10, p = 0.005). In addition, we found that subjects carrying the haplotype of rs1801260-A, rs4864548-A, and rs3736544-G are likely to be overweight or obese (OR 1.47, 95% CI 1.03-2.09, p = 0.030), compared with those with other haplotypes. Moreover, a significant relation was observed between third-trimester lipid parameters and genetic variants-namely, CD36 rs1984112, CD36 rs1761667, BMAL1 rs7950226, and CLOCK rs1801260. A multivariate logistic regression model revealed that CLOCK rs4864548 A-allele carriage was a strong risk factor for obesity (OR 2.05, 95% CI 1.07-3.93, p = 0.029); on the other hand, greater adherence to Mediterranean diet (OR 0.80, 95% CI 0.65-0.98, p = 0.038) and higher HDL levels (OR 0.96, 95% CI 0.94-0.99, p = 0.021) were related to a reduced risk of obesity. Interestingly, an association between maternal CLOCK rs4864548 and neonatal birthweight was detected (p = 0.025). These data suggest a potential role of the polymorphisms in clock systems and in fat taste perception in both susceptibility to overweight/obesity and influencing the related metabolic traits in pregnant women.

Genetic Variants in CD36 Involved in Fat Taste Perception: Association with Anthropometric and Clinical Parameters in Overweight and Obese Subjects Affected by Type 2 Diabetes or Dysglycemia-A Pilot Study.

Obesity and overweight represent a growing health problem worldwide. Genes regulating the intake and metabolism of different nutrients can positively or negatively influence the efficacy of nutritional interventions against obesity and its complications. The aim of this study was to assess changes in anthropometric and clinical parameters and the adherence to a Mediterranean diet (MedDiet) over time in relation to nutrigenetic variants in overweight or obese subjects affected by Type 2 Diabetes (T2D) or dysglycemia, who were included in a nutritional program. A total of 23 subjects were included in this study. Clinical parameters, physical activity levels, and the adherence to a MedDiet were evaluated at baseline, at 6 (T6), and at 12 months (T12) during and after a diet/lifestyle intervention. In a single blood sample from each subject, rs1984112 (A>G) and rs1761667 (G>A) in CD36; rs7950226 (G>A) in BMAL1; and rs1801260 (A>G), rs4864548 (A>G), and rs3736544 (G>A) in CLOCK were genotyped with Real-Time PCR. Significant associations were observed between CD36 rs1761667 and weight (p = 0.025), hip circumference (p = 0.042), triglycerides (p = 0.047), and HbA1c (p = 0.012) at baseline. Moreover, the genotype AA in CD36 rs1761667 was significantly associated with a lower BMI when compared to G carriers at baseline, at T6, and also at T12. In addition, subjects with the AA genotype at CD36 rs1984112 had significantly lower levels of HbA1c (p = 0.027) than the GG and AG genotypes at baseline. These results show that variants in CD36 can have an impact on anthropometric and clinical parameters in overweight or obese subjects affected by T2D or dysglycemia, and that it might influence the success of the diet/lifestyle intervention.

Reference intervals for glycated albumin during physiological pregnancy of Europid women: Evidences from a prospective observational study.

BACKGROUND AND AIMS: Glycated albumin (GA) may assess glycometabolic control over a short period of time respect to HbA1c, and its use to screen for gestational diabetes in pregnancy has been suggested. To this regard few data on reference intervals (RI) for GA on Europid women have been collected, only from cross-sectional investigations. Aim of this work has been to collect trimester-specific RI for GA in physiological pregnancies, following a longitudinal prospective study. METHODS: Forty-five healthy pregnant Europid women have been enrolled for whom a GDM screening test was scheduled at 24-28 weeks, in 5 different Italian centers. Only those negative to the OGTT were included. The women had 4 successive visits at 6-10 weeks of gestation, at 16-18 weeks, at 24-28 weeks and at the end of pregnancy. ALT, AST, total bilirubin, C-reactive protein, cholinesterase, creatinine, GGT, glycated albumin, iron, total serum proteins, transferrin were measured in duplicate on aliquots of serum samples by a central laboratory. RESULTS: The RI (2.5-97.5 percentiles) for GA were 11.1-14.8 % (I visit), 10.9-15.6 % (II visit), 10.6-14.1 % (III visit) and 10.7-14.3 % (IV visit). The RI of other biomarkers confirmed previously published data. The RI for serum cholinesterase we present are novel, and were 5049-9906 U/L (Iv), 4212-8965 U/L (IIv), 3518-8470 U/L (IIIv) and 3945-8727 U/L (IVv). CONCLUSIONS: Trimester-specific RI are important for using GA and serum cholinesterase in pregnancy. However, considering the high inter-individual variability of both markers, the use of longitudinal interpretations of the individual variations of both proteins during pregnancy should be preferred.

Chrono-Nutrition: Circadian Rhythm and Personalized Nutrition.

The human circadian system has a period of approximately 24 h and studies on the consequences of "chornodisruption" have greatly expanded. Lifestyle and environmental factors of modern societies (i.e., artificial lighting, jetlag, shift work, and around-the-clock access to energy-dense food) can induce disruptions of the circadian system and thereby adversely affect individual health. Growing evidence demonstrates a complex reciprocal relationship between metabolism and the circadian system, in which perturbations in one system affect the other one. From a nutritional genomics perspective, genetic variants in clock genes can both influence metabolic health and modify the individual response to diet. Moreover, an interplay between the circadian rhythm, gut microbiome, and epigenome has been demonstrated, with the diet in turn able to modulate this complex link suggesting a remarkable plasticity of the underlying mechanisms. In this view, the study of the impact of the timing of eating by matching elements from nutritional research with chrono-biology, that is, chrono-nutrition, could have significant implications for personalized nutrition in terms of reducing the prevalence and burden of chronic diseases. This review provides an overview of the current evidence on the interactions between the circadian system and nutrition, highlighting how this link could in turn influence the epigenome and microbiome. In addition, possible nutritional strategies to manage circadian-aligned feeding are suggested.

SLC6A4 DNA Methylation Levels and Serum Kynurenine/Tryptophan Ratio in Eating Disorders: A Possible Link with Psychopathological Traits?

Background: The incidence of eating disorders (EDs), serious mental and physical conditions characterized by a disturbance in eating or eating-related behaviors, has increased steadily. The present study aims to develop insights into the pathophysiology of EDs, spanning over biochemical, epigenetic, psychopathological, and clinical data. In particular, we focused our attention on the relationship between (i) DNA methylation profiles at promoter-associated CpG sites of the SCL6A4 gene, (ii) serum kynurenine/tryptophan levels and ratio (Kyn/Trp), and (iii) psychopathological traits in a cohort of ED patients. Among these, 45 patients were affected by restricting anorexia nervosa (AN0), 21 by purging AN (AN1), 21 by bulimia (BN), 31 by binge eating disorders (BED), 23 by unspecified feeding or eating disorders (UFED), and finally 14 by other specified eating disorders (OSFED) were compared to 34 healthy controls (CTRs). Results: Kyn level was higher in BED, UFED, and OSFED compared to CTRs (p ≤ 0.001). On the other hand, AN0, AN1, and BN patients showed significatively lower Kyn levels compared to the other three ED groups but were closed to CTRs. Trp was significantly higher in AN0, AN1, and BN in comparison to other ED groups. Moreover, AN1 and BN showed more relevant Trp levels than CTRs (p <0.001). BED patients showed a lower Trp as compared with CTRs (p ≤ 0.001). In addition, Kyn/Trp ratio was lower in the AN1 subtype but higher in BED, UFED, and OSFED patients than in CTRs (p ≤ 0.001). SCL6A4 DNA methylation level at CpG5 was lower in AN0 compared to BED (p = 0.021), and the CpG6 methylation was also significantly lower in AN0 in comparison to CTRs (p = 0.025). The mean methylation levels of the six CpGs analyzed were lower only in the AN0 subgroup compared to CTRs (p = 0.008). Relevant psychological trait EDI-3 subscales were correlated with biochemical and epigenetic data. Conclusions: These findings underline the complexity of psychological and pathophysiological components of EDs.

A nutritional web-based approach in obesity and diabetes before and during the COVID-19 lockdown.

INTRODUCTION: Obesity and type 2 diabetes (T2D) are two closely related pandemic conditions. Novel technologies represent promising tools for their management, the use of which has been greatly encouraged during the COVID-19 pandemic. The aim of the present study is to compare a web-based nutritional intervention versus a traditional one, before and during the Italian 'lockdown' period due to the COVID-19 outbreak, in overweight and obese subjects affected by T2D or impaired glucose regulation (IGR). METHODS: For the study, 36 subjects were randomly allocated into two arms: a traditional arm, providing face-to-face individual and group-based intervention; and a web arm, deploying the in-presence traditional approach with intervention provided through web technologies. The outcomes were the data resulting from the comparison between the subjects' anthropometric and clinical parameters as well as PREDIMED scores at baseline with those at 3 months (T3), 6 months (T6) and at lockdown. RESULTS: In the web arm we detected a progressive reduction in weight and body mass index (BMI) from baseline to T6 and a minimal increase of both parameters during the lockdown. Improvement of these parameters compared with baseline was observed in controls during the lockdown. The PREDIMED score improved at T6 compared with baseline in both arms. Significant variations were observed considering weight (p < 0.001), BMI (p = 0.001) and PREDIMED scores (p = 0.023) over time. DISCUSSION: The study showed the effectiveness and feasibility of a short-term nutritional web-based intervention in patients affected by T2D or IGR before and during the COVID 19 pandemic.Clinical Trial registration number: NCT04386200, ClinicalTrials.gov.

The epigenetic aging, obesity, and lifestyle.

The prevalence of obesity has dramatically increased worldwide over the past decades. Aging-related chronic conditions, such as type 2 diabetes and cardiovascular disease, are more prevalent in individuals with obesity, thus reducing their lifespan. Epigenetic clocks, the new metrics of biological age based on DNA methylation patterns, could be considered a reflection of the state of one's health. Several environmental exposures and lifestyle factors can induce epigenetic aging accelerations, including obesity, thus leading to an increased risk of age-related diseases. The insight into the complex link between obesity and aging might have significant implications for the promotion of health and the mitigation of future disease risk. The present narrative review takes into account the interaction between epigenetic aging and obesity, suggesting that epigenome may be an intriguing target for age-related physiological changes and that its modification could influence aging and prolong a healthy lifespan. Therefore, we have focused on DNA methylation age as a clinical biomarker, as well as on the potential reversal of epigenetic age using a personalized diet- and lifestyle-based intervention.

The Obesogenic Environment: Epigenetic Modifications in Placental Melanocortin 4 Receptor Gene Connected to Gestational Diabetes and Smoking.

Background: Maternal metabolic insults as well as Gestational Diabetes Mellitus (GDM) influence the fetal health and may affect 'offspring's susceptibility to chronic diseases via epigenetic modifications. GDM, the most common metabolic disorder in pregnancy, can be considered the result of complex interactions between genetic and environmental factors. A critical point in this view is the identification of genes which are epigenetically modified under the influence of GDM. The melanocortin 4 receptor (MC4R) gene plays a crucial role in nutritional health by suppressing appetite and participating in energy control regulation. The correlations between pregnant 'women's metabolic profiles and placental epigenetic modifications of this gene have been poorly investigated. Objective: The aim of this study was to evaluate the effect of GDM and maternal clinical parameters at the third trimester of pregnancy to DNA methylation levels in the placenta at CpG sites of MC4R gene. Design and Methods: Socio-demographic and clinical characteristics, Mediterranean diet adherence, smoking habits, and physical activity were assessed at the third trimester of pregnancy of 60 Caucasian pregnant women, of which 33 with GDM. Clinical parameters of the newborns were recorded at birth. MC4R DNA methylation on maternal and fetal sides of the placenta was analyzed using bisulfite pyrosequencing. Results: MC4R DNA methylation levels at CpG1 and CpG2 were lower on the fetal side of the placenta in GDM-affected women than in non-GDM-affected recruits (p = 0.033). Moreover, DNA methylation levels on the maternal side at CpG1 were positively related to glucose concentration at 2-h oral glucose tolerance test (OGTT). On the other hand, CpG2 DNA methylation was positively related to both 1-h and 2-h during OGTT. Maternal DNA methylation level at CpG2 was also associated with low density lipoprotein cholesterol (LDL-C) at the third trimester of pregnancy (rho = 0.340, p < 0.05), while CpG1 methylation was negatively related to maternal weight variations at delivery (rho = -0.316, p < 0.05). Significant associations between MC4R DNA methylation on the maternal side and lipid profile at third trimester of pregnancy in women smokers were found. Conclusion: Our results suggest that MC4R methylation profile in the placenta is related to maternal metabolic and nutritional conditions, potentially affecting fetal programming and the future metabolic health of the newborn.

Inositols, Probiotics, and Gestational Diabetes: Clinical and Epigenetic Aspects.

There is growing interest in the potential role of different stereoisomers of inositol or their combination as well as probiotics supplementation in healthy glucose metabolism during pregnancy and in promoting offspring health. The aim of this review is to clarify the effects of several inositol and probiotics-based supplements in the prevention and treatment of gestational diabetes (GDM). Moreover, we will discuss the epigenetic aspects and their short- and long-term effects in response to probiotic intervention as well as the possible implications of these findings in guiding appropriate supplementation regimens in pregnancy.

S100B Maternal Blood Levels in Gestational Diabetes Mellitus Are Birthweight, Gender and Delivery Mode Dependent.

Gestational Diabetes Mellitus (GDM) is one of the main causes of perinatal mortality/morbidity. Today, a parameter offering useful information on fetal central nervous system (CNS) development/damage is eagerly awaited. We investigated the role of brain-protein S100B in the maternal blood of GDM pregnancies by means of a prospective case-control study in 646 pregnancies (GDM: n = 106; controls: n = 530). Maternal blood samples for S100B measurement were collected at four monitoring time-points from 24 weeks of gestation to term. Data was corrected for gender and delivery mode and correlated with gestational age and weight at birth. Results showed higher (p < 0.05) S100B from 24 to 32 weeks and at term in GDM fetuses than controls. Higher (p < 0.05) S100B was observed in GDM male new-borns than in females from 24 to 32 weeks and at term, in GDM cases delivering vaginally than by caesarean section. Finally, S100B positively correlated with gestational age and weight at birth (R = 0.27; R = 0.37, respectively; p < 0.01). The present findings show the usefulness of S100B in CNS to monitor high-risk pregnancies during perinatal standard-of-care procedures. The results suggest that further investigations into its potential role as an early marker of CNS growth/damage in GDM population are needed.

Nutrigenetic variants and response to diet/lifestyle intervention in obese subjects: a pilot study.

AIMS: Nutritional and lifestyle interventions can contribute to prevent and treat obesity and its complications; however, genetic background may influence the success of a therapy. The aim of this pilot study is to evaluate the effects of the interaction between nutrigenetic variants and nutritional intervention, as well as the changes in clinical parameters and the adherence to Mediterranean diet (MedDiet) and to physical activity, of 18 overweight or obese subjects affected by T2D or dysglycemia included in a nutritional program. METHODS: The subjects' clinical parameters as well as their PREDIMED score and physical activity levels were recorded and compared at baseline, at 6 months and at the end of the intervention. Rs9939609 in FTO, rs17782313 near MC4R, rs326 in LPL, rs16147 in NPY, rs2943641 near IRS-1 were genotyped. RESULTS: The subjects carrying the A allele in FTO lost less weight (p = 0.022) and had a lower BMI decrease from baseline to 12 months (p-interaction = 0.047) than TT carriers. In addition, there was a significant PREDIMED score modification over time, according to genotypes for FTO rs9939609 (p = 0.025) and NPY rs16147 (p = 0.039), respectively. CONCLUSIONS: These preliminary findings show a significant interaction between genetic variants and the PREDIMED score, suggesting that individuals carrying the FTO variant may lose less weight than non-carriers through diet/lifestyle intervention.

Hyperglycemia at 1h-OGTT in Pregnancy: A Reliable Predictor of Metabolic Outcomes?

Gestational diabetes mellitus (GDM) is associated with a high risk of developing type 2 diabetes (T2DM) and cardiovascular disease (CVD). Identifying among GDM women those who are at high risk may help prevent T2DM and, possibly CVD. Several studies have shown that in women with GDM, hyperglycemia at 1 h during an oral glucose tolerance test (OGTT) (1-h PG) is not only associated with an increase in adverse maternal and perinatal outcomes but is also an independent predictor of T2DM. Interestingly, also in pregnant women who did not meet the criteria for a GDM diagnosis, 1-h PG was an independent predictor of postpartum impaired insulin sensitivity and beta-cell dysfunction. Moreover, maternal 1- and 2-h PG levels have been found to be independently associated with insulin resistance and impaired insulin secretion also during childhood. There is evidence that hyperglycemia at 1h PG during pregnancy may identify women at high risk of future CVD, due to its association with an unfavorable CV risk profile, inflammation, arterial stiffness and endothelial dysfunction. Overall, hyperglycemia at 1h during an OGTT in pregnancy may be a valuable prediction tool for identifying women at a high risk of future T2DM, who may then benefit from therapeutic strategies aimed at preventing cardiovascular outcomes.

Efficacy of flash glucose monitoring in pregnant women with poorly controlled pregestational diabetes (FlashMom): A randomized pilot study.

BACKGROUND AND AIMS: Good glycemic control is crucial to reduce the risk of adverse pregnancy outcomes. Our aim was to evaluate the efficacy of Flash Glucose Monitoring (FGM) on glucose control in women with pregestational diabetes. METHODS AND RESULTS: Forty women with inadequately controlled type 1 (T1D, n = 34) and type 2 (T2D, n = 6) diabetes at conception were randomly assigned to two arms: the Flash Glucose group (FG, n = 21) using FGM, and the control group (CG, n = 19) using self-monitoring of blood glucose (SMBG). Glycated hemoglobin (HbA1c, %), time in (TIR), below (TBR) and above (TAR) range, glucose variability as well as the occurrence of maternal and neonatal adverse outcomes, were evaluated. HbA1c decreased significantly (p < 0.01) and similarly (-0.65 ± 0.7 vs. -0.67 ± 0.8 for FG and CG, respectively; p = 0.89) in both groups during pregnancy. HbA1c reduction was positively associated with the number of daily FGM scans (p < 0.01). TBR (12.1 ± 2.0% vs. 19.6 ± 3.9%, p = 0.04) and the mean of the daily serum glucose difference (MODD) index (59.1 ± 5.4 vs. 77.7 ± 4.6, p = 0.02) were significantly lower in FG at second trimester. The rates of perinatal adverse outcomes were not different in the two studied groups. CONCLUSIONS: In women with pregestational diabetes, FGM and SMBG had similar efficacy on glucose control during pregnancy. FGM showed additional advantages in terms of TBR and glucose variability. Achievement of good metabolic results depended on the adequate use of glucose sensor. REGISTRATION: At ClinicalTrials.gov as NCT04666818 on December 14, 2020.

Screening of postpartum diabetes in women with gestational diabetes: high-risk subgroups and areas for improvements-the STRONG observational study.

AIMS: To assess the proportion of women with gestational diabetes (GDM) by performing postpartum Oral Glucose Tolerance Test (OGTT) and to identify GDM phenotypes at high-risk of postpartum dysglycemia (PPD). METHODS: Observational, retrospective, multicenter study involving consecutive GDM women. Recursive partitioning (RECPAM) analysis was used to identify distinct and homogeneous subgroups of women at different PPD risk. RESULTS: From a sample of 2,736 women, OGTT was performed in 941 (34.4%) women, of whom 217 (23.0%) developed PPD. Insulin-treated women having family history of diabetes represented the subgroup with the highest PPD risk (OR 5.57, 95% CI 3.60-8.63) compared to the reference class (women on diet with pre-pregnancy BMI < = 28.1 kg/m2). Insulin-treated women without family diabetes history and women on diet with pre-pregnancy BMI > 28.1 kg/m2 showed a two-fold PPD risk. Previous GDM and socioeconomic status represent additional predictors. Fasting more than post-prandial glycemia plays a predictive role, with values of 81-87 mg/dl (4.5-4.8 mmol/l) (lower than the current diagnostic GDM threshold) being associated with PPD risk. CONCLUSIONS: Increasing compliance to postpartum OGTT to prevent/delay PPD is a priority. Easily available characteristics identify subgroups of women more likely to benefit from preventive strategies. Fasting BG values during pregnancy lower than those usually considered deserve attention.

Sperm DNA Methylation at Metabolism-Related Genes in Vegan Subjects.

Objective: To investigate if epigenome of sperm cells could be dynamically affected by nutrition. Design and Methods: We assessed 40 healthy volunteers with different dietary habits and collected their demographic characteristics, as well as clinical and anthropometric parameters. We compared methylation profiles in sperm quantified by bisulfite pyrosequencing, at promoter-associated CpG sites of genes involved in metabolism including fat mass and obesity-associated (FTO) and melanocortin-4 receptor (MC4R) from six vegans and 34 omnivores. In addition, the FTO rs9939609 (T>A) was genotyped. Results: Higher DNA methylation levels were detected in the sperm of vegan at FTO gene CpG1 (p=0.02), CpG2 (p=0.001), CpG3 (p=0.004), and CpG4 (p=0.003) sites and at MC4R-CpG2 site [p=0.016] as compared to sperm of omnivores. This association was not related to FTO genotype. Conclusions: Although limited by the small number of investigated cases, our data provide insight into the role of diet on sperm DNA methylation in genes involved in metabolism.

Fat mass and obesity-associated (FTO) gene epigenetic modifications in gestational diabetes: new insights and possible pathophysiological connections.

AIMS: Gestational diabetes mellitus (GDM) can lead to short- and long-term complications for the child. Epigenetic alterations could contribute to explaining the metabolic disturbances associated with foetal programming. Although the role of the FTO gene remains unclear, it affects metabolic phenotypes probably mediated by epigenetic mechanisms. The aim of this study was to assess whether placental DNA epigenetic modifications at FTO promoter-associated cysteine-phosphate-guanine (CpG) sites are correlated with GDM. A secondary aim was to evaluate the association between the placental FTO DNA methylation and the maternal metabolic traits in women with and without GDM. METHODS: Socio-demographic characteristics, clinical parameters at the third trimester of pregnancy, Mediterranean diet adherence, and physical activity were assessed in 33 GDM women and 27 controls. Clinical information about the newborns was registered at birth. The FTO rs9939609 (T > A) was genotyped. RESULTS: No association between FTO DNA methylation and GDM was found. DNA methylation on the maternal side at the CpG1 was associated with maternal smoking in GDM (p = 0.034), and DNA methylation at the CpG3 was correlated with smoking or former smoking in controls (p = 0.023). A higher level of TGs was correlated with higher foetal placental DNA methylation at the CpG2 (p = 0.036) in GDM. An inverse association between HDL-C and maternal placental DNA methylation at the CpG3 in controls (p = 0.045) was found. An association between FTO rs9939609 and neonatal birthweight (p = 0.033) was detected. CONCLUSIONS: In the awareness that the obesity pathophysiology is complex, the study adds a piece to this intricate mosaic.