Metabolic Biomarkers in Adults with Type 2 Diabetes: The Role of PPAR-γ2 and PPAR-ß/δ Polymorphisms.

Glucose and lipid metabolism regulation by the peroxisome proliferator-activated receptors (PPARs) has been extensively reported. However, the role of their polymorphisms remains unclear. OBJECTIVE: To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-ß/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with type 2 diabetes (T2D). MATERIALS AND METHODS: We included 314 patients with T2D. Information on anthropometric, fasting plasma glucose (FPG), HbA1c and lipid profile measurements was taken from clinical records. Genomic DNA was obtained from peripheral blood. End-point PCR was used for PPAR-γ2 rs1801282, while for PPAR-ß/δ rs2016520 the PCR product was digested with Bsl-I enzyme. Data were compared with parametric or non-parametric tests. Multivariate models were used to adjust for covariates and interaction effects. RESULTS: minor allele frequency was 12.42% for PPAR-γ2 rs1801282-G and 13.85% for PPAR-ß/δ rs2016520-C. Both polymorphisms were related to waist circumference; they showed independent effects on HbA1c, while they interacted for FPG; carriers of both PPAR minor alleles had the highest values. Interactions between FPG and polymorphisms were identified in their relation to triglyceride level. CONCLUSIONS: PPAR-γ2 rs1801282 and PPAR-ß/δ rs2016520 polymorphisms are associated with anthropometric, glucose, and lipid metabolism biomarkers in T2D patients. Further research is required on the molecular mechanisms involved.

Pro12Ala PPAR-γ2 and +294T/C PPAR-δ Polymorphisms and Association with Metabolic Traits in Teenagers from Northern Mexico.

Peroxisome proliferator-activated receptors (PPARs) play roles in glucose and lipid metabolism regulation. Pro12Ala PPAR-γ2 and +294T/C PPAR-δ have been associated with dyslipidemia, hyperglycemia and high body mass index (BMI). We compared metabolic traits and determined associations with Pro12Ala PPAR-γ2 or +294T/C PPAR-δ polymorphism among teenagers from different ethnicity. Four hundred and twelve samples with previous biochemical and biometric measurements were used. Genomic DNA from peripheral blood was extracted and analyzed by end-point PCR for Pro12Ala PPAR-γ2. The +294T/C PPAR-δ PCR product was also digested with Bsl I. Two genotype groups were formed: major allele homozygous and minor allele carriers. Pro12Ala PPAR-γ2 G minor allele frequencies were: 10% in Mestizo-1, 19% in Mestizo-2, 23% in Tarahumara, 12% in Mennonite, and 17% in the total studied population. The +294T/C PPAR-δ C minor allele frequencies were: 18% in Mestizo-1, 20% in Mestizo-2, 6% in Tarahumara, 13% in Mennonite, and 12% in the total studied population. Teenagers with PPAR-γ2 G allele showed a greater risk for either high waist/height ratio or low high-density lipoprotein; and, also had lower total cholesterol. Whereas, PPAR-γ2 G allele showed lower overweight/obesity phenotype (BMI Z-score) frequency, PPAR-δ C allele was a risk factor for it. Metabolic traits were associated with both PPAR polymorphisms.

Relation between pregestational obesity and characteristics of the placenta.

Objective: To evaluate the morphology of the placenta in patients with pregestational overweight (OW), pregestational obesity (PGOB), or normal weight.Methods: A cross-sectional study including women (n = 114) ≥20 years of age with a singleton pregnancy was carried out. The groups were integrated according to pregestational body mass index (BMI): 51 patients had a normal BMI (18.5-24.99 kg/m2), 30 were overweight (25-29.99 kg/m2), and 33 women were obese (≥30.0 kg/m2). A morphometric study of the placenta was performed and the placental maturity index (PMI) was calculated according to the formula: PMI = number of vasculo-syncytial membranes (VSM) in 1 mm2/VSM thickness. In the histopathological study, the presence of infarcts, calcifications, hemorrhage, thrombosis, fibrosis, cysts, and edema was determined.Results: The weight and length of newborns at birth were greater in the group with PGOB (p < .01). We observed a lower number of VSM (29 ± 9 versus 39 ± 13 and 34 ± 11) and a greater thickness (1.05 ± 0.24 versus 0.95 ± 0.08 and 0.89 ± 0.09) and, therefore, a lower PMI (29.75 ± 12.63 versus 40.88 ± 15.25 and 39.28 ± 14.4) in the group of women with PGOB compared with the group of women with OW or normal weight (p < .01). The histopathological analyses showed a greater frequency of edema and cysts in the PGOB group.Conclusion: PGOB is associated with a higher placental weight and newborn weight, a lower PMI, and the presence of histopathological alterations. The preceding points highlight the importance of promoting an appropriate pregestational weight in women of reproductive age.

Folate transporter expression in placenta from pregnancies complicated with birth defects.

BACKGROUND: Folate plays a fundamental role for fetal development, participating in cell division, embryogenesis, and fetal growth. The fetus depends on maternal supply of folate across the placenta. The objective of this study was to compare the expression of Folate Receptor-α (FR-α), Reduced Folate Carrier (RFC), and Proton Coupled Folate Transporter (PCFT) in placentas from pregnancies complicated with birth defects (BD) and controls. METHODS: Case-control study, including placentas of BD-complicated pregnancies (n = 25) and a control group (n = 25). We determined the placental expression of FR-α, RFC, and PCFT by immunohistochemistry. Optical density was measured to obtain a relative quantification of the expression. RESULTS: The expression of PCFT was greater in placentas from pregnancies complicated with BD than in those from the control group (p < .01). The expression of FR-α and RFC was not different between groups. CONCLUSION: The expression of PCFT in placentas from BD-complicated pregnancies is increased, possibly as an adaptive response to increase the folate flux at the maternal-fetal interface.

Maternal and postweaning folic acid supplementation interact to influence body weight, insulin resistance, and food intake regulatory gene expression in rat offspring in a sex-specific manner.

Maternal intake of multivitamins or folic acid above the basal dietary requirement alters the growth and metabolic trajectory of rat offspring. We hypothesized that a modest increase in the folic acid content of maternal diets would alter the offspring's metabolic phenotype, and that these effects could be corrected by matching the folic acid content of the offspring's diet with that of the maternal diet. Female Sprague-Dawley rats were placed on a control or a 2.5× folic acid-supplemented diet prior to mating and during pregnancy and lactation. At weaning, pups from each maternal diet group were randomized to the control or to the 2.5× folic acid-supplemented diet for 25 weeks. Male pups from dams fed the folic acid-supplemented diet were 3.7% heavier than those from control-fed dams and had lower mRNA expression for leptin receptor Obrb isoform (Lepr) (11%) and Agouti-related protein (Agrp) (14%). In contrast, female pups from folic acid-supplemented dams were 5% lighter than those from control-fed dams and had lower proopiomelanocortin (Pomc) (42%), Lepr (32%), and Agrp (13%), but higher neuropeptide Y (Npy) (18%) mRNA expression. Folic acid supplementation ameliorated the alterations induced by maternal folic acid supplementation in male pups and led to the lowest insulin resistance, but the effects were smaller in female pups and led to the highest insulin resistance. In conclusion, maternal folic acid supplementation at 2.5× the control level was associated with alterations in body weight and hypothalamic gene expression in rat offspring in a sex-specific manner, and some of these effects were attenuated by postweaning folic acid supplementation.

High vitamin A intake during pregnancy modifies dopaminergic reward system and decreases preference for sucrose in Wistar rat offspring.

High multivitamin (HV) content in gestational diets has long-term metabolic effects in rat offspring. These changes are associated with in utero modifications of gene expression in hypothalamic food intake regulation. However, the role of fat-soluble vitamins in mediating these effects has not been explored. Vitamin A is a plausible candidate due to its role in gene methylation. Vitamin A intake above requirements during pregnancy affects the development of neurocircuitries involved in food intake and reward regulation. Pregnant Wistar rats were fed AIN-93G diets with the following content: recommended multivitamins (1-fold multivitamins: RV), high vitamin A (10-fold vitamin A: HA) or HV with only recommended vitamin A (10-fold multivitamins, 1-fold vitamin A: HVRA). Body weight, food intake and preference, mRNA expression and DNA methylation of hippocampal dopamine-related genes were assessed in male offspring brains at different developmental windows: birth, weaning and 14weeks postweaning. HA offspring had changes in dopamine-related gene expression at all developmental windows and DNA hypermethylation in the dopamine receptor 2 promoter region compared to RV offspring. Furthermore, HA diet lowered sucrose preference but had no effect on body weight and expression of hypothalamic genes. In contrast, HVRA offspring showed only at adulthood changes in expression of hippocampal genes and a modest effect on hypothalamic genes. High vitamin A intake alone in gestational diets has long-lasting programming effects on the dopaminergic system that are further translated into decreased sucrose preference but not food intake.

Maternal and Perinatal Outcomes Among Adolescents and Mature Women: A Hospital-Based Study in the North of Mexico.

STUDY OBJECTIVE: To compare maternal and newborn pregnancy outcomes from adolescents and mature women. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study was carried out in a public hospital, including women with singleton pregnancies, who were classified according to their age, as follows: group 1: younger than 16 years old (n = 37), group 2: 16-19 years old (n = 288), and group 3: 20-34 years old (n = 632). INTERVENTIONS AND MAIN OUTCOME MEASURES: Information on clinical characteristics, gynecological and obstetric history, pregnancy complications, and perinatal outcomes was obtained through interviews and from clinical records. RESULTS: Thirty-four percent of deliveries were from adolescents. Mature women were more likely to have prepregnancy overweight or obesity than adolescents (odds ratio [OR] = 2.4, 95% confidence interval [CI], 1.7-3.4). The frequency of maternal complications during pregnancy or delivery was not different between groups. Birth asphyxia was more frequent in group 2 (P = .02). Women with inadequate prenatal care had an increased risk of preterm deliveries (OR = 1.64; 95% CI, 1.06-2.54) and of having newborns with low birth weight (OR = 2.02; 95% CI, 1.22-3.35). Weight of newborns from noncomplicated pregnancies was lower in group 1 (P = .02), after adjustment for prepregnancy body mass index, gestational weight gain, preterm delivery, and newborn sex. CONCLUSION: The frequency of maternal and perinatal complications was similar in adolescents and mature women. Birth weight was decreased in noncomplicated pregnancies of adolescents younger than 16 years of age. Adequate prenatal care might be helpful in prevention of some adverse perinatal outcomes.

Increasing vitamin A in post-weaning diets reduces food intake and body weight and modifies gene expression in brains of male rats born to dams fed a high multivitamin diet.

High multivitamin gestational diets (HV, 10-fold AIN-93G levels) increase body weight (BW) and food intake (FI) in rat offspring weaned to a recommended multivitamin (RV), but not to a HV diet. We hypothesized that high vitamin A (HA) alone, similar to HV, in post-weaning diets would prevent these effects of the HV maternal diet consistent with gene expression in FI and reward pathways. Male offspring from dams fed HV diets were weaned to a high vitamin A (HA, 10-fold AIN-93G levels), HV or RV diet for 29 weeks. BW, FI, expression of genes involved in regulation of FI and reward and global and gene-specific DNA methylation of pro-opiomelanocortin (POMC) in the hypothalamus were measured. Both HV and HA diets slowed post-weaning weight gain and modified gene expression in offspring compared to offspring fed an RV post-weaning diet. Hypothalamic POMC expression in HA offspring was not different from either HV or RV, and dopamine receptor 1 was 30% (P<.05) higher in HA vs. HV, but not different from RV group. Hippocampal expression of serotonin receptor 1A (40%, P<.01), dopamine receptor 2 (40%, P<.05) and dopamine receptor 5 (70%, P<.0001) was greater in HA vs. RV fed pups and is 40% (P<.01), 50% (P<.05) and 40% (P<.0001) in HA vs. HV pups, respectively. POMC DNA methylation was lower in HA vs. RV offspring (P<.05). We conclude that high vitamin A in post-weaning diets reduces post-weaning weight gain and FI and modifies gene expression in FI and reward pathways.

Placental maturity, hypertensive disorders of pregnancy and birth weight.

OBJECTIVES: To compare maturity of placentas from women with hypertensive disorders with those from normotensive pregnancies and to determine the relationship between placental maturity (PM) and the diagnosis of small-for-gestational-age (SGA) in the newborns. MATERIALS AND METHODS: We examined placental stained specimens from women with normotensive pregnancies (n = 100), diagnosis of gestational hypertension (n = 38), mild (n = 10), or severe preeclampsia (n = 34) in an optical microscope. Placental Maturity Index (PMI) was calculated as the number of vasculo-syncytial membranes (VSM) in 1 mm(2) divided by VSM thickness (µm). Hypermaturity was defined as >90th percentile of the PMI from placentas of normotensive pregnancies. Newborns were classified as SGA, adequate-for-gestational-age (AGA) or large-for-gestational-age (<10th, 10-90th, and >90th percentile from weight for gestational age reference tables, respectively). RESULTS: PMI in preeclamptic women (taking together mild and severe preeclampsia, PMI = 43.4 ± 1.6) was significantly higher than in normotensive women (PMI = 36 ± 2, p = 0.045). Hypermaturity was more frequent (p < 0.05) in placentas from women with preeclampsia than in those from normotensive women only in preterm pregnancies (<37 weeks), but not in those at term (p = 0.41). The frequency of hypermaturity in placentas from women with gestational hypertension was not statistically different than in normotensive women. Hypermaturity was also more frequent in placentas from SGA (OR = 2.63, p < 0.05) than in AGA newborns. CONCLUSION: The PMI was increased in preeclampsia, but not in gestational hypertension. Placental hypermaturity was also associated with the diagnosis of SGA in newborns. PM might have a role in the relationship between maternal factors and SGA.

High Folic Acid Intake during Pregnancy Lowers Body Weight and Reduces Femoral Area and Strength in Female Rat Offspring.

Rats fed gestational diets high in multivitamin or folate produce offspring of altered phenotypes. We hypothesized that female rat offspring born to dams fed a gestational diet high in folic acid (HFol) have compromised bone health and that feeding the offspring the same HFol diet attenuates these effects. Pregnant rats were fed diets with either recommended folic acid (RFol) or 10-fold higher folic acid (HFol) amounts. Female offspring were weaned to either the RFol or HFol diet for 17 weeks. HFol maternal diet resulted in lower offspring body weights (6%, P = 0.03) and, after adjusting for body weight and femoral length, smaller femoral area (2%, P = 0.03), compared to control diet. After adjustments, HFol pup diet resulted in lower mineral content (7%, P = 0.01) and density (4%, P = 0.002) of lumbar vertebra 4 without differences in strength. An interaction between folate content of the dam and pup diets revealed that a mismatch resulted in lower femoral peak load strength (P = 0.01) and stiffness (P = 0.002). However, the match in folate content failed to prevent lower weight gain. In conclusion, HFol diets fed to rat dams and their offspring affect area and strength of femurs and mineral quantity but not strength of lumbar vertebrae in the offspring.

High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring.

Excess vitamins, especially folate, are consumed during pregnancy but later-life effects on the offspring are unknown. High multivitamin (10-fold AIN-93G, HV) gestational diets increase characteristics of metabolic syndrome in Wistar rat offspring. We hypothesized that folate, the vitamin active in DNA methylation, accounts for these effects through epigenetic modification of food intake regulatory genes. Male offspring of dams fed 10-fold folate (HFol) diet during pregnancy and weaned to recommended vitamin (RV) or HFol diets were compared with those born to RV dams and weaned to RV diet for 29 weeks. Food intake and body weight were highest in offspring of HFol dams fed the RV diet. In contrast, the HFol pup diet in offspring of HFol dams reduced food intake (7%, p = 0.02), body weight (9%, p = 0.03) and glucose response to a glucose load (21%, p = 0.02), and improved glucose response to an insulin load (20%, p = 0.009). HFol alone in either gestational or pup diet modified gene expression of feeding-related neuropeptides. Hypomethylation of the pro-opiomelanocortin (POMC) promoter occurred with the HFol pup diet. POMC-specific methylation was positively associated with glucose response to a glucose load (r = 0.7, p = 0.03). In conclusion, the obesogenic phenotype of offspring from dams fed the HFol gestational diet can be corrected by feeding them a HFol diet. Our work is novel in showing post-weaning epigenetic plasticity of the hypothalamus and that in utero programming by vitamin gestational diets can be modified by vitamin content of the pup diet.

High multivitamin intakes during pregnancy and postweaning obesogenic diets interact to affect the relationship between expression of PPAR genes and glucose regulation in the offspring.

High multivitamin intake (HV) during pregnancy increases body fat and weight and alters glucose and fatty acid metabolism in Wistar rat offspring. This study investigated the expression of peroxisome-proliferator activated receptors (PPARs) genes involved in regulation of glucose and fatty acid metabolism in their tissues. Dams received the AIN-93G diet with either the regular (RV) or 10-fold multivitamins (HV) during pregnancy. Male offspring were weaned to either the RV diet (RV-RV and HV-RV) or an obesogenic diet (RV-Ob and HV-Ob). Gene expression of PPARs in tissues was analyzed by real-time reverse transcriptase polymerase chain reaction. Gestational diet (GD) did not affect PPARs gene expression in offspring at either birth or weaning. In liver, at 14 weeks postweaning, PPAR-γ was 30% lower in the HV-RV and 30% higher in HV-Ob than in the RV-RV group [GD P=.76, postweaning diet (PD) P=.19, interaction P=.02, by two-way analysis of variance]. In muscle, PPAR-α expression was affected by GD and PD (GD P=.05, PD P<.01, interaction P=.07). In adipose tissue, PPAR-α expression was higher in all groups compared to RV-RV (GD P=.25, PD P=.85, interaction P=.03). PPAR-γ mRNA levels correlated with abdominal fat (r=0.45, P<.05) and insulin resistance index (r=0.39, P<.05). In liver, PPAR-γ expression correlated with insulin resistance index in offspring from RV (r=-0.62, P<.05), but not in those from HV dams (r=0.13, P>.05). In conclusion, the HV diet during pregnancy interacts with postweaning diets in determining the expression of PPARs genes in a tissue- and age-dependent manner and uncouples the relationship between these genes and glucose regulation and fat mass in the rat offspring.

High vitamin intake by Wistar rats during pregnancy alters tissue fatty acid concentration in the offspring fed an obesogenic diet.

Diet during pregnancy affects the long-term health of the offspring. Vitamins are known to modulate lipid metabolism, which may be reflected in tissue fatty acid (FA) concentrations. The objective of this study was to investigate the effect of high vitamin intake during pregnancy on tissue FA concentration of the offspring. Wistar rats were fed an AIN-93G diet with either the recommended vitamin or 10-fold higher amounts (HV) during pregnancy. Afterward, offspring were weaned onto an obesogenic diet. Liver, quadriceps, adipose, and brain were collected over 48 weeks. Fatty acid concentration of tissue total lipids was analyzed by gas chromatography. At birth, the liver from HV offspring was higher in monounsaturated, stearic, and arachidonic acids. At weaning, the liver from HV offspring was higher in stearic and oleic acids; and in adipose tissue, n-6 and n-3 FAs were lower only in the male HV offspring (P < .05). At 12 weeks, HV offspring had higher concentrations of total fat, saturates, monounsaturates, and n-6 FA in muscle (P < .05), but not in other tissues. At 48 weeks, gestational diet did not affect tissue total lipid FA concentrations; but differences remained in specific tissue phospholipids species. Liver phospholipids from HV offspring were lower in monounsaturates and n-6 FA. Brain phosphatidylethanolamine was higher in oleic, n-6 FA, and docosahexaenoic acid in the HV offspring. Phosphatidylinositol was lower in saturates, monounsaturates, arachidonic, and docosahexaenoic acids only in HV female offspring. These observations demonstrate that high vitamin intake during pregnancy has short- and long-term effects on tissue FA concentration in the offspring.

Relación entre el índice de masa corporal pregestacional y la composición corporal en el puerperio inmediato / Correlation between pregestational body mass index and body composition parameters in immediate puerperal period

Con los objetivos de establecer la correlación entre el índice de masa corporal pregestacional y los parámetros de la composición corporal medidos por impedancia bioeléctrica (porcentaje de peso graso, masa de grasa y peso magro) y comparar la composición corporal de mujeres en el puerperio inmediato con mujeres sanas no embarazadas, se realizó un estudio transversal que incluyó 86 mujeres en puerperio fisiológico y 90 sanas no embarazadas, derechohabientes del Instituto Mexicano del Seguro Social, en Chihuahua, México con edad entre 16 y 40 años. Las variables consideradas fueron índice de masa corporal (IMC) pregestacional, porcentaje de grasa, masa de grasa, peso magro, agua total y biorresistencia. La composición corporal se midió por impedancia bioeléctrica (IBE) entre cuatro y 12 horas después del parto. El coeficiente de correlación entre IMC y porcentaje de grasa fue r = 0.66 (p < 0.01) y entre IMC y masa grasa fue r = 0.74 (p < 0.01). En mujeres no embarazadas el total de agua fue de 35.5 ñ 5 L y en las mujeres del grupo en puerperio de 38.5 ñ 5 L (p < 0.01). En conclusión, el IMC pregestacional es un predictor adecuado de la composición corporal en el puerperio. Sin embargo, no discrimina variables importantes como el agua corporal total, por lo cual quizá sea conveniente el uso de BIA para la vigilancia de la composición corporal durante el embarazo.