Marcelino Hernández

Relationship Between Circulating Adipokines and Insulin Resistance During Pregnancy and Postpartum in Women with Gestational Diabetes

BACKGROUND AND AIMS We undertook this study to assess the relationship between circulating adipokines and insulin resistance during pregnancy and postpartum in women with gestational diabetes mellitus (GDM). METHODS This was a prospective study including 60 women with GDM and 60 subjects with normal gestation who were evaluated at gestational week 30, 6 weeks and 6 months postpartum. Circulating adipokines that were evaluated during the study were leptin, adiponectin, retinol-binding protein-4 (RBP4), and tumor necrosis factor-alpha (TNF-α). RESULTS Women with GDM showed higher insulin resistance measured by HOMA-IR than subjects with normal gestation (2.3 ± 2.3 vs. 1.3 ± 0.95). There was no difference between groups in adipokines; however, in women with a healthy pregnancy, RBP4 was associated with insulin resistance (r = 0.47, p <0.05). At 6 weeks and 6 months postpartum, women with previous GDM exhibited persistent elevated leptin and insulin resistance. RBP4 was associated with insulin resistance only in women with a previous healthy pregnancy (r = 0.51, p <0.05). In addition, progressively impaired glucose tolerance was observed after delivery in women with previous GDM. CONCLUSIONS It was demonstrated that GDM is associated with greater insulin resistance than observed in normal pregnancy; however, adipokines are similar in both groups. RBP4 levels are significantly associated with insulin resistance in healthy women during pregnancy and postpartum. After a pregnancy complicated by GDM, leptin and insulin resistance remain elevated and glucose tolerance worsens.

Fetal Malnutrition Affects Hypothalamic Leptin Receptor Expression After Birth in Male Mice

BACKGROUND AND AIMS Epidemiological associations between an adverse intrauterine environment and the induction of obesity in adult life led to the concept of fetal programming whereby an unfavorable prenatal environment induces adaptations that improve fetal survival or prepare the fetus in expectation of a particular range of postnatal environments. However, these adaptations (predictive adaptive responses) may later prove to be a disadvantage when the pre- and postnatal environments show discrepancies. We investigated the effect of maternal restricted diet on body weight and expression of hypothalamic Ob-Rb of the offspring. METHODS Balb C mice were mated after pregnancy and were randomly assigned to control (C) and undernutrition group (UN) groups. Control group was allowed food ad libitum and UN group had a 50% restriction of food intake during gestation. In the present study we assessed changes in hypothalamic Ob-Rb mRNA by RT-PCR in offspring from C and UN groups. RESULTS The offspring of UN at birth showed 17% less body weight compared with C, but at 90 days the UN had a greater body weight than C (p<0.01). The UN group also presented an increase in the expression of Ob-Rb at 90 postnatal days (p<0.01). CONCLUSIONS The results suggest that maternal caloric restriction programs a greater expression of Ob-Rb in the hypothalamus in offspring, as well as a body weight gain that persists into adulthood. In addition, changes in Ob-Rb expression suggest that Ob-Rb mRNA in the hypothalamus is sensitive to fetal undernutrition.

Serum leptin and somatotropin components correlate with neonatal birth weight.

Objective: To determine whether cord sera leptin and components of the somatotropin axis – growth hormone (GH), total (t) and free (f) insulin-like growth factor (IGF), IGF-binding protein-3 (IGFBP-3), and insulin – correlate with birth weight. Design: Cross-sectional study of 22 newborns, 12 with normal birth weight (NBW) and 10 with low birth weight (LBW), in a population of healthy mothers with an apparent normal pregnancy. Methods: Paired mother–neonate blood samples were obtained at vaginal delivery in order to measure leptin and the somatotropin axis components. Results: In all cases maternal blood concentrations of leptin, t and fIGF-I, its carrier protein IGFBP-3, and insulin were higher than in the cord sera of the newborns, regardless of their birth weight. On the contrary, maternal GH levels were lower than in their neonates. LBW neonates had decreased levels of leptin, tIGF-I, and IGFBP-3 as compared with those levels in NBW offspring; however, GH concentrations were higher in LBW neonates. Birth weight showed a significant correlation with cord sera leptin, tIGF-I, IGFBP-3, and GH; nevertheless birth weight was neither interrelated with fIGF-I nor with insulin levels. Conclusion: These data demonstrate that birth weight is significantly correlated with both leptin and some components of the somatotropin axis; on the other hand, no correlation was observed between leptin concentrations and each one of the components of the somatotropin axis. It is suggested that fetal leptin and the somatotropin axis cooperate in intrauterine growth and birth weight.

Early Disturbed Placental Ischemia and Hypoxia Creates Immune Alteration and Vascular Disorder Causing Preeclampsia

Preterm preeclampsia (PE) remains a leading cause of maternal death and perinatal morbidity. The pathophysiological process that underlies PE has been proposed to occur in two episodes, the first is a reduced placental perfusion and then the maternal clinical syndrome. Placental ischemia/hypoxia is believed to result in the release of a variety of placental factors such as cytokines including TNF-α and interleukin 6, activated circulating immune cells and autoantibodies that have profound effects on blood flow and arterial pressure regulation. PE is also associated with decreased formation of vasodilators such as nitric oxide and prostacyclin. It is accompanied by widespread maternal vascular dysfunction and a chronic inflammatory response. Additionally, anti-angiogenic peptides are released, inhibiting vascular remodeling essential for increased blood flow to the growing uteroplacental unit. Although these factors accompany the clinical syndrome of PE, it is suggested that they are secondary to the maternal decrease in placental blood flow. Experimental evidence has demonstrated the importance of these soluble factors to increase blood pressure and stimulate the production of such anti-angiogenic factors, thereby eliciting a vicious cycle existing within the maternal vasculature as well as within the placental unit. These alterations in vascular function not only lead to hypertension but to multi-organ dysfunction. The quantitative importance of the various endothelial and humoral factors that mediate vascular dysfunction and hypertension during PE remains to be elucidated.

Increased serum levels of growth hormone and insulin-like growth factor-I associated with simultaneous decrease of circulating insulin in postmenopausal women receiving hormone replacement therapy.

OBJECTIVE Decreases in circulating growth hormone (GH) and its main biological messenger insulin-like growth factor-I (IGF-I) have been interpreted as part of the aging process. Because estrogens participate in modulating GH synthesis and secretion, hypoestrogenism in menopausal women may lead to GH deficiency. The aim of the present study was to determine the effect of hormone replacement therapy (HRT) on both GH and IGF-I levels as well as insulin concentrations in 50 menopausal women. DESIGN Patients were assigned randomly into two treatment groups of 25 each; one group received three cycles of conjugated equine estrogen (CEE) 0.625 mg/day for 21 days, and the other, 1.25 mg/day during 21 days. Each also received chlormadinone acetate for 5 days. There was a control group consisting of regularly menstruating women. RESULTS In the menopausal women, HRT increased significantly (p < 0.001) the low levels of GH and IGF-I; on the contrary the baseline insulin levels declined (p < 0.001) with HRT. A significant linear correlation (r = 0.90) was found between GH and IGF-I as well as with estradiol levels (r = 0.74) in the group of menopausal women receiving CEE 0.625 mg/day. This group of patients had a significant correlation (r = -0.63) between insulin and estradiol levels. No correlation was observed in the group receiving CEE 1.25 mg/day. CONCLUSIONS HRT restored GH, IGF-I, and insulin levels to normal values in all women. Further research needs to be done to establish the beneficial effect of HRT regarding the prevention of the metabolic effects presumably caused by derangement in the somatotropic axis associated with aging.

Women with Gestational Diabetes Develop Glucose Intolerance with High Frequency within One Year Postpartum

Objective: To investigate the incidence of glucose intolerance postpartum in women with gestational diabetes (GDM) and assess body weight, cholesterol and triglyceride concentrations after delivery. Methods: This was a study of an initial cohort of 100 women with GDM who were tested at 6 weeks, 6 months, and 1 year postpartum. Postpartum evaluations were glucose tolerance, weight and cholesterol and triglycerides. Results: Impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) was present in 36.5% of 52 participants who were assessed at 6 weeks postpartum and diabetes in 17.3%; the remaining 48 women failed to return for the 3 evaluations. By 6 months, IFG/IGT was demonstrated in 55.8% and diabetes in 32.7% of the women. At 1 year, 46.2% exhibited IFG/IGT and 48% diabetes. Moreover, the weight was higher in those women who presented IFG/IGT (75.5 ± 15.2 kg, mean ± SD) and diabetes (79.0 ± 16.2 kg) compared with those who had normal glucose tolerance (65.3 ± 14.5 kg; p < 0.05). In addition, triglycerides were higher in mothers with glucose intolerance (181.3 ± 85.9 mg/dl in IFG/IGT and 230.9 ± 90.9 mg/dl in diabetes) than in women with normal glycemia (147.8 ± 11.2 mg/dl; p < 0.05). Conclusion: We demonstrated an increased incidence of women exhibiting glucose intolerance within 1 year postpartum, mainly in those who remained obese.

Effect of Pulsed Estrogen Therapy on Hemostatic Markers in Comparison with Oral Estrogen Regimen in Postmenopausal Women

Background/Aims: Hormone replacement therapy (HRT) is associated with an increased risk of thromboembolism dependent on the type of HRT; therefore, we compared therapy effects of intranasal with oral estrogens on coagulation and fibrinolysis markers in postmenopausal women. Methods: A randomized study in which 29 healthy hysterectomized women received intranasal 17β-estradiol or oral estrogens for 3 months. Results: There were no significant differences in the baseline characteristics between groups. Those women receiving intranasal estradiol showed a mild increment in plasminogen activator inhibitor-1 (PAI-I) (from 6.8 ± 3.5 to 9.6 ± 3.9 U/ml, p < 0.01); however, fibrinogen, factor VII-tissue factor complex (VIIa-rTF), antithrombin III (ATIII), protein C (PC) activity, protein S (PS) activity, plasminogen (PLG), and tissue-type plasminogen activator antigen (t-PA) were unchanged. In contrast, oral unopposed estrogens elevated t-PA (from 4.9 ± 2.9 to 9.6 ± 5.1 ng/ml, p < 0.01) in parallel with a decrement in PAI-I (from 5.2 ± 4.0 to 2.7 ± 1.7 U/ml, p < 0.05) and VIIa-rTF (from 201.2 ± 181.0 to 140.6 ± 108.7 mU/ml, p < 0.05). Fibrinogen, ATIII, PC, PS, and PLG were unchanged. Conclusions: Nasal 17β-estradiol had no effect on the coagulation markers, except a moderate increment in PAI-1. In contrast, oral estrogens elicited a decrement in both VIIa-rTF and PAI-1; however, those changes did not surpass normal limits.

Low-dose conjugated equine estrogens elevate circulating neurotransmitters and improve the psychological well-being of menopausal women

OBJECTIVE To assess the effect of low-dose conjugated equine estrogens (E) on circulating neurotransmitters and the efficacy for the treatment of psychological symptoms. DESIGN Controlled comparative clinical study. SETTING Endocrine Research Unit, Instituto Mexicano del Seguro Social, Mexico. PATIENT(S) Thirty postmenopausal women received conjugated equine E. Ten women acted as a comparison group. INTERVENTION(S) Conjugated equine E, 0.312 mg/day, for 21 days per cycle during six cycles and added chlormadinone acetate, 2 mg/day, for the last 5 days of each cycle. Green scale for climateric women and Blatt-Kupperman Menopausal Index were used for measuring psychological well-being. MAIN OUTCOME MEASURE(S) Serum levels of dopamine (DA), noradrenaline, serotonin, and beta-endorphin were quantified by specific assays at baseline and at the end of treatment. RESULT(S) Low baseline levels of DA, serotonin, and beta-endorphin increased significantly (P<.001) from 181.9 +/- 47.8 pg/mL to 202.9 +/- 32.8 pg/mL (mean +/- SD); from 206.4 +/- 94.2 ng/mL to 279.2 +/- 67.9 ng/mL; from 11.2 +/- 1.8 pmol/L to 13.8 +/- 2.4 pmol/L, respectively, after conjugated equine E. In parallel, augmented baseline noradrenaline levels diminished significantly (P<.05) from 30.2 +/- 4.7 ng/mL to 24.0 +/- 4.7 ng/mL. All neurotransmitter levels had a significant correlation with 17beta-E(2) concentrations at the end of the study. Alleviation of psychological symptoms was observed in all but eight treated women. CONCLUSION(S) Low-dose conjugated equine E associated with periodic administration of chlormadinone acetate elicited favorable changes in neurotransmitters and relieved psychological symptoms.

Gene variants in the FTO gene are associated with adiponectin and TNF-alpha levels in gestational diabetes mellitus

BackgroundObesity may have a role in the development of gestational diabetes mellitus (GDM). Single-nucleotide-polymorphisms (SNPs) of the FTO (fat mass and obesity associated) gene have been associated with obesity. The aim of this study was to investigate SNPs rs8050136, rs9939609, and rs1421085 of the FTO gene in women with GDM and their associations with maternal pre-pregnancy weight and body mass index, gestational weight gain and mediators of insulin resistance in GDM like leptin, adiponectin, ghrelin and tumor necrosis factor-alpha (TNF-alpha), compared with healthy pregnant controls.Methods80 women with GDM and 80 women with normal pregnancy were considered for the present study. Genotyping of selected SNPs in all study subjects was done using the Taq-Man assay and the adipokines and ghrelin were measured by immunoassays. Chi square test, odds ratios (OR) and their respective 95% confidence intervals were used to measure the strength of association between FTO SNPs and GDM.ResultsThere was no association among FTO SNPs and GDM. Interestingly, in GDM group, women carrying the risk alleles of the three SNPs had increased TNF-alpha, and decreased adiponectin levels; these associations remained significant after adjusting for pre-gestational body weight and age. Moreover, the risk allele of rs1421085 was also associated with increased weight gain during pregnancy.ConclusionsThe FTP SNPs rs8050136, rs9939609, and rs1421085 are not a major genetic regulator in the etiology of GDM in the studied ethnic group. However, these SNPs were associated with adiponectin and TNF-alpha concentrations in GDM subjects.

RBP4 Gene Variants Are Associated with Insulin Resistance in Women with Previous Gestational Diabetes

Objective. This study aimed to examine possible genetic effects of some retinol binding protein-4 (RBP4) single nucleotide polymorphisms (SNPs) on the risk of gestational diabetes mellitus (GDM). In addition, the SNPs were examined for their possible association with insulin resistance at 6 weeks after delivery. Methods. This was a prospective study of 100 women with GDM and 100 participants with normal gestation who were evaluated at gestational week 30 and 6 weeks postpartum. Three SNPs of RBP4 (rs3758539, rs116736522, and rs34571439) were genotyped using TaqMan assay. The genotype distributions between GDM patients and normal controls were analyzed using logistic regression models. In addition, differences in clinical characteristics among subjects grouped by genotype were assessed using the analysis of covariance test. Results. The frequencies of the rare alleles were not significantly different between GDM patients and controls. However, we identified two variants rs3758539 and rs34571439 associated with insulin levels and insulin resistance in women with previous GDM. Conclusion. Noncoding SNPs of the RBP4 gene are not associated with GDM, but two SNPs showed associations with insulin resistance and insulin levels in women with prior GDM. Additional studies with increased sample size will be necessary in other GDM cohorts.