IRS-1 gene polymorphism and DNA damage in pregnant women with diabetes or mild gestational hyperglycemia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Changes in T-cell phenotype and cytokines profile in maternal blood, cord blood and colostrum of diabetic mothers

The present study evaluated the cells and cytokine of maternal blood, cord blood and colostrum of diabetic mothers. The women evaluated were divided according to their body mass index (BMI) and glycemic status into non-diabetic (ND - N = 15), mild gestational hyperglycemic (MGH - N = 15), diabetes mellitus gestational (DMG - N = 13) and type-2 diabetes mellitus (DM2 - N = 15) groups. The subsets of cells and cytokine profile were determined by flow cytometry. Maternal blood from MGH group had increase percentage of CD3(+)T cells, and DM-2 group had decrease percentage of CD4(+) T cells. The cord blood from hyperglycemic groups showed lower percentage of CD3(+) T cells expressing CD45RO(+) and higher of CD4(+) T cells and CD4(+) T cells expressing CD45RA(+). In the colostrum, the CD4(+) T cells and CD4(+) T cells expressed CD45RA(+) increase in hyperglycemic groups. The DM2 group exhibited higher IL17 levels in maternal blood. IFN-γ was lower in cord blood from MGH and DMG groups with overweight/obese. Irrespective of the glycemic status, IL6 was higher in colostrum. The results obtained suggest that maternal hyperglycemia modifies the phenotypes of T cells and cytokines profile in maternal, cord blood and colostrum.

Depression and anxiety in pregnant women with diabetes or mild hyperglycemia

A number of physical and psychological changes that occur during pregnancy can stimulate the development of psychological disorders such as anxiety and depression. The study evaluated psychological aspects related to maternal depression and anxiety in pregnant women with diabetes mellitus or hyperglycemia, contrasting the results with those of non-diabetic pregnant women. In a prospective and longitudinal approach, two questionnaires were applied and validated for use in Brazil, the Beck depression inventory and the State-Trait Anxiety Inventory. The questionnaires were applied to pregnant women at the first prenatal visit or at the time of disease diagnosis (T1) and reapplied at admission for delivery (T2). Regardless of the degree of hyperglycemia, both at first and in the second stage most women had severe anxiety trait. In early pregnancy (T1), however, severe state anxiety was more frequent in women with hyperglycemia than in those from the NG group. Most pregnant women showed moderate state anxiety over their pregnancy, regardless of glycemic status. In early pregnancy, however, severe state anxiety was more prevalent in hyperglycemic women than in those with normal glycemic status. Most women showed moderate trait anxiety and mild depression in both early and late pregnancy, irrespective of glycemic status. The incidence of severe state anxiety in early pregnancy is more frequent in women with diabetes or hyperglycemia, but their levels of trait anxiety and depression are not affected by glycemic status.

Efeito Diabetes mellitus gestacional na modulação de genes relacionados ao metabolismo mitocondrial e a implicação na predisposiçao do recém-nascido à obesidade

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Diabetes mellitus gestacional: enfoque nos novos critérios diagnósticos

Alterations in maternal metabolism are important in order to supply the demands of the fetus. However, pregnant women with some degree of insulin resistance, such as in cases of overweight/obesity, central obesity and polycystic ovaries syndrome, associated to the action of anti-insulin placental hormones, contribute to a case of hyperglycemia of varied intensity, characterizing gestational diabetes mellitus (GDM) and leading to adverse effects both maternal and fetal. At the absence of a universal consensus to the tracking and diagnosis of GDM, this review had the purpose of listing the various protocols that have been proposed, as well as highlighting the risk factors associated with GDM and its complications. The most recent protocol is the one from the American Diabetes Association, with changes that would be justified by the alarming raise in worldwide obesity and, consequently, the potential increase to the occurrence of type 2 diabetes mellitus, not always diagnosed before the gestational period. The intention of this protocol is to identify the gestating women that could benefit from hyperglycemia control, improving the prognostic of these pregnancies and preventing future complications for mothers and their children.

Maternal Melatonin Programs the Daily Pattern of Energy Metabolism in Adult Offspring

Background: Shift work was recently described as a factor that increases the risk of Type 2 diabetes mellitus. In addition, rats born to mothers subjected to a phase shift throughout pregnancy are glucose intolerant. However, the mechanism by which a phase shift transmits metabolic information to the offspring has not been determined. Among several endocrine secretions, phase shifts in the light/dark cycle were described as altering the circadian profile of melatonin production by the pineal gland. The present study addresses the importance of maternal melatonin for the metabolic programming of the offspring. Methodology/Principal Findings: Female Wistar rats were submitted to SHAM surgery or pinealectomy (PINX). The PINX rats were divided into two groups and received either melatonin (PM) or vehicle. The SHAM, the PINX vehicle and the PM females were housed with male Wistar rats. Rats were allowed to mate and after weaning, the male and female offspring were subjected to a glucose tolerance test (GTT), a pyruvate tolerance test (PTT) and an insulin tolerance test (ITT). Pancreatic islets were isolated for insulin secretion, and insulin signaling was assessed in the liver and in the skeletal muscle by western blots. We found that male and female rats born to PINX mothers display glucose intolerance at the end of the light phase of the light/dark cycle, but not at the beginning. We further demonstrate that impaired glucose-stimulated insulin secretion and hepatic insulin resistance are mechanisms that may contribute to glucose intolerance in the offspring of PINX mothers. The metabolic programming described here occurs due to an absence of maternal melatonin because the offspring born to PINX mothers treated with melatonin were not glucose intolerant. Conclusions/Significance: The present results support the novel concept that maternal melatonin is responsible for the programming of the daily pattern of energy metabolism in their offspring.

Insulin analogues in the treatment of diabetes in pregnancy

Pregnancy affects both maternal and fetal metabolism, and even in non-diabetic women, it exerts a diabetogenic effect. Among pregnant women, 2% to 14% develop gestational diabetes. Pregnancy can also occur in women with preexisting diabetes, which may predispose the fetus to many alterations in organogenesis, restrict growth, and the mother, to some diabetes-related complications, such as retinopathy and nephropathy, or to acceleration of the course of these complications, if they are already present. Women with gestational diabetes generally start their treatment with diet and lifestyle changes; when these changes are not enough for optimal glycemic control, insulin therapy must then be considered. Women with type 2 diabetes using oral hypoglycemic agents are advised to change to insulin therapy. Those with preexisting type 1 diabetes should start intensive glycemic control. As basal insulin analogues have frequently been used off-label in pregnant women, there is a need to evaluate their safety and efficacy. The aim of this review is to report the use of both short- and long-acting insulin analogues during pregnancy and to enable clinicians, obstetricians, and endocrinologists to choose the best insulin treatment for their patients.

Neonatally induced mild diabetes: influence on development, behavior and reproductive function of female Wistar rats

Abstract Background Neonatal STZ treatment induces a state of mild hyperglycemia in adult rats that disrupts metabolism and maternal/fetal interactions. The aim of this study was investigate the effect of neonatal STZ treatment on the physical development, behavior, and reproductive function of female Wistar rats from infancy to adulthood. Methods At birth, litters were assigned either to a Control (subcutaneous (s.c.) citrate buffer, n = 10) or STZ group, (streptozotocin (STZ) - 100 mg/kg-sc, n = 6). Blood glucose levels were measured on postnatal days (PND) 35, 84 and 120. In Experiment 1 body weight, length and the appearance of developmental milestones such as eye and vaginal opening were monitored. To assess the relative contribution of the initial and long term effects of STZ treatment this group was subdivided based on blood glucose levels recorded on PND 120: STZ hyperglycemic (between 120 and 300 mg/dl) and STZ normoglycemic (under 120 mg/dl). Behavioral activity was assessed in an open field on PND 21 and 75. In Experiment 2 estrous cyclicity, sexual behavior and circulating gonadotropin, ovarian steroid, and insulin levels were compared between control and STZ-hyperglycemic rats. In all measures the litter was the experimental unit. Parametric data were analyzed using one-way or, where appropriate, two-way ANOVA and significant effects were investigated using Tukey’s post hoc test. Fisher’s exact test was employed when data did not satisfy the assumption of normality e.g. presence of urine and fecal boli on the open field between groups. Statistical significance was set at p < 0.05 for all data. Results As expected neonatal STZ treatment caused hyperglycemia and hypoinsulinemia in adulthood. STZ-treated pups also showed a temporary reduction in growth rate that probably reflected the early loss of circulating insulin. Hyperglycemic rats also exhibited a reduction in locomotor and exploratory behavior in the open field. Mild hyperglycemia did not impair gonadotropin levels or estrous cylicity but ovarian steroid concentrations were altered. Conclusions In female Wistar rats, neonatal STZ treatment impairs growth in infancy and results in mild hyperglycemia/hypoinsulinemia in adulthood that is associated with changes in the response to a novel environment and altered ovarian steroid hormone levels.

Long-term type 1 diabetes impairs decidualization and extracellular matrix remodeling during early embryonic development in mice

Introduction: Endometrial decidualization and associated extracellular matrix (ECM) remodeling are critical events to the establishment of the maternal-fetal interface and successful pregnancy. Here, we investigated the impact of type 1 diabetes on these processes during early embryonic development, in order to contribute to the understanding of the maternal factors associated to diabetic embryopathies. Methods: Alloxan-induced diabetic Swiss female mice were bred after different periods of time to determine the effects of diabetes progression on the development of gestational complications. Furthermore, the analyses focused on decidual development as well as mRNA expression, protein deposition and ultrastructural organization of decidual ECM. Results: Decreased number of implantation sites and decidual dimensions were observed in the group mated 90-110 days after diabetes induction (D), but not in the 50-70D group. Picrosirius staining showed augmentation in the fibrillar collagen network in the 90e110D group and, following immunohistochemical examination, that this was associated with increase in types I and V collagens and decrease in type III collagen and collagen-associated proteoglycans biglycan and lumican. qPCR, however, demonstrated that only type I collagen mRNA levels were increased in the diabetic group. Alterations in the molecular ratio among distinct collagen types and proteoglycans were associated with abnormal collagen fibrillogenesis, analyzed by transmission electron microscopy. Conclusions: Our results support the concept that the development of pregnancy complications is directly related with duration of diabetes (progression of the disease), and that this is a consequence of both systemic factors (i.e. disturbed maternal endocrine-metabolic profile) and uterine factors, including impaired decidualization and ECM remodeling

Maternal cholestasis during pregnancy programs metabolic disease in offspring

The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.

Maternal factors, fetal parameters and the risk of shoulder dystocia

Introduction. Shoulder dystocia is a serious complication of vaginal birth, with an incidence ranging from 0.15% to 2.1% of all births. There are approximately 4 million births per year in the United States and shoulder dystocia will be experienced by approximately 20,000 women each year. Although studies have been reported on shoulder dystocia, few studies have addressed both maternal and fetal risk factors. The purpose of this study was to identify maternal and fetal risk factors for shoulder dystocia while proposing factors that could be used to predict impending shoulder dystocia. ^ Material and methods. Articles were reviewed from Medline Pubmed using the search phrase "Risk factors of shoulder dystocia" and Medline Ovid using the search words "Dystocia", "Shoulder" and "Risk factors". Rigorous selection criteria were used to identify articles to be included in the study. Data collected from identified articles were transferred to STATA 10 software for trend analysis of the incidence of shoulder dystocia and the year of publication and a pair wise correlation was also determined between these two variables. ^ Results. Among a total of 343 studies identified, only 20 met our inclusion criteria and were retained for this review. The incidence of shoulder dystocia ranged from 0.07% to 2% and there was no particular trend or correlation between the incidence of shoulder dystocia and year of publication between 1985 and 2007. Pre-gestational and gestational diabetes, postdatism, obesity, birth weight > 4000g and fundal height at last visit > 40cm were identified as major risk factors in our series of studies. ^ Conclusion. Future strategies to predict shoulder dystocia should focus on pre-gestational and gestational diabetes mellitus, postdatism, obesity, birth weight > 4000g and fundal height at last visit > 40cm. ^

Diabetes gestacional : el rol del ejercicio físico en su prevención

Introducción. La prevalencia de la Diabetes Gestacional (DG) varía en todo el mundo, así como entre los grupos raciales y étnicos del mismo país. Hasta la fecha actual, no se ha llegado a un consenso en el criterio diagnóstico, y eso dificulta una estimación veraz de prevalencia entre países. A pesar de ello, es ineludible obviar el incremento en la incidencia de esta complicación en todo el mundo, y la trascendencia de sus riesgos a la salud pública. En España, según los criterios clásicos –del National Diabetes Data Group- existe una alta prevalencia en un 8,8 % de DG en gestantes. Es importante encontrar la mejor vía para la prevención de la DG y, uno de los factores de riesgo parece ser el aumento excesivo de peso durante el embarazo. El ejercicio es un elemento fundamental para el control del metabolismo de la glucosa y para reducir los niveles de hiperlipidemia. Sin embargo, existe controversia para definir el tipo de sesiones, duración e intensidad que puedan contribuir a su prevención. Objetivo. Conocer en qué medida el ejercicio físico programado durante el embarazo, combinado en agua y tierra, con ejercicios aeróbicos y de tonificación muscular, puede actuar como un factor de prevención de la DG. Al mismo tiempo, valorar si exceder las recomendaciones de peso puede influir el diagnóstico de la DG. Material y Métodos. Este estudio se desarrolló mediante una colaboración entre la Universidad Politécnica de Madrid y los Servicios de Ginecología y Obstetricia del Hospital Universitario de Puerta de Hierro, el Hospital Universitario de Torrelodones y el Centro de Salud de Torrelodones. Se obtuvo la aprobación del Comité Ético de Investigación Clínica (CEIC). Se realizó un ensayo clínico, aleatorizado, controlado, no enmascarado. 272 mujeres gestantes sanas dieron su consentimiento informado para la inclusión en el estudio. De las cuáles, finalmente 257 (edad= 33,2±4,4 años) fueron analizadas, 101 de ellas correspondientes al grupo intervención (GI, n=101) y 156 al grupo control (GC, n=156). El inicio del programa correspondió a la semana 10-14 del embarazo hasta el final, la 38-40. Con una frecuencia de 3 sesiones semanales y una duración de 60 y 50 minutos, en tierra y agua, respectivamente. Resultados. Se halló diferencias significativas en los valores en los 180 min del test de tolerancia oral a la glucosa [GI: 98,00±29,48 mg/dl vs. GC: 116,25±29,90 mg/dl (t64= 2,37; p= 0,021)] y, de igual modo, el GI mostró menor prevalencia de la DG [GI: 1 %, Ejercicio y DG n= 1 vs. GC: 8,8 %, n= 13 (2 1= 6,84; p= 0,009)] y una estimación de riesgo significativa (OR= 9,604; 95 % CI: 1,23-74,66). La excesiva ganancia de peso fue menor en el GI [GI: 22,8 %, n= 23 vs. GC: 34,9 %, n= 53 (2 1= 4,22; p= 0,040)], pero no existió una correlación con la incidencia de DG (ϕ= -0,007; p= 0,910). Conclusiones. El programa de ejercicio desarrollado durante el embarazo mostró efectividad en la reducción de la prevalencia de la DG, preservó la tolerancia a la glucosa y redujo la excesiva ganancia de peso materno. Background. The prevalence of Gestational Diabetes (GD) varies around the world, as well as between racial and ethnic groups within the same country. Currently, there is not a consensus about the diagnostic criteria, and that makes it difficult to obtain accurate estimates of prevalence between countries. The increased trend in the prevalence across the globe and the risks for public health cannot be ignored. In Spain, according to the diagnostic criteria of National Diabetes Data Group, there is a prevalence of 8.8 % for GD in pregnant women. It is important to look for the best way to prevent GD and one of the risk factors seems to be excessive weight gained during pregnancy. Exercise is an essential element for glucose metabolic control and reducing hyperlipidemia levels. However, there is controversy to define the type of activity, duration and intensity to prevent GD. Objective. To assess the effectiveness of an exercise programme carried out during pregnancy (land/aquatic activities), both aerobic and muscular conditioning can help to the prevent GD. Also, to assess if excessive maternal weight gain influences the GD diagnosis. Material and methods. Collaboration between the Technical University of Madrid and the Gynecology and Obstetrics Department of Puerta de Hierro University Hospital, Torrelodones University Hospital and Health Center of Torrelodones supported the study. It was approved by the Clinical Research Ethics Committee (CEIC). A clinical, randomized controlled trial recruited 272 pregnant women without obstetric contraindications and gave informed consent for inclusion in the study. Of these women, 257 were studied (age= 33,2±4,4 years), 101 in intervention group (IG, n= 101) and 156 in control group (CG, n= 156). A physical exercise program three times per week during pregnancy was developed. The duration of the sessions was 60 minutes and 50 minutes in land and water, respectively. Results. The IG showed lower maternal values in the Oral Glucose Tolerance Test (OGTT) at 180 minutes [IG: 98,00±29,48 mg/dl vs. CG: 116,25±29,90 mg/dl (t64= 2,37; p= 0,021)] and the IG reduced the prevalence of GD [IG: 1%, n= 1 vs. CG: 8,8 %, n= 13 (2 1= 6,84; p= 0,009)] with a significance risk estimate (OR= 9,604; 95 % CI: 1,23- 74,66). Excessive maternal weight gain was less in the IG [IG: 22,8 %, n= 23 vs. CG: Exercise and GD 34,9 %, n= 53 (2 1= 4,22; p= 0,040)] but there was no correlation with the prevalence of GD (ϕ= -0,007; p= 0,910). Conclusions. The exercise programme performed during pregnancy reduced the prevalence of GD, preserved glucose tolerance and reduced excessive maternal weight gain.

Exercise during pregnancy improves maternal glucose screen at 24-28 weeks: a randomised controlled trial

Objective. The influence of an exercise programme performed by healthy pregnant women on maternal glucose tolerance was studied. Study design. A physical activity (PA, land/aquatic activities) programme during the entire pregnancy (three sessions per week) was conducted by a qualified instructor. 83 healthy pregnant women were randomly assigned to either an exercise group (EG, n=40) or a control (CG, n=43) group. 50 g maternal glucose screen (MGS), maternal weight gain and several pregnancy outcomes were recorded. Results. Significant differences were found between study groups on the 50 g MGS. Values corresponding to the EG (103.8±20.4 mg/dl) were better than those of the CG (126.9±29.5 mg/dl), p=0.000. In addition, no differences in maternal weight gain and no cases of gestational diabetes in EG versus 3 in CG (7%) (p>0.05) were found. Conclusion. A moderate PA programme performed during pregnancy improves levels of maternal glucose tolerance.

Orexigenic Gene Expression in Late Gestation Ovine Foetal Hypothalamus is Sensitive to Maternal Undernutrition and Realimentation

Acknowledgements Research was funded by the Scottish Government's Rural and Environment Science and Analytical Services Division (RESAS), including the Strategic Partnership for Animal Science Excellence (SPASE). The authors have no conflicts of interest to declare.

Orexigenic Gene Expression in Late Gestation Ovine Foetal Hypothalamus is Sensitive to Maternal Undernutrition and Realimentation

Acknowledgements Research was funded by the Scottish Government's Rural and Environment Science and Analytical Services Division (RESAS), including the Strategic Partnership for Animal Science Excellence (SPASE). The authors have no conflicts of interest to declare.