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Aims/hypothesis: Dietary patterns characterised by high intakes of vegetables may lower the risk of pre-eclampsia and premature birth in the general population. The effect of dietary patterns in women with type 1 diabetes, who have an increased risk of complications in pregnancy, is not known. The aim of this study was to investigate the relationship between dietary patterns and physical activity during pregnancy and maternal complications and birth outcomes in women with type 1 diabetes. We also compared dietary patterns in women with and without type 1 diabetes., Methods: Diet was assessed in the third trimester using a validated food frequency questionnaire in participants followed prospectively in the multi-centre Environmental Determinants of Islet Autoimmunity (ENDIA) study. Dietary patterns were characterised by principal component analysis. The Pregnancy Physical Activity Questionnaire was completed in each trimester. Data for maternal and birth outcomes were collected prospectively., Results: Questionnaires were completed by 973 participants during 1124 pregnancies. Women with type 1 diabetes (n=615 pregnancies with dietary data) were more likely to have a 'fresh food' dietary pattern than women without type 1 diabetes (OR 1.19, 95% CI 1.07, 1.31; p=0.001). In women with type 1 diabetes, an increase equivalent to a change from quartile 1 to 3 in 'fresh food' dietary pattern score was associated with a lower risk of pre-eclampsia (OR 0.37, 95% CI 0.17, 0.78; p=0.01) and premature birth (OR 0.35, 95% CI 0.20, 0.62, p<0.001). These associations were mediated in part by BMI and HbA 1c . The 'processed food' dietary pattern was associated with an increased birthweight (β coefficient 56.8 g, 95% CI 2.8, 110.8; p=0.04). Physical activity did not relate to outcomes., Conclusions/interpretation: A dietary pattern higher in fresh foods during pregnancy was associated with sizeable reductions in risk of pre-eclampsia and premature birth in women with type 1 diabetes., (© 2024. The Author(s).)

Objective: Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii . Immunocompromised individuals and pregnant women are at risk, with the latter group being susceptible to miscarriages. This study aimed to determine the seropositivity of T. gondii antibodies and potential risk factors in pregnant women diagnosed with diabetes mellitus., Methods: The research was conducted at the Ankara City Hospital Perinatology Clinic between October 2021 and June 2022. The study included 277 pregnant women diagnosed with diabetes mellitus and 277 healthy pregnant women who had given birth. Retrospective analysis of anti- T. gondii immunoglobulin (Ig)G and IgM levels was performed for patients between January 2020 and February 2022. Participants were administered an informed consent form and a questionnaire. Data were analysed using SPSS 22., Results: Among pregnant women with diabetes, IgG seropositivity was 18.4%, IgM was 0.0%, and IgG+IgM was 0.0%. In healthy pregnant women, IgG seropositivity was 12.3%, IgM was 0.4%, and IgG+IgM was 0.4%. Overall, seropositivity rates were 15.3% for IgG, 0.2% for IgM, and 0.2% for IgG+IgM. The difference between the two groups was statistically significant (p<0.05). Among pregnant women with diabetes, there was a significant statistical difference (p<0.05) in anti- T. gondii IgG seropositivity related to education, employment status, number of pregnancies and live births, history of toxoplasmosis diagnosis in children, previous toxoplasmosis diagnosis, hygiene, nutrition, and social habits. Among healthy pregnant women, significant statistical differences were found (p<0.05) in IgG seropositivity related to age, income, education level, number of pregnancies and live births, previous toxoplasmosis diagnosis, hygiene, nutrition, and social habits. No invasive interventions were performed on infants born to seropositive mothers, and perinatal data were not available., Conclusion: The seroprevalence of toxoplasmosis in Ankara appears to be decreasing, but T. gondii infections continue to pose a public health concern and are significant in pregnant women with diabetes mellitus., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

Group B Streptococcus (GBS), also known as Streptococcus agalactiae is a Gram-positive bacterium commonly encountered as part of the microbiota within the human gastrointestinal tract. A common cause of infections during pregnancy, GBS is responsible for invasive diseases ranging from urinary tract infections to chorioamnionitis and neonatal sepsis. Diabetes mellitus (DM) is a chronic disease resulting from impaired regulation of blood glucose levels. The incidence of DM has steadily increased worldwide to affecting over 450 million people. Poorly controlled DM is associated with multiple health comorbidities including an increased risk for infection. Epidemiologic studies have clearly demonstrated that DM correlates with an increased risk for invasive GBS infections, including skin and soft tissue infections and sepsis in non-pregnant adults. However, the impact of DM on risk for invasive GBS urogenital infections, particularly during the already vulnerable time of pregnancy, is less clear. We review the evolving epidemiology, immunology, and pathophysiology of GBS urogenital infections including rectovaginal colonization during pregnancy, neonatal infections of infants exposed to DM in utero, and urinary tract infections in pregnant and non-pregnant adults in the context of DM and highlight in vitro studies examining why DM might increase risk for GBS urogenital infection., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

During the last decades the incidence of diabetes has dramatically increased as well as the number of pregnant diabetic women. There is still missing data regarding patterns and shifts of immune cell populations due to pregnancy with or without diabetes. The study aimed to investigate the impact of pregnancy, type 1 diabetes (T1D) and gestational diabetes mellitus (GDM) on different immune cells in female. The number and proportion of CD3-, CD4-, CD8- and γδ T-cells as well as B-, NK-, NKT- and dendritic cells (DC) incl. rate of apoptosis was analyzed in peripheral blood samples from 24 non-pregnant women, 24 pregnant controls, 25 non-pregnant T1D, 18 women with GDM and 15 pregnant T1D (PT1D) women. Compared to healthy controls, healthy pregnant women had reduced numbers of lymphoid DC and γδ T-cells, while women with gestational diabetes presented with increased numbers of γδ T-cells. Pregnant women with T1D showed increased NKT cells and a decrease of NK cells compared to healthy pregnant or non-pregnant T1D women. Apoptosis of γδ T-cells in healthy pregnant women was found to be decreased in comparison to their non-pregnant controls while apoptosis of myeloid and lymphoid DC was increased in pregnant T1D in comparison to non-pregnant T1D. Those results may indicate that increased complication rates during diabetic pregnancies might be due to an impaired adaptation of the immune system., Competing Interests: Conflicts of Interest: The authors have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Diabetes mellitus (DM) during pregnancy causes congenital malformation, macrosomia, respiratory distress syndrome, and other abnormalities in neonates, but whether maternal DM affects the neonatal innate immune system is unknown. Therefore we aimed to reveal the influence of DM in pregnancy on the toll-like receptor (TLR)-mediated innate immune response in neonates. Cord blood was collected after full-term vaginal or cesarean delivery and classified into a DM group (n=8) and non-DM (control) group (n=7). Mononuclear cells were harvested from cord blood by using density gradient centrifugation, after which anti-CD14 magnetic beads were used to isolate monocytes from the mononuclear population. After monocytes were cultured with lipopolysaccharide (TLR4 ligand), flagellin (TLR5 ligand), Pam3CSK4 (TLR1/TLR2 ligand), zymosan (TLR2/TLR6 ligand), or macrophage-activating lipopeptide (TLR2/TLR6 ligand) for 12h, the cytokine levels (interleukin [IL]-8, IL-6, IL-1β, IL-10, tumor necrosis factor alpha and IL-12) in the culture supernatants were measured. Compared with the control group, the DM group had higher concentrations of IL-8 (P=0.01) and tumor necrosis factor alpha (P=0.02) after monocyte cultures were stimulated with Pam3CSK4 and higher concentrations of IL-8 (P=0.01) after flagellin treatment. In contrast, stimulation with lipopolysaccharide, zymosan, or macrophage-activating lipopeptide did not lead to any difference in cytokine profiles between the two groups. These data indicate that maternal DM induces excessive inflammatory activation in neonates via a TLR5- or TLR1/2-mediated innate immune response., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: The present study evaluated the cells and cytokine of maternal blood, cord blood and colostrum of diabetic mothers., Methods: 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., Results: 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., Conclusion: The results obtained suggest that maternal hyperglycemia modifies the phenotypes of T cells and cytokines profile in maternal, cord blood and colostrum.

In pregnancy, the immunologic system plays an important role that ensures normal pregnancy development and can as well promote the development of complications. Pregnancy success appears to rely on a discrete balance between the Th cytokines, which are involved in fetal growth and development. Preeclampsia and gestational diabetes are known complications associated with pregnancy. However, the source of the increased IL-17 cytokine in preeclampsia and other pregnancy associated diseases still remains unclear amidst numerous inconsistencies. The recent identification of innate lymphoid cells (ILC) has raised more doubts about the sources of most of the Th associated cytokines. We investigated the source of peripheral IL-17 levels in preeclamptic, gestational diabetics and chronic diabetics compared to healthy pregnancy subjects. To evaluate the source of the increased IL-17 cytokine among preeclampsia, chronic diabetic and gestational diabetic patients we investigated the proportion of Th17 cell populations in peripheral blood mononuclear cells using flow cytometry as well as analyzing levels of IFN-γ, IL-17, IL-1β and HMGB1. This study found that the Th17 cell populations in peripheral blood of preeclamptic, gestational nor chronic diabetes during pregnancy did not correlate with the increased IL-17. We report that the increased IL-17 levels observed in patients with preeclampsia, gestational diabetes and chronic diabetes are associated with innate lymphoid cells 3 (ILC3) and may pose threats to the fetus if disregulated.

Introduction: Type 1 diabetes (T1D) is associated with adverse pregnancy outcome, usually attributed to hyperglycemia. Recently, we showed that pregnancy outcome in normoglycemic T1D rats was characterized by decreased fetal and placental weight, suggesting impaired placental development. In the present study, we tested the hypothesis that trophoblast invasion and spiral artery (SA) remodeling is impaired in T1D rats ant that this is associated with aberrant local presence of NK cells and macrophages in the mesometrial triangle (MT)., Methods: Placentae with MT from pregnant biobreeding diabetes-prone (BBDP; T1D model) rats, control biobreeding diabetes-resistant (BBDR) and Wistar-rats were dissected at day 18 of gestation and stained for trophoblast invasion, SA remodeling, uNK cells and macrophages., Results: Interstitial trophoblast invasion and SA remodeling was impaired in BBDP-rats vs. control rats, coinciding with increased presence of NK cells and an increased iNOS+/CD206+ ratio of macrophages., Discussion: Decreased fetal and placental weight in BBDP-rats was associated with diminished interstitial trophoblast invasion and less optimal SA remodeling, increased numbers of NK cells and increased iNOS+/CD206+ macrophage ratio in the MT of BBDP-rats., Conclusions: The impaired trophoblast invasion and SA remodeling may be due to an aberrant local immune-response and may result in damage to the fetal placenta and insufficient supply of nutrients towards the fetus with eventually decreased fetal weight as a consequence., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Type 1 diabetes is preceded by the appearance of islet autoantibodies. Seroconversion to islet autoantibodies is greatest around 1 yr of age and is more frequent in children born to fathers with type 1 diabetes as compared to children born to mothers with type 1 diabetes. Here we asked whether changes in beta-cell function in the neonate and infant reflect variations in the incidence of islet autoantibody seroconversion. Insulin, proinsulin, and c-peptide concentrations were measured in sequential samples taken from birth to age 2 yr in 103 children who had a first degree relative with type 1 diabetes and who had been followed for islet autoantibody seroconversion. Serum insulin and proinsulin concentrations were highest at birth declining by age 3 months and stable thereafter until age 2 yr. C-peptide concentrations, proinsulin/insulin, and proinsulin/c-peptide ratios were stable from age 3 months. No differences were observed between children who developed islet autoantibodies and children who remained islet autoantibody negative. Children born to a mother with type 1 diabetes had higher birth concentrations of insulin (p = 0.005) and proinsulin (p = 0.014) as compared with children of non-diabetic mothers. Increased insulin concentrations in children of type 1 diabetes mothers persisted until age 6 months. In conclusion, we could not relate excursions in beta-cell hormones to autoantibody development, but suggest that the higher exposure to insulin and proinsulin in neonates born to mothers with type 1 diabetes may be linked to the relative protection against islet autoantibody seroconversion observed in these children., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A 33-year-old woman with type 2 diabetes mellitus (DM) was suspected of being primarily infected with Toxoplasma gondii at 12 weeks of gestation (GW). Although acetylspiramycin was started at 17 GW, the T. gondii DNA gene was detected in the amniotic fluid at 18 GW. Chemotherapy was changed to pyrimethamine plus sulfadiazine from 20 GW, but was changed back to acetylspiramycin after 2 weeks because of vomiting. Acetylspiramycin was continued until her delivery. DM was controlled well during the pregnancy. An asymptomatic male baby was born by cesarean section at 37 GW, and was treated with acetylspiramycin for 4 weeks because the polymerase chain reaction results of umbilical cord blood were positive. He has developed normally until the present, that is, 6 months of age. Herein, we describe a case report in which symptomatic congenital toxoplasmosis was avoided in a pregnant woman with an immunosuppressive risk due to prompt chemotherapy., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Objective: The aim of the study was to evaluate the significance of the presence of thyroid peroxidase autoantibodies (anti-TPO Abs) in type 1 diabetes mellitus (DM1) pregnant women relative to the course of pregnancy and, especially, with regard to metabolic control, thyroid function, maternal complications and neonatal outcome., Methods: In a prospective observational study of 91 DM1 women with singleton pregnancies, anti-TPO, anti-thyroglobulin, thyroid-stimulating hormone (TSH), and free thyroxine index (T4/thyroid binding capacity) were measured in each trimester. At each visit, HbA1c, body mass index, and units of insulin per kilogram were recorded, as were complications and pregnancy outcome., Results: Twenty-one (27%) of the 78 women who met the inclusion criteria presented with positive anti-TPO Abs. There were no differences regarding glycemic control (HbA1c) or insulin dose. First-trimester TSH levels were significantly higher in the anti-TPO-positive group than in the anti-TPO-negative group. Finally, no differences were observed regarding diabetic or obstetric complications and neonatal outcome., Conclusion: One fourth of DM1 pregnant women presented with positive anti-TPO Abs. However, the presence of anti-TPO Abs does not seem to be related with worse metabolic control or adverse pregnancy outcome. Further investigation is needed; meanwhile, the effort for early treatment of thyroid dysfunction and strict metabolic control in all DM1 women should be continued.

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 90-110D 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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored., (Copyright © 2013 Wiley Periodicals, Inc.)

Introduction: Despite tight glycemic control, pregnancy complication rate in type 1 diabetes patients is higher than in normal pregnancy. Other etiological factors may be responsible for the development of adverse pregnancy outcome. Acceptance of the semi-allogeneic fetus is accompanied by adaptations in the maternal immune-response. Maladaptations of the immune-response has been shown to contribute to pregnancy complications. We hypothesized that type 1 diabetes, as an autoimmune disease, may be associated with maladaptations of the immune-response to pregnancy, possibly resulting in pregnancy complications., Methods: We studied pregnancy outcome and pregnancy-induced immunological adaptations in a normoglycemic rat-model of type 1 diabetes, i.e. biobreeding diabetes-prone rats (BBDP; 5 non-pregnant rats, 7 pregnant day 10 rats and 6 pregnant day 18 rats) , versus non-diabetic control rats (i.e. congenic non-diabetic biobreeding diabetes-resistant (BBDR; 6 non-pregnant rats, 6 pregnant day 10 rats and 6 pregnant day 18 rats) and Wistar-rats (6 non-pregnant, 6 pregnant day 10 rats and 5 pregnant day 18 rats))., Results: We observed reduced litter size, lower fetal weight of viable fetuses and increased numbers of resorptions versus control rats. These complications are accompanied by various differences in the immune-response between BBDP and control rats in both pregnant and non-pregnant animals. The immune-response in non-pregnant BBDP-rats was characterized by decreased percentages of lymphocytes, increased percentages of effector T-cells, regulatory T-cells and natural killer cells, an increased Th1/Th2-ratio and activated monocytes versus Wistar and BBDR-rats. Furthermore, pregnancy-induced adaptations in BBDP-rats coincided with an increased Th1/Th2-ratio, a decreased mean fluorescence intensity CD161a/NKR-P1b ratio and no further activation of monocytes versus non-diabetic control rats., Conclusion: This study suggests that even in the face of strict normoglycemia, pregnancy complications still occur in type 1 diabetic pregnancies. This adverse pregnancy outcome may be related to the aberrant immunological adaptations to pregnancy in diabetic rats.

Background: Populations in Africa mostly rely on herbal concoctions for their primarily health care, but so far scientific studies supporting the use of plants in traditional medicine remain poor. The present study was undertaken to evaluate the anti-hyperglycemic effects of Picralima nitida (seeds), Nauclea latifolia (root and stem) and Oxytenanthera abyssinica (leaves) commonly used, in diabetic pregnancy., Methods: Pregnant wistar rats, rendered diabetic by multiple low injections of streptozotocin, were treated with selected plant extracts based on their antioxidant activities. Vitamin C concentrations, fatty acid compositions and phytochemical analysis of plants extracts were determined. Effect of selected plant extracts on human T cell proliferation was also analysed., Results: All analysed plant extracts exhibited substantial antioxidant activities probably related to their content in polyphenols. Picralima nitida exhibited the highest antioxidant capacity. Ethanolic and butanolic extracts of Picralima nitida, butanolic extract of Nauclea latifolia and ethanolic extract of Oxytenanthera abyssinica significantly decreased hyperglycemia in the diabetic pregnant rats. Butanolic extract of Picralima, also appeared to be the most potent immunosuppressor although all of the analysed extracts exerted an immunosuppressive effect on T cell proliferation probably due to their linolenic acid (C18:3n-3) and/or alkaloids content. Nevertheless, all analysed plants seemed to be good source of saturated and monounsaturated fatty acids., Conclusion: By having antioxidant, anti-hyperglycemic and immunosuppressive activities, these plants could be good candidates in the treatment of diabetes and diabetic pregnancy.

Fulminant Type 1 diabetes is a subtype of Type 1 diabetes characterized by (1) abrupt onset of diabetes, (2) very short duration of hyperglycaemia with mildly elevated HbA(1c) (< 69 mmol/mol, 8.5%), (3) rapid progression to diabetic ketoacidosis, (4) very low C-peptide level, and (5) often associated with elevated serum pancreatic enzymes, and absence of diabetes-related autoantibodies. We encountered a case of fulminant Type 1 diabetes that developed with an initial manifestation of the insulin autoimmune syndrome and rapidly progressed to diabetic ketoacidosis during pregnancy. A 31-year-old Korean woman presented with recurrent sudden onset of sweating and change of consciousness during sleep at 19 weeks gestation. During a 72-h fasting test, hypoglycaemia (1.72 mmol/l) occurred at 4 h after the start of the test. At that time, there was a high insulin level (370.2 μU/ml), a paradoxically low C-peptide level (0.01 nmol/l) and a positive insulin autoantibody test. An oral glucose tolerance test revealed postprandial hyperglycaemia. She was initially diagnosed as the insulin autoimmune syndrome. On the day 5 of admission, she developed diabetic ketoacidosis. Her HbA(1c) was 62 mmol/mol (7.8%). The rapid progression of diabetic ketoacidosis altered the diagnosis to fulminant Type 1 diabetes. This case differed from typical fulminant Type 1 diabetes because it presented with hypoglycaemia, and positive insulin and anti-phospholipid antibody tests. Her HLA typing was HLA-DQA1*0302, 0501, HLA-DRB1*0301 (DR3), 0901(DR9). Her glucose level was subsequently very well controlled with multiple insulin injections and she successfully delivered a healthy baby., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Aims: This study was conducted to evaluate maternal and placental concentrations of interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF-α) in pregnant women with glycemic mean (GM) < or ≥100 mg/dL, as well as correlate IL-10 and TNF-α placental concentrations with perinatal outcomes., Methods: One hundred eighty-six pregnant women were distributed in groups determined by a GM <100 mg/dL or a GM ≥100 mg/dL. The GM, HbA1c levels, maternal and placental concentrations of IL-10 and TNF-α, and the correlation of placental cytokines with perinatal outcomes were evaluated., Results: In maternal blood, the lowest concentrations of IL-10 (p = 0.0019) and TNF-α (p = 0.0185) were observed in the GM ≥100-mg/dL group. The placentas from GM ≥100 mg/dL group exhibited higher TNF-α concentrations (p = 0.0385). Placental IL-10 directly correlated with hemoglobin (r = 0.63; p = 0.02) and insulin (r = 0.78; p = 0.01) levels in the umbilical cord and with 1-min (r = 0.53; p = 0.0095) and 5-min (r = 0.69; p = 0.0003) Apgar scores. Placental TNF-α displayed a tendency to inversely correlate with fetal weight (r = -0.41; p = 0.05)., Conclusion: Compared to GM <100 mg/dL, GM ≥100 mg/dL was associated with a reduction in maternal IL-10 and TNF-α concentrations and increased placental TNF-α production. Placental IL-10 production was similar in both groups studied and directly correlated with hemoglobin and umbilical cord insulin levels, as well as with the 1- and 5-min Apgar scores.

Objectives: Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in placental development and function, although related to the pro-inflammatory environment when produced in excess. Previous studies have identified MMP-2 and MMP-9 overactivities in the placenta from diabetic rats. In this study, we aimed to determine whether diets supplemented with olive and safflower oil, enriched in natural PPAR ligands, are able to regulate MMP-2 and MMP-9 activities in the placenta and serum from diabetic rats., Study Design: Diabetes was induced in rat neonates by streptozotocin administration (90mg/kg s.c.). Control and diabetic rats were fed with 6% olive oil- or 6% safflower oil-supplemented diets from days 0.5-13.5 of gestation., Main Outcome Measures: On day 13.5 of gestation, placentas and sera were isolated for further determination of matrix metalloproteinases (MMPs) 2 and 9 activities by zymography. Placental MMP-2 and MMP-9 protein concentration and immunolocalization were also determined., Results: Sera from diabetic pregnant animals showed MMP-2 and MMP-9 overactivities when compared to controls. Serum MMP-9 activity was significantly decreased when the diabetic animals received the olive and safflower oil dietary treatments. Placentas from diabetic rats showed increased MMP-2 and MMP-9 activities and protein concentrations, and both were decreased when diabetic rats received the olive and safflower dietary treatments., Conclusions: This study demonstrates that both olive and safflower oil-supplemented diets were able to prevent MMPs overactivities in the placenta from diabetic rats, and that these beneficial effects are reflected in rat sera., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Aim of the Study: To evaluate the correlations between Zn2+, Cu2+, Mg2+, Se2+ and Cr3+ and alteration in T cell subsets during diabetic and normal pregnancy., Methods: The study involved 63 women with gestational diabetes mellitus (GD) and 16 pregnant women with Type 2 diabetes and 48 healthy, non-pregnant women were included as controls. Ten ml of whole venous blood from each participant was analyzed for electrolytes by atomic absorption; total antioxidant activity, individual enzymatic antioxidants by spectrophotometry; and lymphocyte sub-populations by flow cytometry., Results: There were significant changes in lymphocyte sub-populations: Naïve T cells were decreased and memory T-cells and activated T cells (CD4+HLA-DR+, CD4+CD29+) were increased in diabetes in pregnancy. Zn2+ and Cr3+ deficiency were observed in Type 2 diabetics with an increase in Cu2+ in all pregnant cohorts. In healthy pregnant subjects, CD4+-HLA-DR+ was increased in direct proportion to serum Mg2+ (p<0.05) and Se2+ (p<0.01). In insulin-treated GD patients, CD4+CD29+ cells were increased proportionally to serum Zn2+ (p<0.05) while in diet controlled GD cohort CD45RO+/ CD45RA+ T cells correlated directly with serum Mg (p<0.05) and Zn2+ (p<0.01) while it correlated inversely with serum Cu2+ (p<0.01)., Conclusions: The results of the present study show a correlation between trace element deficiency and increased lipid peroxidation in diabetes in pregnancy and lymphocyte activation. Dietary manipulation may, therefore, point to improvement in existing approaches to management of diabetes mellitus in pregnancy., (Copyright © 2012 by Academy of Sciences and Arts of Bosnia and Herzegovina.)

This study was carried out with hyperglycemic pregnant women to investigate the transfer of antibody classes to newborns across the placenta or by colostrum and the functional activity of phagocytes in maternal blood, cord blood, and colostrum from diabetes mothers. Samples from maternal blood, cord blood, and colostrum were collected from 20 normoglycemic and 20 hyperglycemic pregnant women. We determined antibodies levels, superoxide release, phagocytosis and bactericidal activity of phagocytes. We demonstrated that IgG levels in cord blood were higher in the hyperglycemic group. IgA and IgM levels were higher in maternal than in cord blood samples. Plasma antibody levels were lower in hyper- than in normoglycemic women. The colostrum of diabetic mothers had lower IgA and IgG levels. Colostrum and maternal blood phagocytes when exposed to EPEC increased the superoxide release. Cord blood phagocytes of hyperglycemic group, independently of bacteria, had higher superoxide release. Colostrum and blood phagocytes from diabetic group exhibited some phagocytic and microbicidal activity in response to EPEC. Mononuclear phagocytes from cord blood had the lowest phagocytosis, and bactericidal activity for EPEC, regardless of glycemic status. These data showed that hyperglycemia altered IgG transfer across the placenta and decreases immunoglobulin levels in maternal blood and colostrum.

The effects of secretory immunoglobulin A (SIgA) interaction with its specific Fcα receptors on colostral phagocytes needs further investigation, especially with respect to diabetic women. Accordingly, we studied the colostrum of hyperglycemic women to assess SIgA interactions with Fcα receptors of macrophages as well as the functional activity of these cells. The women were divided for colostrum sampling according to their glycemic status: normoglycemia (N = 51), mild hyperglycemia (N = 23), and diabetes (N = 25) groups. We determined the FcαR expression, the IgA on the surface and the surface-bound IgA in colostrum macrophages. We also evaluated the superoxide release and bactericidal killing of these cells. Colostral phagocytes expressed FcαR, contained IgA on the surface and are able to bind to purified SIgA. The bactericidal activity of colostral phagocytes from the hyperglycemic women was similar to that of normoglycemic only when SIgA was used as opsonin. Addition of a MoAb anti-human Fcα receptor resulted in a significant decrease of superoxide release and bacterial killing by macrophages when bacteria were opsonized with purified SIgA, suggesting an interaction between SIgA and FcαR. The stimulatory effects of SIgA on the functional activity of phagocytes therefore protect infants, especially of diabetic women, against intestinal infections., (© 2011 The Authors. APMIS © 2011 APMIS.)

Background: Human uterine natural killer (uNK) cells, the dominant lymphocytes in early pregnancy decidua, are important for spiral arterial remodelling. uNK cells are thought to arise from circulating CD56(bright) NK cells that egress into decidualizing endometrium. Both incomplete spiral arterial modification and aberrant NK cell function have been linked with pre-eclampsia, a syndrome that is more prevalent in diabetic women. Since previous in vitro studies have shown that changes in decidual endothelium induced by type 1 diabetes (T1D) reduce its interactions with circulating leucocytes, we hypothesized that diabetes additionally has direct effects on circulating CD56(+) NK cells that impair their decidual homing potential., Methods: Serial blood samples were collected from control, T1D and T2D pregnant women throughout and after pregnancy. In vitro adhesion under shear forces was used to assay the functional capacity of circulating leucocytes and of CD56(+) cells to adhere to endothelium in cryostat sections of gestation day (gd) 7 normal mouse decidua, pancreas and lymph node., Results: Fewer CD56(+) cells from diabetic compared with control women adhered to normal decidual endothelium. The CD56(+) cell/total cell adhesion ratio was also lower in diabetics. More diabetic CD56(+) cells adhered to pancreatic endothelium and their proportion was greater than for controls. Neither absolute nor proportional adhesion of CD56(+) cells to lymph node endothelium differed between diabetics and controls., Conclusions: The CD56(+) cell adhesion patterns of T1D and T2D women differ from those of non-diabetic women and support the hypothesis that diabetes impairs mechanisms that could be used by CD56(+) cells for egress into decidua.

The adverse outcomes on the offspring from maternal diabetes in pregnancy are substantially documented. In this paper, we report main knowledge on impacts of maternal diabetes on early and long-term health of the offspring, with specific comments on maternal obesity. The main adverse outcome on progenies from pregnancy complicated with maternal diabetes appears to be macrosomia, as it is commonly known that intrauterine exposure to hyperglycemia increases the risk and programs the offspring to develop diabetes and/or obesity at adulthood. This "fetal programming", due to intrauterine diabetic milieu, is termed as "metabolic memory". In gestational diabetes as well as in macrosomia, the complications include metabolic abnormalities, degraded antioxidant status, disrupted immune system and potential metabolic syndrome in adult offspring. Furthermore, there is evidence that maternal obesity may also increase the risk of obesity and diabetes in offspring. However, women with GDM possibly exhibit greater macrosomia than obese women. Obesity and diabetes in pregnancy have independent and additive effects on obstetric complications, and both require proper management. Management of gestational diabetes mellitus and maternal obesity is essential for maternal and offspring's good health. Increasing physical activity, preventing gestational weight gain, and having some qualitative nutritional habits may be beneficial during both the pregnancy and offspring's future life., (Copyright © 2011 A. Yessoufou and K. Moutairou.)

Background: Progression of diabetic retinopathy occurs at least temporarily during pregnancy. Although the cause of this progression is not entirely understood, the immune phenomenon and chronic inflammation may play a significant role. During pregnancy in order to avoid fetus rejection, certain components of the immune system that are knowingly implicated in the pathogenesis of diabetic retinopathy are activated including generalized leukocyte activation and an increase in certain cytokine plasma levels. Activated leukocytes with up regulated adhesion molecules have an increased potential to bind to the endothelium cells of blood vessels. Leukocyte-endothelial interaction and the consequent leukostasis with capillary occlusion, ischemia and vascular leakage have a substantial role in the development of diabetic retinopathy. Furthermore, certain increased cytokines are known to cause blood-retinal-barrier breakdown whilst others promote angiogenic and fibrovascular proliferation and thereby can also be implicated in the pathogenesis of this diabetic complication., Presentation of the Hypothesis: We hypothesized that the activation of the immune system during gestation may have an influence on the course of retinopathy in pregnant diabetic women., Testing the Hypothesis: We suggest two prospective follow up studies conducted on women with type 1 diabetes mellitus. The first study would include a group of non-pregnant women and a group of diabetic women undergoing normal pregnancy matched for age and duration of diabetes. In the second study pregnant women would be divided into two groups: one with normal pregnancy and the other with preeclampsia. The procedure and data collection in both studies will be identical: a complete ophthalmological examination, glycaemic control, blood pressure measurement and venous blood samples for the determination of plasma levels of cytokines (TNF-alpha, IL-1beta, IL-6, IL-8) and adhesion molecules (ICAM-1, VCAM-1)., Implications of the Hypothesis: Considering the present assumption, the gestational immune activation could be suggested as a potential risk factor for the development and progression of retinopathy in diabetic women. A better understanding of immunomodulatory effects of pregnancy on diabetic retinopathy pave the way for further investigations of the mechanism of its pathogenesis and could be essential for novel approaches to the treatment of this serious sight threatening complication of diabetes mellitus.

The course of the diabetes type I at pregnants (n=120) with different levels of idiotypic (ABI) and antiidiotypic (AB2) antibodies to insulin was investigated. It is known that AB2 to insulin can interact with insulin receptor. It was shown that changes of levels AB1 and AB2 to insulin are often observed at pregnants suffered from diabetes type I. Isolated high levels of AB1 to insulin is relatively good prognostic sign of the course of the diabetes type I at pregnants. On the contrary, isolated high levels of AB2 to insulin lead to decompensation of the diabetes type I and deep glycohemia. High levels of AB1 and AB2 to insulin together lead to unstable course of the diabetes type I. The same situation is observed in case of abnormal low levels AB1 and AB2 to insulin, taking into consideration that serum of health people contains the certain level of autoantibodies (AB1 and AB2) to insulin. The conclusion about significance of detection AB1 and AB2 to insulin during pregnancy of patients with diabetes type I was made.

The levels of idiotypic (AB1) and antiidiotypic (AB2) antibodies were investigated in pregnants (n = 248) suffer from diabetes. It was proved that AB2 to insulin conditionally can be regards as antibodies to insulin receptor. It was shown that condition of newborns much depends on levels of these antibodies and their proportion. Condition of newborns from women with isolated high levels of AB1 to insulin was much better in comparison with ones from mothers with isolated high levels of AB2 to insulin. Conception about mechanisms of acting of AB1 and AB2 to insulin on fetus was represented.

Background: Unlike other strains, spontaneously type 1 non-obese diabetic (NOD) experience transient hyperinsulinemia after weaning. The same applies for NOD/SCID mice, which lack functional lymphocytes, and unlike NOD mice, do not develop insulitis and diabetes like NOD mice., Aims: Given that beta-cell stimulation is a natural feature of gestation, we hypothesized that glucose homeostasis is disturbed in gestate pre-diabetic NOD and non-diabetic NOD/SCID mice, which may accelerate the onset of diabetes and increase diabetes prevalence., Methods: During gestation and postpartum, mice were analyzed under basal feed conditions followed by glucose injection (1 g/kg, i.p.) after overnight fast, using glucose tolerance test (GTT). Glycemia, corticosteronemia, blood and pancreatic insulin, glucagon levels, islet size, and islet morphology were evaluated. Glycemia and mortality were assessed after successive gestations in NOD mice mated for the first time at 2 different ages., Results: 1. Basal glucagonemia rose markedly in first-gestation fed NOD mice. 2. beta-cell hyperactivity was present earlier in first-gestation non-diabetic fasted NOD and NOD/SCID mice than in age-matched C57BL/6 mice, assessed by increased insulin/glucose ratio after GTT. 3. Overnight fasting increased corticosteronemia rapidly and sharply in pre-diabetic gestate NOD and NOD/SCID mice. 4. Islet size increased in non-diabetic gestate NOD mice compared with C57BL/6 mice. 5. Successive gestations accelerated diabetes onset, and contributed to increased mortality in NOD mice., Conclusions: First-gestation pre-diabetic NOD and non-diabetic NOD/SCID mice exhibited beta-cell hyperactivity and deregulation of glucagon and/or corticosterone secretion. This amplified normally occurring insulin resistance, further exhausted maternal beta-cells, and accelerated diabetes in NOD mice.

Problem: Interleukin (IL)-12, IL-10, tumor necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 alter as pregnancy progresses, implying continuous immune regulation associated with the maintenance of pregnancy. We aimed to evaluate the peripheral blood neutrophil-derived production of these cytokines in the course of pregnancy complicated by type 1 diabetes., Method: of study These parameters were measured in samples from healthy non-pregnant (C), diabetic non-pregnant (D), healthy pregnant (P) and pregnant diabetic (PD) women., Results: Neutrophil-derived secretion of TNF-alpha and IL-12 increased along with progression of pregnancy in PD and P groups. The concentration of IL-10 from lipopolysaccharide (LPS)-stimulated neutrophils increased during the course of uncomplicated pregnancy but decreased in diabetic pregnancy. Concentration of IL-8 decreased with the advancing gestational age in P and PD groups. LPS-stimulated neutrophil-derived IL-6 concentration increased only in PD patients., Conclusion: Our results show that diabetes creates pro-inflammatory environment thus potentially influencing the outcome of pregnancy. We conclude that neutrophil-derived cytokine production could contribute to the complications seen in pregnant women with type 1 diabetes.

The immune-competent cells of placenta play the important role in protection of developing fetus against infectious agents; but their dysfunction can lead to development of placental insufficiency that affects health both fetus and mother. The aim of this study was the comparative analysis of presence of immune competent cells in villous chorion of mature placenta, taken from women with diabetes of different age groups. In our study we found three subpopulations of immune cells in villous chorion of mature placenta: natural killer cells (NK), B-lymphocytes and macrophages. Prevailing subpopulation are macrophages, they are detected 1,8 times more often than B-lymphocytes, and 2,3 times more often than NK. The quantity of immune competent cells in groups with diabetes of various types is different. Thus, the greatest number of macrophages was detected in group with diabetes type II of middle age (29-35 years)-- 4.62 +/- 0.93%, B-lymphocytes in group of women with diabetes type I of younger age (18-28 years)--2.50 +/- 0.30%, NK-cells in group with diabetes type I of younger age--1.98 +/- 0,42%. Analysis of received data showed the differences in expression of markers of immune cells in women of different age groups, which brings about the conclusion of various reactance of immune system of women with diabetes depending on age.

In preeclampsia, there is exacerbation of physiological changes associated with pregnancy such as insulin resistance, altered immune responses and inflammatory pathway activation. These exaggerated responses seen in preeclampsia are reminiscent of metabolic syndrome, and also are evident in gestational diabetes mellitus. The link between these phenomena is not clear but novel findings providing some insight have been reported recently. Inositol phosphoglycan P-type (P-IPG) in preeclampsia has been extensively investigated and increased production has been demonstrated. This molecule acts as a second messenger of insulin, enhances the metabolic effects of insulin and is associated with insulin resistance. This review article summarizes current evidence of the role of inositol phosphoglycans in the metabolic syndrome that occurs in preeclampsia, discussed in the light of modifications found in gestational diabetes mellitus and diabetes type 2 in pregnancy in humans and animal models. An increase in urinary release of P-IPG during pregnancy may herald the onset of preeclampsia. Further knowledge about the nature of the metabolic syndrome during preeclampsia and the degree of association between its components will help to inform future research efforts and to identify biochemical markers that could help in clinical practice, for example early markers that will have utility in managing disease progression.

Background: Previous work in our laboratory showed reduced myocardium and dilated ventricular chambers in gestation day (GD) 17 hearts that were collected from hyperglycemic CD1 mouse dams. Pre-breeding maternal immune stimulation, using Freund's complete adjuvant (FCA), diminished the severity of these fetal heart lesions. The following experiments were performed to detect possible changes in fetal heart apoptotic cell death, under hyperglycemic conditions and with or without maternal immune stimulation., Methods: Female CD1 mice were injected with 200 mg/kg of streptozocin (STZ) to induce insulin-dependent diabetes mellitus. Half of these mice received prior FCA injection. Fetal hearts were collected on GD 17 and myocardial apoptotic cells were quantified using flow cytometry. A panel of apoptosis regulatory genes (Bcl2, p53, Casp3, Casp9, PkCe) was then examined in the fetal myocardium using RT-PCR., Results: Early apoptotic cells and late apoptotic/necrotic cells were significantly increased in fetal hearts from STZ or STZ+FCA dams. Pre-treatment with FCA reduced late apoptotic/necrotic cells to control level, suggesting some cell death protection was rendered by FCA. Paradoxically in the face of such increased cell death, the expression of pro-apoptotic genes Casp3 and Casp9 was decreased by diabetes, while the anti-apoptotic gene Bcl2 was increased., Conclusions: Maternal hyperglycemia causes dys-regulated apoptosis of fetal myocardial cells. Such effect may be prevented by maternal immune stimulation., ((c) 2009 Wiley-Liss, Inc.)

Unlabelled: Perfect maternal diabetes compensation is crucial for the outcome of the baby. However, little is known how hyperglycaemia influences the specific immune response. Furthermore, babies of type 1 diabetes (T1D) mothers have less risk of development T1D than babies with a T1D father. This study aimed to analyze the effect of maternal hyperglycaemia on newborns with focus on the response to diabetes-associated autoantigens., Populations: (1) Newborns of T1D mothers split into groups according to maternal diabetes compensation during the 3rd trimester: perfect (n = 15) or acceptable (n = 25) compensation. (2) newborns with T1D father (n = 12) (3) newborns with a mother treated for either gestational or type 2 diabetes (n = 10) (4) control newborns (n = 25). Spontaneous as well as diabetes-associated autoantigen-stimulated production of 23 cytokines and chemokines were tested using protein microarray. In addition, the influence of glucose on cytokine and chemokine responsiveness was analyzed in vitro. The study groups differed in their spontaneous as well as stimulated cytokine and chemokine spectra. A prominent Th1 response (high IFN-gamma) from autoantigen stimulation was observed especially in babies of T1D fathers (P = 0.001) and also in mothers with perfect diabetes compensation during the 3rd trimester (P = 0.016) in comparison with control newborns. By contrast, cord blood mononuclear cells cultivated in vitro in high glucose concentration decreased the diabetogenic stimulated Th1 cytokine response. Maternal 'sweet' as well as 'autoimmune environment' may both lead to lower occurrence of T1D within their offspring. Further studies will reveal the exact immunological mechanism of this observation.

Introduction: There are numerous indications that either mannan-binding lectin (MBL) deficiency or its excessive activity are associated with adverse pregnancy outcomes. High MBL concentrations and corresponding MBL2 genotypes were shown to be associated with microvascular complications in type 1 diabetes. The aim of this study was to evaluate levels of MBL and MBL-dependent activity of the lectin pathway (LP) of complement in the course of pregnancy in diabetic mothers, based on genetic background., Materials and Methods: These parameters were determined in samples from healthy non-pregnant (control), diabetic non-pregnant, healthy pregnant, and pregnant diabetic women., Results: No significant differences in median MBL levels or LP activities were found in any study group compared to the control. However, statistically significant differences in MBL levels were noted during pregnancy between the 1st and 3rd trimesters in both healthy controls and pregnant diabetics. With regard to LP values, similar trends were evident, but statistically significant results were obtained only in the healthy pregnant group. When data analysis was confined to patients carrying the A/A (wild-type) MBL2 genotype, an increase in MBL level during pregnancy (in both healthy and diabetic pregnant women) was still observed. Similarly, LP activity increased during both healthy and diabetic pregnancies, significantly so for the former., Conclusions: Diabetes, an autoimmune disease, is a serious complication of pregnancy. Therefore, determination of MBL status might be beneficial in identifying type 1 diabetic patients who are at increased risk of developing both vascular complications and poor pregnancy outcomes.

Maternal diabetes can induce a number of developmental abnormalities in both laboratory animals and humans, including deformities of the face and palate. The incidence of birth defects in newborns of women with diabetes is approximately 3 to 5 times higher than among nondiabetics. In mice, nonspecific activation of the maternal immune system can reduce fetal abnormalities caused by various etiologies including hyperglycemia. This study was conducted to determine whether nonspecific maternal immune stimulation could reduce diabetes-induced palate defects and orofacial clefts. Female ICR mice were immune stimulated before induction of hyperglycemia with Freund's complete adjuvant (FCA), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interferon-gamma (IFNgamma). Streptozocin was used to induce hyperglycemia (26-35 mmol blood glucose) in females before breeding. Fetuses from 12 to 18 litters per treatment group were collected on Day 17 of gestation. Palate width and length were measured, and the incidence of orofacial clefts was determined. Palate length and width were both decreased by maternal hyperglycemia. Maternal immune stimulation with GM-CSF or FCA limited the degree of palate shortening from the hyperglycemia. Each of the three immune stimulants attenuated significant narrowing of the palate. Rates of orofacial clefts were not significantly different between treatment groups. Palatogenesis is a complex process driven by cellular signals, which regulate cell growth and apoptosis. Dysregulation of cellular signals by maternal hyperglycemia can result in fetal malformations. Maternal immune stimulation may prevent dysregulation of these signaling pathways thus reducing fetal malformations and normalizing palate growth., ((c) 2008 Wiley-Liss, Inc.)

To investigate the role that CD25(+) natural killer (NK) cells may play in the establishment of pregnancy, the effect of adoptive CD25(+) NK cell transfer on pregnancy outcome in subfertile non-obese diabetic (NOD) mice was investigated. Phenotypic analysis of NK cells was performed by flow cytometry before and after the transfer. The proportion of subfertile NOD female mice that failed to become pregnant when co-caged with C57Bl/6 males for 16 weeks was significantly higher in female NOD mice than in normal female BALB/c controls (53.1% versus 15.1%; P < 0.01). The subfertile NOD mice were divided into three groups receiving CD25(+) NK cells (group 1), CD25(-) cells (group 2) or RPMI 1640 medium only (group 3). Group 1 had significantly more pregnancies than those receiving CD25(-) NK cells (77.8% versus 11.1%; P < 0.01) and controls injected with RPMI 1640 medium (0.0%; P < 0.01). Improved fertility was concomitant with an increase in placental CD49b(+) NK cells expressing Foxp3. Foxp3 expression was confirmed in the CD25(+) NK cells before the transfer. These results indicate that subfertility in NOD mice may be partially attributed to the insufficiency of CD25(+) and Foxp3(+) NK cells recruited into the pregnant uterus.

Aims/hypothesis: The risk of type 1 diabetes is reduced in the children of mothers with type 1 diabetes compared with children of fathers with type 1 diabetes. We asked whether children of mothers with type 1 diabetes also have a decreased risk of developing islet autoantibodies, and which factors associated with maternal diabetes contribute to a reduced islet autoantibody risk in offspring., Methods: Singleton offspring of a mother (n = 1,008) or father with type 1 diabetes (n = 578) from the BABYDIAB study were included. Children were followed from birth for the development of islet autoantibodies defined as two or more autoantibodies to insulin, glutamic acid decarboxylase or insulinoma antigen 2 in two or more blood samples., Results: Islet autoantibody risk was lower in children of mothers with type 1 diabetes (5 year risk, 3.2% vs 5.7% in children of fathers with type 1 diabetes; p = 0.04). Among factors that differed between pregnancies from mothers with and without type 1 diabetes, birthweight was associated with islet autoantibody risk. Risk was reduced in children with birthweights in the lower (adjusted HR 0.33; 95% CI 0.14-0.75; p = 0.009) and upper (HR 0.45; 95% CI 0.21-0.97; p = 0.04) tertiles compared with the middle tertile. A sub-analysis of maternal HbA(1c) suggested that moderately elevated third trimester maternal HbA(1c) was also associated with a reduced islet autoantibody risk in children of mothers with type 1 diabetes (5.7-7%; HR 0.38; 95% CI 0.15-0.96; p = 0.04 vs children of mothers with HbA(1c) < 5.7%)., Conclusions/interpretation: The risk of islet autoimmunity is modified by maternally influenced events such as birthweight.

Pathological immune complexes (PIC) are revealed in high percent (100%) of cases by placental immunomorphological studies in insulin-dependent tissue. This leads to the development of an immunopathological process in the placental tissue. Parallel electron microscopy shows that some placental vessels are in close contact with the basal membrane of syncytiotrophoblast. PIC deposition in the area of confluence of the basal membranes of a syncytiotrophoblast and the vascular endothelium, which act as filters, results in the destruction of the basal membranes to rupture formation, causing the transplacental transport of substances together with immune complexes in the form of endocytotic vacuoles from the intervillous lacuna directly to the vessel. Active proliferation of vascular endotheliocyes leads to typical angiopathy as the body's defense reaction.

Objective: Human leukocyte antigen DQ (HLA-DQ) genetic factors and islet autoantibodies are strongly associated with type 1 diabetes (T1D) and are currently used to predict T1D. This study examined whether islet autoantibodies in the cord blood of newborns to nondiabetic mothers were associated with the (T1D) high-risk genotype HLA-DQ2/8, gestational infections or both., Study Design: Cord blood samples were taken from 33 683 newborns and used for HLA typing and analyses of islet autoantibodies. Parents completed questionnaires when the child was 2 months of age., Result: The prevalence of newborn islet autoantibodies consistently varied with season over 4 years (P<0.0001); lowest in first quarter (1.2%) and highest in third (2.4%). Cord blood islet autoantibodies were associated with HLA-DQ2/8 in the second (OR, 2.30; P=0.02), third (OR, 2.12; P=0.008) and fourth quarters (OR, 2.49; P=0.007), but not in the first (OR, 1.13). Reported gastroenteritis was additionally associated with islet autoantibodies in the third quarter (OR, 1.80, P=0.04)., Conclusion: An association between HLA and islet autoimmunity may depend on environmental exposure during pregnancy. Follow-up of mothers and children will determine risk of T1D.

Background: Several types of regulators (i.e. chemokines and metalloproteinases) are considered to play a crucial role in pregnancy by local modulation of the immune system at the level of peripheral leukocytes. The aim of this study was to determine whether changes in chemokines (interferon-gamma-inducible protein (IP-10), monocyte chemotactic peptide-1(MCP-1), cytokines regulated upon activation normal T cell expressed and secreted (RANTES) and matrix metalloproteinase-9 (MMP-9)) concentrations in diabetic patients could affect the course of pregnancy., Methods: The study group consisted of 65 diabetics in the first trimester of pregnancy. Some 47 pregnancies were successfully continued to delivery, 18 were terminated with spontaneous miscarriages. Twenty healthy women matched for gestational age served as a control group., Results: Glycated haemoglobin (HbA1C), vascular complications and lipoproteins (cholesterol, HDL-cholesterol, low density lipoprotein (LDL)-cholesterol and triglicerides) concentrations in maternal blood did not influence the chemokines concentrations. Lower RANTES level and higher MMP-9 concentrations were found in diabetic women. MCP-1 and RANTES levels differed significantly between pregnancies with good and poor perinatal outcome. A logistic regression model revealed that not only duration of diabetes, age of patients, HbA1C and insulin requirements, but also MMP-9,RANTES, MCP-1 and LDL-cholesterol levels seem to be involved in first trimester metabolism., Conclusions: Our results suggest the possible role of chemokines in early pregnancy development, especially in well-controlled diabetic patients, when hyperglycaemia is unlikely to be the main reason for an unfavourable outcome. Our results show that MCP-1 and RANTES might serve as predictive factors for an unfavourable outcome in diabetic pregnancy, whereas MMP-9 seems to be a marker of immunological changes related to mild hyperglycaemia. However, the open question of how the modulation of chemokines concentrations might be applied to prevent miscarriage in diabetic patients remains.

Objective: In pregnant women with type 1 diabetes, we evaluated whether the presence of thyroid peroxidase autoantibodies (anti-TPO) was associated with changes in thyroid function, metabolic control and pregnancy outcome., Design/setting: Prospective study, Denmark., Population: Ninety-six consecutive pregnant women with type 1 diabetes. Twenty-five healthy pregnant controls., Methods: At 8, 14, 21, 27 and 33 weeks, the diabetic women self-monitored plasma glucose (SMPG) (8/day) for 3 days and had blood samplings obtained., Main Outcome Measures: Thyroid-stimulating hormone (TSH), free thyroxin (T4), hemoglobin A1C (HbA1C), anti-TPO, pregnancy outcome., Results: Anti-TPO was detected in 31 (32%) of the pregnant diabetic women compared with two women (8%) in the healthy controls (p=0.015). The presence of anti-TPO was associated with higher TSH at 8 (p<0.0001) and 14 weeks (p<0.05) and lower free T4 at 8 weeks (p<0.05) compared with anti-TPO negative women. Twenty untreated anti-TPO positive women had higher TSH compared with untreated, anti-TPO negative women (p<0.05), but comparable free T4. At inclusion, 25% had TSH above the recommended treatment goal for levothyroxine (TSH>2.5 mIU/l), most prevalently among anti-TPO positive women. Sixteen women (17%) were treated for thyroid disorder during pregnancy. No differences were detected between the diabetic women with and without anti-TPO regarding HbA1C, insulin dose, median SMPG or pregnancy outcome., Conclusions: Anti-TPO was present in one-third of pregnant women with type 1 diabetes and associated with slightly higher TSH, but not poorer glycemic control or adverse birth outcome. A total of 17% of women with type 1 diabetes were treated for thyroid disorder during pregnancy.

Diabetic pregnancy frequently results in macrosomia or fetal obesity. It seems that the anomalies in carbohydrate and lipid metabolism in macrosomic infants of diabetic mothers are due to maternal hyperglycemia, which leads to fetal hyperinsulinemia. We have developed a rat model of macrosomic offspring and assessed the onset of obesity in these animals. The macrosomic offspring born to diabetic mothers are prone to the development of glucose intolerance and obesity as a function of age. It seems that in utero programming during diabetic pregnancy creates a "metabolic memory" which is responsible for the development of obesity in macrosomic offspring. We have demonstrated that the metabolism of lipids, and altered anti-oxidant status and immune system are implicated in the etiopathology of obesity in these animals. We have reported beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) in obese animals, born to diabetic dams.

Maternal transmission of islet autoantibodies to children born to mothers with type 1 diabetes (T1D) has been shown to protect from autoantibodies and diabetes development later in life. However, the factors conferring disease protection are poorly understood. The aim of this study was to evaluate comparatively proinflammatory cytokines, autoantibodies and lymphocyte subsets in cord blood (CB) of children born to mothers with either T1D (n = 13), gestational diabetes (GDM) (n = 32) or healthy mothers (n = 81) in relation to transplacental passage of autoantibodies. The results are consistent with early priming of the fetal immune system only in children born to mothers with T1D. Levels of interleukin (IL)-1beta (P = 0.022), tumour necrosis factor (TNF)-alpha (P = 0.002) and IL-8 (P = 0.0012), as well as the frequency of CD4(+) CD25(+) T cells (P < 0.01) were significantly increased, and the increased levels correlated positively with anti-GAD65 autoantibody (GADA) levels. Moreover, CD4(+) CD25(+) T cells of children born to T1D mothers exhibited a more pronounced memory phenotype with increased CCR4 expression and down-regulation of CD62L. These data suggest that early activation of the fetal immune system as a consequence of maternal autoimmunity and transplacental passage of GADA may influence the generation and expansion of fetal regulatory T cells. This might induce an early antigen-specific immunological tolerance that could protect against T1D later in life.

We assessed the implication of Th (helper)-cells and the modulation of the Th1/Th2 dichotomy by n-3 polyunsaturated fatty acids (PUFA) in type I diabetic pregnancy (DP) and macrosomia. Female gestant rats fed a standard diet or n-3 PUFA regimen were rendered diabetic by administration of five low doses of streptozotocin. The macrosomic (MAC) offspring were sacrificed at the age of 90 days. The mRNAs of IL-2 and IFN-gamma (Th1 cytokines) and IL-4 (Th2 cytokine) were downregulated in the pancreas and spleen of diabetic pregnant rats. The levels of IL-10 mRNA, another Th2 cytokine, were unchanged in the spleen or upregulated in the pancreas of these animals. Feeding an n-3 PUFA diet to rats with DP upregulated IL-10 mRNA in the pancreas and IL-4 and IL-10 mRNA in the spleen. In MAC offspring, high expression of IL-2 and IFN-gamma mRNA, but not of Th2 cytokines, was observed. The n-3 PUFA diet diminished Th1 mRNA quantities and increased the levels of IL-4, but not of IL-10, mRNA in MAC offspring. Our study shows that DP is associated with a decreased Th1 phenotype and IL-4 mRNA expression in the pancreas and spleen, and an n-3 PUFA diet upregulates Th2 profile. In MAC offspring, the Th1 phenotype is upregulated and an n-3 PUFA diet downregulates this phenomenon.

Objective: The objective of this study was to characterize the clinical and immunogenetic features of Japanese pregnancy-associated fulminant type 1 diabetes (PF). A group of patients with PF was compared with a group of patients of child-bearing age with fulminant type 1 diabetes that was not associated with pregnancy (NPF) in a nationwide survey conducted from 2000-2004., Patients: The clinical characteristics of the 22 patients in the PF group were compared with those of the 48 patients in the NPF group. Human leukocyte antigen (HLA) class II DR and DQ genotyping of 17 PF and 20 NPF patients was performed., Results: Arterial pH was significantly lower (P = 0.0366), and amylase values tended to increase in PF patients compared with NPF patients (P = 0.0515). In 22 PF patients, 18 developed disease during pregnancy (26.3 wk; range, 7-38), whereas four cases occurred immediately after delivery (10.5 d; range, 7-14 d). Twelve cases that developed during pregnancy resulted in stillbirth (67%), and five of the six fetal cases that survived were delivered by cesarean section. The haplotype frequency of HLA DRB1*0901-DQB1*0303 in PF was significantly higher than those in NPF (P = 0.0244) and controls (P = 0.0001), whereas that of DRB1*0405-DQB1*0401 in NPF was significantly higher than those in PF (P = 0.0162) and controls (P < 0.0001)., Conclusions: The clinical symptoms of PF patients were more severe than those of NPF patients, and the prognosis of their fetuses was extremely poor. The type 1 diabetes-susceptible HLA class II haplotype is distinct in PF and NPF patients, suggesting that different HLA haplotypes underlie the presentation of PF or NPF.

The maternal diabetic environment alters the embryo and the feto-placental development. The results of these alterations are: increased embryo resorption and malformation rates, placental dysfunction, fetal alterations that lead to increased neonatal morbidity and mortality rates, and also diseases that will be evident later in the adult life of the newborn. The etiology of these many maternal diabetes-induced complications are not yet understood in full. In this review the role of maternal diabetes as an inductor of a pro-inflammatory environment that impairs embryo and placental development is discussed. An overproduction of pro-inflammatory agents is found in the uterus during implantation and the developing embryo and placenta from experimental models of diabetes, as well as in placenta from diabetic women. In these tissues there are increases in reactive oxygen species, pro-inflammatory cytokines and prostaglandins, nitric oxide and peroxynitrites. These pro-inflammatory agents lead to the intrauterine activation of matrix metalloproteinases, proteases involved in remodeling the extracellular matrix during implantation and feto-placental development. Many of these pro-inflammatory agents have overlapping mechanisms of action and cross regulatory pathways that propagate the inflammatory processes. Antioxidants, PPARgamma activators, and NF-kappaB inhibitors are able to reduce the concentrations of these agents in intrauterine gestational tissues. This article reviews the current understanding of maternal diabetes-induced changes in pro-inflammatory and anti-inflammatory pathways that affect the embryo and placental development in maternal diabetes, and stresses the need of a strict maternal control of the pathology to prevent deleterious consequences in the offspring.

It has been demonstrated that good metabolic control maintained throughout pregnancy can reduce maternal and fetal complications in diabetes. To achieve good metabolic control, before conception and throughout pregnancy, insulin therapy needs to be optimized, and, in this context, the new insulins currently on the market may help. We therefore review here what is known about the potential benefits and risks related to the use of these new insulins in pregnancy. Clinical and experimental data on insulin lispro strongly suggest that lispro does not have adverse maternal or fetal effects during pregnancy in women with preexisting diabetes, and also that its use in these women results in improved glycemic control, fewer hypoglycemic episodes, and improved patient satisfaction. In women with gestational diabetes mellitus (GDM), the use of insulin lispro is efficient in reducing postprandial hyperglycemia and some neonatal features related to hyperglycemia, thus stressing its usefulness in this condition. As for insulin aspart, clinical data on GDM patients shows the same efficacy as insulin lispro in lowering postprandial hyperglycemia, indicating that insulin aspart may be used in GDM when this condition is characterized by postprandial hyperglycemia. The results of a multicentric study now in progress on the efficacy and safety of insulin aspart in type 1 pregnant diabetic patients will definitely be useful in establishing whether this insulin is safe in pregnancy. For the moment, the use of insulin glargine during pregnancy is not recommended owing to the lack of data on maternal and fetal effects., (Copyright 2005 John Wiley & Sons, Ltd.)

Objective: We investigated the effects of a diet containing EPAX-7010, rich in PUFAs such as eicosapentaenoic acid [20:5(n-3)] and docosahexaenoic acid [22:6(n-3)], i.e., a PUFA/EPAX regimen, on T-cell activation in diabetic pregnant rats and their obese pups., Research Methods and Procedures: Mild hyperglycemia in pregnant rats was induced by intraperitoneal injection of streptozotocin on Day 5 of gestation. T-cell blastogenesis was assayed by using (3)H-thymidine, whereas intracellular free calcium concentrations ([Ca(2+)]i) were measured by using Fura-2 in diabetic pregnant rats and their obese offspring., Results: Concavalin-A-stimulated T-cell proliferation was decreased in both pregnant diabetic rats and their obese pups as compared with control animals. Feeding the PUFA/EPAX diet restored T-cell proliferation in both groups of animals. We also employed ionomycin, which at 50 nM opens calcium channels, and thapsigargin (TG), which recruits [Ca(2+)]i from endoplasmic reticulum pool. We observed that ionomycin-induced increases in [Ca(2+)]i in T-cells of diabetic mothers and obese offspring were greater than in those of control rats. Furthermore, feeding PUFA/EPAX diet diminished significantly the ionomycin-evoked rise in [Ca(2+)]i in diabetic and obese animals. TG-induced increases in [Ca(2+)]i in T-cells of diabetic pregnant rats and their obese offspring were greater than in those of control rats. The feeding of the experimental diet significantly curtailed the TG-evoked increases in [Ca(2+)]i in both diabetic and obese rats., Discussion: Together, these observations provide evidence that T-cell activation and T-cell calcium signaling are altered during gestational diabetes and macrosomia. Hence, dietary fish oils, particularly eicosapentaenoic acid and docosahexaenoic acid, may restore these T-cell abnormalities.