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Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.

Background Gestational diabetes mellitus (GDM) – a transitory form of diabetes first recognised during pregnancy complicates between < 1% and 28% of all pregnancies. GDM has important short and long-term health consequences for both the mother and her offspring. To prevent adverse pregnancy outcomes and to prevent or delay future onset of type 2 diabetes in mother and offspring, timely detection, optimum treatment, and preventive postpartum care and follow-up is necessary. However the area remains grossly under-prioritised. Methods To investigate determinants and barriers to GDM care from initial screening and diagnosis to prenatal treatment and postpartum follow-up, a PubMed database search to identify quantitative and qualitative studies on the subject was done in September 2012. Fifty-eight relevant studies were reviewed. Results Adherence to prevailing GDM screening guidelines and compliance to screening tests seems sub-optimal at best and arbitrary at worst, with no clear or consistent correlation to health care provider, health system or client characteristics. Studies indicate that most women express commitment and motivation for behaviour change to protect the health of their unborn baby, but compliance to recommended treatment and advice is fraught with challenges, and precious little is known about health system or societal factors that hinder compliance and what can be done to improve it. A number of barriers related to health care provider/system and client characteristics have been identified by qualitative studies. Immediately following a GDM pregnancy many women, when properly informed, desire and intend to maintain healthy lifestyles to prevent future diabetes, but find the effort challenging. Adherence to recommended postpartum screening and continued lifestyle modifications seems even lower. Here too, health care provider, health system and client related determinants and barriers were identified. Studies reveal that sense of self-efficacy and social support are key determinants. Conclusions The paper identifies and discusses determinants and barriers for GDM care, fully recognising that these are highly dependent on the context.

Background Imbalances of gut microbiota composition are linked to a range of metabolic perturbations. In the present study, we examined the gut microbiota of women with gestational diabetes mellitus (GDM) and normoglycaemic pregnant women in late pregnancy and about 8 months postpartum. Methods Gut microbiota profiles of women with GDM ( n  = 50) and healthy ( n  = 157) pregnant women in the third trimester and 8 months postpartum were assessed by 16S rRNA gene amplicon sequencing of the V1-V2 region. Insulin and glucose homeostasis were evaluated by a 75 g 2-h oral glucose tolerance test during and after pregnancy. Results Gut microbiota of women with GDM was aberrant at multiple levels, including phylum and genus levels, compared with normoglycaemic pregnant women. Actinobacteria at phylum level and Collinsella , Rothia and Desulfovibrio at genus level had a higher abundance in the GDM cohort. Difference in abundance of 17 species-level operational taxonomic units (OTUs) during pregnancy was associated with GDM. After adjustment for pre-pregnancy body mass index (BMI), 5 of the 17 OTUs showed differential abundance in the GDM cohort compared with the normoglycaemic pregnant women with enrichment of species annotated to Faecalibacterium and Anaerotruncus and depletion of species annotated to Clostridium (sensu stricto) and to Veillonella . OTUs assigned to Akkermansia were associated with lower insulin sensitivity while Christensenella OTUs were associated with higher fasting plasma glucose concentration. OTU richness and Shannon index decreased from late pregnancy to postpartum regardless of metabolic status. About 8 months after delivery, the microbiota of women with previous GDM was still characterised by an aberrant composition. Thirteen OTUs were differentially abundant in women with previous GDM compared with women with previous normoglycaemic pregnancy. Conclusion GDM diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with normoglycaemic pregnant women, and 8 months after pregnancy, differences in the gut microbiota signatures are still detectable. The gut microbiota composition of women with GDM, both during and after pregnancy, resembles the aberrant microbiota composition reported in non-pregnant individuals with type 2 diabetes and associated intermediary metabolic traits.

The breast milk plays a crucial role in shaping the initial intestinal microbiota and mucosal immunity of the infant. Interestingly, breastfeeding has proven to be protective against the early onset of immune-mediated diseases including type 1 diabetes. Studies have shown that exosomes from human breast milk are enriched in immune-modulating miRNAs suggesting that exosomal miRNAs (exomiRs) transferred to the infant could play a critical role in the development of the infant's immune system. We extracted exomiRs from breast milk of 52 lactating mothers (26 mothers with type 1 diabetes and 26 healthy mothers), to identify any differences in the exomiR content between the two groups. Small RNA-sequencing was performed to identify known and novel miRNAs in both groups. A total of 631 exomiRs were detected by small RNA sequencing including immune-related miRNAs such as hsa-let-7c, hsa-miR-21, hsa-miR-34a, hsa-miR-146b, and hsa-miR-200b. In addition, ~200 novel miRNAs were identified in both type 1 diabetes and control samples. Among the known miRNAs, nine exomiR's were found differentially expressed in mothers with type 1 diabetes compared to healthy mothers. The highly up-regulated miRNAs, hsa-miR-4497, and hsa-miR-3178, increased lipopolysaccharide-induced expression and secretion of tumor necrosis factor α (TNFα) in human monocytes. The up-regulated miRNA target genes were significantly enriched for longevity-regulating pathways and FoxO signaling. Our findings suggest a role of breast milk-derived exomiRs in modulating the infant's immune system.

Improved Pregnancy Outcome in Type 1 Diabetic Women With Microalbuminuria or Diabetic Nephropathy Effect of intensified antihypertensive therapy? Lene Ringholm Nielsen , MD, PHD 1 2 , Peter Damm , MD, DMSC 1 3 and Elisabeth R. Mathiesen , MD, DMSC 1 2 1 Center for Pregnant Women with Diabetes, Rigshospitalet, Faculty of Health Sciences, Copenhagen, Denmark 2 Department of Endocrinology, Rigshospitalet, Faculty of Health Sciences, Copenhagen, Denmark 3 Department of Obstetrics, Rigshospitalet, Faculty of Health Sciences, Copenhagen, Denmark Corresponding author: Lene Ringholm Nielsen, enel{at}dadlnet.dk Abstract OBJECTIVE —To describe pregnancy outcome in type 1 diabetic women with normoalbuminuria, microalbuminuria, or diabetic nephropathy after implementation of an intensified antihypertensive therapeutic strategy. RESEARCH DESIGN AND METHODS —Prospective study of 117 pregnant women with type 1 diabetes. Antihypertensive therapy, mainly methyldopa, was given to obtain blood pressure <135/85 mmHg and urinary albumin excretion <300 mg/24 h. Blood pressure and A1C were recorded during pregnancy. The pregnancy outcome was compared with recently published studies of pregnant women with microalbuminuria or diabetic nephropathy. RESULTS —Antihypertensive therapy was given in 14 of 100 women with normoalbuminuria, 5 of 10 women with microalbuminuria, and all 7 women with diabetic nephropathy. Mean systolic blood pressure during pregnancy was 120 mmHg (range 101–147), 122 mmHg (116–135), and 135 mmHg (111–145) in women with normoalbuminuria, microalbuminuria, and diabetic nephropathy, respectively ( P = 0.0095). No differences in mean diastolic blood pressure or A1C were detected between the groups. No women with microalbuminuria developed preeclampsia. The frequency of preterm delivery was 20% in women with normoalbuminuria and microalbuminuria in contrast to 71% in women with diabetic nephropathy ( P < 0.01) where the median gestational age was 258 days (220–260). Compared with previous studies using less stringent antihypertensive therapeutic strategy and less strict metabolic control, gestational age was longer and birth weight was larger in our study. CONCLUSIONS —With intensified antihypertensive therapy and strict metabolic control, comparable pregnancy outcome was seen in type 1 diabetic women with microalbuminuria and normoalbuminuria. Although less severe than in previous studies, diabetic nephropathy was associated with more adverse pregnancy outcome. Footnotes Published ahead of print at http://care.diabetesjournals.org on 22 October 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 10, 2008. Received August 19, 2008. DIABETES CARE

Background Women with prior gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes; however, this risk can be reduced by engaging in positive health behaviours e.g. healthy diet and regular physical activity. As such behaviours are difficult to obtain and maintain there is a need to develop sustainable behavioural interventions following GDM. We aimed to report the process of systematically developing a health promotion intervention to increase quality of life and reduce diabetes risk among women with prior GDM and their families. We distil general lessons about developing complex interventions through co-production and discuss our extensions to intervention development frameworks. Methods The development process draws on the Medical Research Council UK Development of complex interventions in primary care framework and an adaptation of a three-stage framework proposed by Hawkins et al. From May 2017 to May 2019, we iteratively developed the Face-it intervention in four stages: 1) Evidence review, qualitative research and stakeholder consultations; 2) Co-production of the intervention content; 3) Prototyping, feasibility- and pilot-testing and 4) Core outcome development. In all stages, we involved stakeholders from three study sites. Results During stage 1, we identified the target areas for health promotion in families where the mother had prior GDM, including applying a broad understanding of health and a multilevel and multi-determinant approach. We pinpointed municipal health visitors as deliverers and the potential of using digital technology. In stage 2, we tested intervention content and delivery methods. A health pedagogic dialogue tool and a digital health app were co-adapted as the main intervention components. In stage 3, the intervention content and delivery were further adapted in the local context of the three study sites. Suggestions for intervention manuals were refined to optimise flexibility, delivery, sequencing of activities and from this, specific training manuals were developed. Finally, at stage 4, all stakeholders were involved in developing realistic and relevant evaluation outcomes. Conclusions This comprehensive description of the development of the Face-it intervention provides an example of how to co-produce and prototype a complex intervention balancing evidence and local conditions. The thorough, four-stage development is expected to create ownership and feasibility among intervention participants, deliverers and local stakeholders. Trial registration ClinicalTrials.gov NCT03997773 , registered retrospectively on 25 June 2019.

Low back pain is highly prevalent among pregnant women, but evidence of an effective treatment are still lacking. Supervised exercise-either land or water based-has shown benefits for low back pain, but no trial has investigated the evidence of an unsupervised water exercise program on low back pain. We aimed to assess the effect of an unsupervised water exercise program on low back pain intensity and days spent on sick leave among healthy pregnant women. In this randomised, controlled, parallel-group trial, 516 healthy pregnant women were randomly assigned to either unsupervised water exercise twice a week for a period of 12 weeks or standard prenatal care. Healthy pregnant women aged 18 years or older, with a single fetus and between 16-17 gestational weeks were eligible. The primary outcome was low back pain intensity measured by the Low Back Pain Rating scale at 32 weeks. The secondary outcomes were self-reported days spent on sick leave, disability due to low back pain (Roland Morris Disability Questionnaire) and self-rated general health (EQ-5D and EQ-VAS). Low back pain intensity was significantly lower in the water exercise group, with a score of 2.01 (95% CI 1.75-2.26) vs. 2.38 in the control group (95% CI 2.12-2.64) (mean difference = 0.38, 95% CI 0.02-0.74 p = 0.04). No difference was found in the number of days spent on sick leave (median 4 vs. 4, p = 0.83), disability due to low back pain nor self-rated general health. There was a trend towards more women in the water exercise group reporting no low back pain at 32 weeks (21% vs. 14%, p = 0.07). Unsupervised water exercise results in a statistically significant lower intensity of low back pain in healthy pregnant women, but the result was most likely not clinically significant. It did not affect the number of days on sick leave, disability due to low back pain nor self-rated health. ClinicalTrials.gov NCT02354430.

Conflicting results have been reported concerning possible adverse effects on the cognitive function of offspring of mothers with type 1 diabetes (O-mT1D). Previous studies have included offspring of parents from the background population (O-BP), but not offspring of fathers with type 1 diabetes (O-fT1D) as the unexposed reference group. This is a population-based retrospective cohort study from 2010 to 2016. Nationally standardized school test scores (range, 1 to 100) were obtained for public school grades 2, 3, 4, 6, and 8 in O-mT1D and compared with those in O-fT1D and O-BP. Of the 622,073 included children, 2,144 were O-mT1D, and 3,474 were O-fT1D. Multiple linear regression models were used to compare outcomes, including the covariates offspring with type 1 diabetes, parity, number of siblings, offspring sex, smoking during pregnancy, parental age, and socioeconomic factors. Mean test scores were 54.2 (standard deviation, SD 24.8) in O-mT1D, 54.4 (SD 24.8) in O-fT1D, and 56.4 (SD 24.7) in O-BP. In adjusted analyses, the mean differences in test scores were -1.59 (95% CI -2.48 to -0.71, p < 0.001) between O-mT1D and O-BP and -0.78 (95% CI -1.48 to -0.08, p = 0.03) between O-fT1D and O-BP. No significant difference in the adjusted mean test scores was found between O-mT1D and O-fT1D (p = 0.16). The study's limitation was no access to measures of glycemic control during pregnancy. O-mT1D achieved lower test scores than O-BP but similar test scores compared with O-fT1D. Glycemic control during pregnancy is essential to prevent various adverse pregnancy outcomes in women with type 1 diabetes. However, the present study reduces previous concerns regarding adverse effects of in utero hyperglycemia on offspring cognitive function.

During placental malaria, Plasmodium falciparum infected erythrocytes sequester in the placenta, causing health problems for both the mother and fetus. The specific adherence is mediated by the VAR2CSA protein, which binds to placental chondroitin sulfate (CS) on chondroitin sulfate proteoglycans (CSPGs) in the placental syncytium. However, the identity of the CSPG core protein and the cellular impact of the interaction have remain elusive. In this study we identified the specific CSPG core protein to which the CS is attached, and characterized its exact placental location. VAR2CSA pull-down experiments using placental extracts from whole placenta or syncytiotrophoblast microvillous cell membranes showed three distinct CSPGs available for VAR2CSA adherence. Further examination of these three CSPGs by immunofluorescence and proximity ligation assays showed that syndecan-1 is the main receptor for VAR2CSA mediated placental adherence. We further show that the commonly used placental choriocarcinoma cell line, BeWo, express a different set of proteoglycans than those present on placental syncytiotrophoblast and may not be the most biologically relevant model to study placental malaria. Syncytial fusion of the BeWo cells, triggered by forskolin treatment, caused an increased expression of placental CS-modified syndecan-1. In line with this, we show that rVAR2 binding to placental CS impairs syndecan-1-related Src signaling in forskolin treated BeWo cells, but not in untreated cells.

OBJECTIVE: To study the association between peri-conceptional A1C and serious adverse pregnancy outcome (congenital malformations and perinatal mortality). RESEARCH DESIGN AND METHODS: Prospective data were collected in 933 singleton pregnancies complicated by type 1 diabetes. RESULTS: The risk of serious adverse outcome at different A1C levels was compared with the background population. The risk was significantly higher when peri-conceptional A1C exceeded 6.9%, and the risk tended to increase gradually with increasing A1C. Women with A1C exceeding 10.4% had a very high risk of 16%. Congenital malformation rate increased significantly at A1C above 10.4%, whereas perinatal mortality was increased even at A1C below 6.9%. CONCLUSIONS: These results support recent guidelines of preconceptional A1C levels <7% in women with type 1 diabetes.