Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy.

BACKGROUND: Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA. METHODS: To identify DMRs, we employed the bump hunter method in samples from young (9-16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28-33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle. RESULTS: One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring's own adiposity. CONCLUSIONS: Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.

Do WHO criteria for gestational diabetes fit a rural population in Tanzania? - A follow-up study assessing mother and child health six years after a pregnancy diagnosed with gestational diabetes.

AIMS AND METHODS: In low- and middle- income countries (LMICs) consequences of gestational diabetes (GDM) is understudied. Using a prospective cohort of mothers (n = 197)and children (n = 251), from rural north-eastern Tanzania, we assessed prediabetes and type 2 diabetes (T2D) prevalence six years after a pregnancy with/without GDM. RESULTS: The prevalence of prediabetes (49.4 % vs. 46.4 %) orT2D (20.0 % vs. 16.1 %), p ≥ 0.36, based on fasting plasma glucose (FPG) or HbA1clevels (prediabetes: 16.9 % vs. 13.8 % and T2D 1.2 % vs. 0 %, p = 0.47), andcardio-metabolic health parameters,weresimilar between women with/without previous GDM. These results were supported by similar perinatal outcomes and child health at follow-up.The overall prevalence ofprediabetes/T2D was high, but no differences in other cardio-metabolic risk markers were observed in women with prediabetes/T2D compared to women with normal glucose tolerance. CONCLUSIONS: Despite high prevalence of GDM amongTanzanian women, the diagnosis was not associated with adverse pregnancy outcomes, nor with increased risk of prediabetes or T2D at follow-up. FPG and HbA1c may be poor markers for diabetes in this population, and further follow-up studies with longer time intervals are warranted to evaluate which GDM diagnostic criteria are most optimal for women in rural Tanzania and similar LMIC settings.

Cord Blood FGF-21 and GDF-15 Levels Are Affected by Maternal Exposure to Moderate to Severe Anemia and Malaria.

Context: Anemia and malaria are global health problems affecting >50% of pregnant women in sub-Saharan Africa and are associated with intrauterine growth restriction. The hormones fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) are involved in metabolic regulation and are expressed in the placenta. No studies exist on FGF-21 and GDF-15 responses to exposures of malaria and anemia in pregnancy. Objective and Methods: Using a prospective, longitudinal pregnancy and birth cohort of women with an average age of 26 years from a rural region in northeastern Tanzania, we examined if FGF-21 and GDF-15 levels in maternal blood at week 33 ± 2 (n = 301) and in cord blood at birth (n = 353), were associated with anemia and malaria exposure at different time points in pregnancy and with neonatal anthropometry. Results: Among mothers at gestation week 33 ± 2, lower FGF-21 levels were observed after exposure to malaria in the first trimester, but not anemia, whereas GDF-15 levels at week 33 ± 2 were not associated with malaria nor anemia. In cord blood, moderate to severe anemia at any time point in pregnancy was associated with higher levels of FGF-21, whereas malaria exposure in the third trimester was associated with lower FGF-21 levels in cord blood. Negative associations were observed between cord blood FGF-21 and GDF-15 levels and neonatal skinfold thicknesses and birthweight. Conclusion: Our results suggest that moderate to severe anemia throughout pregnancy associates with higher FGF-21 levels, and malaria in last trimester associates with lower FGF-21 levels, in the neonates, thereby potentially affecting the future cardiometabolic health of the child.

Barriers and facilitators for sustainable weight loss in the pre-conception period among Danish women with overweight or obesity - a qualitative study.

BACKGROUND: The prevalence of overweight or obesity in women of reproductive age continues to increase. A high pre-pregnancy body mass index (BMI) has been shown to increase the risk of pregnancy complications and predispose offspring to childhood obesity. However, little is known about factors affecting women's ability to achieve sustainable weight management and very few studies have applied behavior change theory to qualitative data. AIM: This study aimed to explore barriers and facilitators for weight management among women with overweight or obesity, who wanted to lose weight before pregnancy. METHODS: We conducted semi-structured interviews with 17 women with a BMI ≥ 27 kg/m2, who planned to become pregnant in the near future. Data were analyzed using an abductive approach and the Capability, Opportunity, Motivation, and Behavior model was applied as a conceptual framework. RESULTS: The women's strongest motivator for pre-conception weight loss was their ability to become pregnant. Barriers to successful weight management included their partners' unhealthy behaviors, mental health challenges, competing priorities, and internalized weight stigmatization. The women described careful planning, partners' health behaviors, social support, and good mental health as facilitators for sustainable weight management. CONCLUSION: Our study provides insights into factors affecting weight management among women with overweight or obesity in the pre-conception period. Future interventions on weight management require a holistic approach, including a focus on social support, especially from the partner, and mental health, as well as an effort to limit internalized weight stigma.

High anti-SARS-CoV-2 seroprevalence among unvaccinated mother-child pairs from a rural setting in north-eastern Tanzania during the second wave of COVID-19.

Background: The reported infection rates and burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in low- and middle-income countries, including those in sub-Saharan Africa, are relatively low compared to the rates and burden in Europe and America, partly due to limited testing capability. Unlike many countries, Tanzania has implemented neither mass screening nor restrictive measures such as lockdowns to date. The prevalence of SARS-CoV-2 infection in rural mainland Tanzania is largely unknown. Methods: A cross-sectional study was conducted between April and October 2021 to assess the anti-SARS-CoV-2 seroprevalence among mother-child pairs (n = 634 children, n = 518 mothers) in a rural setting in north-eastern Tanzania. Results: A very high prevalence of anti-SARS-CoV-2 antibody titres was found, with seroprevalence rates ranging from 29% among mothers and 40% among children, with a dynamic peak in seropositivity incidence at the end of July/early August being revealed. Significant differences in age, socioeconomic status, and body composition were associated with seropositivity in mothers and children. No significant associations were observed between seropositivity and comorbidities, including anaemia, diabetes, malaria, and HIV. Conclusions: The transmission of SARS-CoV-2 in a rural region of Tanzania during 2021 was high, indicating a much higher infection rate in rural Tanzania compared to that reported in the UK and USA during the same period. Ongoing immune surveillance may be vital to monitoring the burden of viral infection in rural settings without access to molecular genotyping, where the load of communicable diseases may mask COVID-19. Surveillance could be implemented in tandem with the intensification of vaccination strategies.

The overlooked paradox of the coexistence of overweight/obesity and anemia during pregnancy.

Globally, the prevalence of overweight and obesity, including among pregnant women, has substantially increased in the past three decades. This has been fueled by, among other factors, an increase in the consumption of high energy-dense foods and a decrease in physical activity. Additionally, global prevalence of anemia among pregnant women remains a public health concern. Overweight/obesity as well as anemia in pregnancy are independently associated with adverse health outcomes for the mother and offspring. In some pregnant women, the two conditions coexist. Yet current knowledge in this field, including prevalence rates, risk factors, and health consequences for mother and offspring being exposed to these conditions, is staggeringly sparse. In this review we describe the current evidence on prevalence rates, risk factors, and effects for mother and offspring regarding coexistence of overweight/obesity and anaemia in pregnant women based on a systematic literature search. We also highlight research gaps and suggest avenues for future research.

High Prevalence of Gestational Diabetes Mellitus in Rural Tanzania-Diagnosis Mainly Based on Fasting Blood Glucose from Oral Glucose Tolerance Test.

Gestational diabetes mellitus (GDM) is associated with poor pregnancy outcomes and increased long-term risk of metabolic diseases for both mother and child. In Tanzania, GDM prevalence increased from 0% in 1991 to 19.5% in 2016. Anaemia has been proposed to precipitate the pathogenesis of GDM. We aimed to examine the prevalence of GDM in a rural area of Tanzania with a high prevalence of anaemia and to examine a potential association between haemoglobin concentration and blood glucose during pregnancy. The participants were included in a population-based preconception, pregnancy and birth cohort study. In total, 538 women were followed during pregnancy and scheduled for an oral glucose tolerance test (OGTT) at week 32-34 of gestation. Gestational diabetes mellitus was diagnosed according to the WHO 2013 guidelines. Out of 392 women screened, 39% (95% CI: 34.2-44.1) had GDM, the majority of whom (94.1%) were diagnosed based solely on the fasting blood sample from the OGTT. No associations were observed between haemoglobin or ferritin and glucose measurements during pregnancy. A very high prevalence of GDM was found in rural Tanzania. In view of the laborious, costly and inconvenient OGTT, alternative methods such as fasting blood glucose should be considered when screening for GDM in low- and middle-income countries.

A prospective study of artificially sweetened beverage intake and cardiometabolic health among women at high risk.

BACKGROUND: Artificially sweetened beverages (ASBs) are commonly consumed and recommended for individuals at high risk for cardiometabolic diseases; however, the health effects of ASBs remain contradictory. Given that cross-sectional analyses are subject to reverse causation, prospective studies with long-term follow-up are needed to evaluate associations between ASBs and cardiometabolic health, especially among high-risk individuals. OBJECTIVE: The aim of this study was to examine associations of ASB intake and cardiometabolic health among high-risk women with prior gestational diabetes mellitus (GDM). METHODS: We included 607 women with GDM from the Danish National Birth Cohort (DNBC; 1996-2002) who completed a clinical exam 9-16 y after the DNBC pregnancy for the Diabetes & Women's Health (DWH) Study (2012-2014). We assessed ASB intake using FFQs completed during the DNBC pregnancy and at the DWH Study clinical exam. We examined cardiometabolic outcomes at the DWH clinical exam. We estimated percentage differences in continuous cardiometabolic markers and RRs for clinical endpoints in association with ASB intake both during pregnancy and at follow-up adjusted for prepregnancy BMI, diet, and lifestyle factors. Sensitivity analyses to account for reverse causation were performed. RESULTS: In pregnancy and at follow-up, 30.4% and 36.4% of women regularly (≥2 servings/wk) consumed ASB, respectively. Consumption of ASBs, both during pregnancy and at follow-up, was associated with higher glycated hemoglobin (HbA1c), insulin, HOMA-IR, triglycerides, liver fat, and adiposity and with lower HDL at follow-up. After adjustment for covariates, particularly prepregnancy BMI, the majority of associations between ASB intake in pregnancy and outcomes at follow-up became null with the exception of HbA1c. ASB intake at follow-up (≥1 serving/d compared with <1 serving/mo) was associated with higher HbA1c (6.5%; 95% CI: 1.9, 11.3; P-trend = 0.007); however, associations were not upheld in sensitivity analyses for reverse causation. CONCLUSIONS: Among Danish women with a history of GDM, ASB intake was not significantly associated with cardiometabolic profiles.

Diabetes & Women's Health (DWH) Study: an observational study of long-term health consequences of gestational diabetes, their determinants and underlying mechanisms in the USA and Denmark.

PURPOSE: Women who experience gestational diabetes mellitus (GDM) are at exceptionally high-risk of developing type 2 diabetes (T2DM) later in life. However, limited information is available about genetic and environmental factors that are implicated in the progression from GDM to T2DM. PARTICIPANTS: The Diabetes & Women's Health (DWH) Study applied a hybrid design, which combined new prospective data collection with existing data in two prospective cohorts, the Danish National Birth Cohort (DNBC) and the Nurses' Health Study II (NHS II). In total, the DWH Study identified 7759 women with a GDM diagnosis from both cohorts; 4457 women participated in the DWH Study data collection, which included two cycles of follow-up from 2012 to 2014 and 2014 to 2016. FINDINGS TO DATE: Progression from GDM to T2DM was high. In the NHS II group, by 2013, 23.1% (n=846/3667) developed T2DM. In the DNBC group, at cycle 1 (2012-2014), the progression rate was even higher: 27.2% (n=215/790) had developed T2DM. Furthermore, we have shown that women who had GDM experienced a significantly greater risk of hypertension and cardiovascular diseases, as well as early stages of glomerular hyperfiltration and renal damage. Moreover, the DWH Study findings have shown that healthful diet and lifestyle factors and weight control were related to a lower risk of T2DM, hypertension and cardiovascular diseases. FUTURE PLANS: Primary data collection for the DWH Study is complete and investigators are currently investigating interactions of the abovementioned modifiable factors with T2DM genetic susceptibility in determining the risk of progression from GDM to T2DM. Findings from ongoing work will provide further insights for identifying more precise prevention strategies for T2DM and comorbidities in this high-risk population. Future work will examine novel biomarkers of health and disease in this cohort.

FOETAL for NCD-FOetal Exposure and Epidemiological Transitions: the role of Anaemia in early Life for Non-Communicable Diseases in later life: a prospective preconception study in rural Tanzania.

PURPOSE: Low-income and middle-income countries such as Tanzania experience a high prevalence of non-communicable diseases (NCDs), including anaemia. Studying if and how anaemia affects growth, placenta development, epigenetic patterns and newborns' risk of NCDs may provide approaches to prevent NCDs. PARTICIPANTS: The FOETALforNCD (FOetal Exposure and Epidemiological Transitions: the role of Anaemia in early Life for Non-Communicable Diseases in later life) Study is a population-based preconception, pregnancy and birth cohort study (n=1415, n=538, n=427, respectively), conducted in a rural region of North-East Tanzania. All participants were recruited prior to conception or early in pregnancy and followed throughout pregnancy as well as at birth. Data collection included: maternal blood, screening for NCDs and malaria, ultrasound in each trimester, neonatal anthropometry at birth and at 1 month of age, cord blood, placental and cord biopsies for stereology and epigenetic analyses. FINDINGS TO DATE: At preconception, the average age, body mass index and blood pressure of the women were 28 years, 23 kg/m2 and 117/75 mm Hg, respectively. In total, 458 (36.7%) women had anaemia (haemoglobin Hb <12 g/dL) and 34 (3.6%) women were HIV-positive at preconception. During pregnancy 359 (66.7%) women had anaemia of which 85 (15.8%) women had moderate-to-severe anaemia (Hb ≤9 g/dL) and 33 (6.1%) women had severe anaemia (Hb ≤8 g/dL). In total, 185 (34.4%) women were diagnosed with malaria during pregnancy. FUTURE PLANS: The project will provide new knowledge on how health, even before conception, might modify the risk of developing NCDs and how to promote better health during pregnancy. The present project ended data collection 1 month after giving birth, but follow-up is continuing through regular monitoring of growth and development and health events according to the National Road Map Strategic Plan in Tanzania. This data will link fetal adverse event to childhood development, and depending on further grant allocation, through a life course follow-up.

Exposure to Gestational Diabetes Is a Stronger Predictor of Dysmetabolic Traits in Children Than Size at Birth.

CONTEXT AND OBJECTIVE: Being born small or large for gestational age and intrauterine exposure to gestational diabetes (GDM) increase the risk of type 2 diabetes in the offspring. However, the potential combined deleterious effects of size at birth and GDM exposure remains unknown. We examined the independent effect of size at birth and the influence of GDM exposure in utero on cardiometabolic traits, body composition, and puberty status in children. DESIGN, PARTICIPANTS, AND METHODS: The present study was a longitudinal birth cohort study. We used clinical data from 490 offspring of mothers with GDM and 527 control offspring aged 9 to 16 years, born singleton at term from the Danish National Birth Cohort with available birthweight data. RESULTS: We found no evidence of a U-shaped association between size at birth (expressed as birthweight, sex, and gestational age adjusted z-score) and cardiometabolic traits. Body size in childhood and adolescence reflected the size at birth but was not reflected in any metabolic outcome. No synergistic adverse effect of being born small or large for gestational age and exposure to GDM was shown. However, GDM was associated with an adverse metabolic profile and earlier onset of female puberty in childhood and adolescence independently of size at birth. CONCLUSION: In childhood and adolescence, we found GDM was a stronger predictor of dysmetabolic traits than size at birth. The combination of being born small or large and exposed to GDM does not exacerbate the metabolic profile in the offspring.

Maternal glycemic index and glycemic load in pregnancy and offspring metabolic health in childhood and adolescence-a cohort study of 68,471 mother-offspring dyads from the Danish National Birth Cohort.

BACKGROUND: High glycemic index (GI) and glycemic load (GL) as indicators of carbohydrate quality and quantity have been found to increase risk of metabolic outcomes in adults. Whether carbohydrate quality may influence metabolic programming already in early life is unknown. We examined the association of maternal GI and GL with offspring body mass index (BMI) in the first 7 years of life among 68,471 mother-offspring dyads from the Danish National Birth Cohort (DNBC). In a sub-cohort of offspring with clinical data (n = 1234) that included 608 dyads exposed to gestational diabetes mellitus (GDM), we also examined the relation to metabolic health at 9-16 years. METHODS: Maternal GI and GL were quantified using a mid-pregnancy food frequency questionnaire. We used birth weight and length to calculate offspring's ponderal index. Age- and sex-specific BMI z scores at 5 mo, 12 mo, and 7 y were standardized against WHO reference data. In the clinical cohort, we quantified body composition, HOMA-IR, and HOMA-B. We used multivariable mixed linear and Poisson regression to model the associations. RESULTS: Median (IQR) of GI and GL were 83 (63-111) and 241 (180-333) g/day, respectively. We found that GI (Q4 vs. Q1:1.09, 95%CI: 1.03, 1.15) and GL (Q4 vs. Q1:1.10, 95%CI: 1.05, 1.16) modestly increased the relative risk of large-for gestational age (LGA). In the clinical sub-cohort, we observed a potential increase in offspring HOMA-IR, adiposity, and metabolic syndrome z score with higher maternal GI and GI. These associations were stronger among the GDM-exposed offspring, but the CI included the null value. CONCLUSION: We found associations of GI and GL in pregnancy with offspring LGA. Potential long-term benefits to offspring exposed to GDM need to be confirmed in larger, well-powered studies.

Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children.

Offspring of women with gestational diabetes mellitus (GDM) are at increased risk of developing metabolic disease, potentially mediated by epigenetic mechanisms. We recruited 608 GDM and 626 control offspring from the Danish National Birth Cohort, aged between 9 and 16 years. DNA methylation profiles were measured in peripheral blood of 93 GDM offspring and 95 controls using the Illumina HumanMethylation450 BeadChip. Pyrosequencing was performed for validation/replication of putative GDM-associated, differentially methylated CpGs in additional 905 offspring (462 GDM, 444 control offspring). We identified 76 differentially methylated CpGs in GDM offspring compared with controls in the discovery cohort (FDR, P < 0.05). Adjusting for offspring BMI did not affect the association between methylation levels and GDM status for any of the 76 CpGs. Most of these epigenetic changes were due to confounding by maternal prepregnancy BMI; however, 13 methylation changes were independently associated with maternal GDM. Three prepregnancy BMI-associated CpGs (cg00992687 and cg09452568 of ESM1 and cg14328641 of MS4A3) were validated in the replication cohort, while cg09109411 (PDE6A) was found to be associated with GDM status. The identified methylation changes may reflect developmental programming of organ disease mechanisms and/or may serve as disease biomarkers.

Maternal protein intake in pregnancy and offspring metabolic health at age 9-16 y: results from a Danish cohort of gestational diabetes mellitus pregnancies and controls.

Background: Recent years have seen strong tendencies toward high-protein diets. However, the implications of higher protein intake, especially during developmentally sensitive periods, are poorly understood. Conversely, evidence on the long-term developmental consequences of low protein intake in free-living populations remains limited.Objective: We examined the association of protein intake in pregnancy with offspring metabolic health at age 9-16 y in a longitudinal cohort that oversampled pregnancies with gestational diabetes mellitus (GDM).Design: Six hundred eight women with an index pregnancy affected by gestational diabetes mellitus and 626 controls enrolled in the Danish National Birth Cohort were used for the analysis. Protein (total, animal, vegetable) intake was assessed by using a food-frequency questionnaire in gestational week 25. The offspring underwent a clinical examination including fasting blood samples and a dual-energy X-ray absorptiometry scan (subset of 650) from which metabolic outcomes were derived. Multivariable analyses were conducted applying a 1:1 substitution of carbohydrates for protein.Results: The mean ± SD protein intake in pregnancy was 93 ± 15 g/d (16% ± 3% of energy) in GDM-exposed women and 90 ± 14 g/d (16% ± 2% of energy) in control women. There were overall no associations between maternal protein intake and offspring fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR). We found that maternal total protein intake was associated with a tendency for a higher abdominal fat mass percentage (quartile 4 compared with quartile 1: 0.40 SD; 95% CI: -0.03, 0.83 SD; P = 0.07) in GDM-exposed offspring and a tendency for a higher total fat mass percentage among male offspring (quartile 4 compared with quartile 1: 0.33 SD; 95% CI: -0.01, 0.66 SD; P = 0.06), but a small sample size may have compromised the precision of the effect estimates. GDM-exposed offspring of mothers with a protein intake in the lowest decile (≤12.5% of energy compared with >12.5% of energy) had lower fasting insulin (ratio of geometric means: 0.82; 95% CI: 0.68, 0.99; P = 0.04) and a tendency toward lower HOMA-IR (ratio of geometric means: 0.82; 95% CI: 0.66, 1.02; P = 0.07), but there was no evidence of associations with body composition. Male offspring seemed to derive a similar benefit from a maternal low protein intake as did GDM-exposed offspring.Conclusions: Overall, our results provide little support for an association of maternal protein intake in pregnancy with measures of offspring metabolic health. Further studies in larger cohorts are needed to determine whether low maternal protein intake in pregnancy may improve glucose homeostasis in GDM-exposed and male offspring.

MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.

Microchimerism of male origin in a cohort of Danish girls.

Male microchimerism, the presence of a small number of male cells, in women has been attributed to prior pregnancies. However, male microchimerism has also been reported in women with only daughters, in nulliparous women and prepubertal girls suggesting that other sources of male microchimerism must exist. The aim of the present study was to examine the presence of male microchimerism in a cohort of healthy nulliparous Danish girls aged 10-15 y using DNA extracted from cells from whole blood (buffy coats) and report the association with potential sources of male cells. A total of 154 girls were studied of which 21 (13.6%) tested positive for male microchimerism. There was a tendency that girls were more likely to test positive for male microchimerism if their mothers previously had received transfusion, had given birth to a son or had had a spontaneous abortion. Furthermore, the oldest girls were more likely to test positive for male microchimerism. However, less than half of microchimerism positivity was attributable to these factors. In conclusion, data suggest that male microchimerism in young girls may originate from an older brother either full born or from a discontinued pregnancy or from transfusion during pregnancy. We speculate that sexual intercourse may be important but other sources of male cells likely exist in young girls.

Genetic versus Non-Genetic Regulation of miR-103, miR-143 and miR-483-3p Expression in Adipose Tissue and Their Metabolic Implications-A Twin Study.

Murine models suggest that the microRNAs miR-103 and miR-143 may play central roles in the regulation of subcutaneous adipose tissue (SAT) and development of type 2 diabetes (T2D). The microRNA miR-483-3p may reduce adipose tissue expandability and cause ectopic lipid accumulation, insulin resistance and T2D. We aimed to explore the genetic and non-genetic factors that regulate these microRNAs in human SAT, and to investigate their impact on metabolism in humans. Levels of miR-103, miR-143 and miR-483-3p were measured in SAT biopsies from 244 elderly monozygotic and dizygotic twins using real-time PCR. Heritability estimates were calculated and multiple regression analyses were performed to study associations between these microRNAs and measures of metabolism, as well as between these microRNAs and possible regulating factors. We found that increased BMI was associated with increased miR-103 expression levels. In addition, the miR-103 levels were positively associated with 2 h plasma glucose levels and hemoglobin A1c independently of BMI. Heritability estimates for all three microRNAs were low. In conclusion, the expression levels of miR-103, miR-143 and miR-483-3p in adipose tissue are primarily influenced by non-genetic factors, and miR-103 may be involved in the development of adiposity and control of glucose metabolism in humans.

Physical activity and sedentary behaviors associated with risk of progression from gestational diabetes mellitus to type 2 diabetes mellitus: a prospective cohort study.

IMPORTANCE: Women with a history of gestational diabetes mellitus (GDM) are at substantially increased risk of type 2 diabetes mellitus (T2DM). The identification of important modifiable factors could help prevent T2DM in this high-risk population. OBJECTIVE: To examine the role of physical activity and television watching and other sedentary behaviors, and changes in these behaviors in the progression from GDM to T2DM. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 4554 women from the Nurses' Health Study II who had a history of GDM, as part of the ongoing Diabetes & Women's Health Study. These women were followed up from 1991 to 2007. EXPOSURES: Physical activity and television watching and other sedentary behaviors were assessed in 1991, 1997, 2001, and 2005. MAIN OUTCOMES AND MEASURE: Incident T2DM identified through self-report and confirmed by supplemental questionnaires. RESULTS: We documented 635 incident T2DM cases during 59,287 person-years of follow-up. Each 5-metabolic equivalent hours per week (MET-h/wk) increment of total physical activity, which is equivalent to 100 minutes per week of moderate-intensity physical activity, was related to a 9% lower risk of T2DM (adjusted relative risk [RR], 0.91; 95% CI, 0.88-0.94); this inverse association remained significant after additional adjustment for body mass index (BMI). Moreover, an increase in physical activity was associated with a lower risk of developing T2DM. Compared with women who maintained their total physical activity levels, women who increased their total physical activity levels by 7.5 MET-h/wk or more (equivalent to 150 minutes per week of moderate-intensity physical activity) had a 47% lower risk of T2DM (RR, 0.53; 95% CI, 0.38-0.75); the association remained significant after additional adjustment for BMI. The multivariable adjusted RRs (95% CIs) for T2DM associated with television watching of 0 to 5, 6 to 10, 11 to 20, and 20 or more hours per week were 1 (reference), 1.28 (1.04-1.59), 1.41 (1.11-1.79), and 1.77 (1.28-2.45), respectively (P value for trend <.001); additional adjustment for BMI attenuated the association. CONCLUSIONS AND RELEVANCE: Increasing physical activity may lower the risk of progression from GDM to T2DM. These findings suggest a hopeful message to women with a history of GDM, although they are at exceptionally high risk for T2DM, promoting an active lifestyle may lower the risk.

The triglyceride content in skeletal muscle is associated with hepatic but not peripheral insulin resistance in elderly twins.

CONTEXT AND OBJECTIVE: Total muscle triglyceride (MT) content has been associated with insulin resistance. We investigated the predictors and impact of MT on relevant metabolic parameters including peripheral and hepatic insulin resistance in elderly twins. DESIGN AND PARTICIPANTS: Seventy-four elderly same-sex twins underwent hyperinsulinemic euglycemic clamps preceded by an iv glucose tolerance test. Aerobic capacity (VO2max) and body composition (dual-energy x-ray absorptiometry scan) were determined in all twins. A biopsy from the vastus lateralis muscle was excised in the fasting state. The muscle triacylglycerol content was analyzed by biochemical extraction from these biopsies. RESULTS: The percentage of total body fat was the only independent predictor of MT content. After adjustment for trunk fat percentages and sex, MT level was significantly associated to fasting plasma levels of glucose and insulin as well as hepatic insulin resistance. However, the association was weakened after adjustment for total fat percentages. A 1 SD (34.5 mmol/kg dry weight) increase in MT content was associated with a 24% increase of hepatic insulin resistance. No association between MT content and peripheral insulin sensitivity was observed. CONCLUSION: MT content is associated with hepatic but not peripheral insulin resistance in elderly twins. We speculate that MT content may reflect the general ectopic accumulation of triglycerides, including fat in the liver.