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IntroductionFetal malaria exposure may lead to intrauterine growth restriction and increase the risk of developing diabetes and cardiovascular diseases in adulthood. We investigated the extent to which fetal peripheral and placental malaria exposure impacts insulin sensitivity and secretion, body composition and cardiometabolic health 20 years after in utero malaria exposure.Research design and methodsWe traced 101 men and women in Muheza district, Tanga region whose mothers participated in a malaria chemosuppression during a pregnancy study in 1989–1992. All potential participants were screened for malaria, hepatitis B and HIV to ascertain study eligibility. Seventy-six individuals (44 men, 32 women) were included in this cohort study. The participants underwent a thorough clinical examination including anthropometric measurements, ultrasound scanning for abdominal fat distribution, blood pressure, 75 g oral glucose tolerance test, an intravenous glucose tolerance test followed by a hyperinsulinemic euglycemic clamp and a submaximal exercise test.ResultsOffspring exposed to placental malaria during pregnancy had significantly higher 30-minute plasma post-glucose load levels, but no significant difference in peripheral insulin resistance, insulin secretion or other cardiometabolic traits compared with non-exposed individuals.ConclusionsUsing the state-of-the-art euglycemic clamp technique, we were unable to prove our a priori primary hypothesis of peripheral insulin resistance in young adult offspring of pregnancies affected by malaria. However, the subtle elevations of plasma glucose might represent an early risk marker for later development of type 2 diabetes if combined with aging and a more obesogenic living environment.

Author(s): Hinkle, Stefanie N; Rawal, Shristi; Bjerregaard, Anne Ahrendt; Halldorsson, Thor I; Li, Mengying; Ley, Sylvia H; Wu, Jing; Zhu, Yeyi; Chen, Liwei; Liu, Aiyi; Grunnet, Louise Groth; Rahman, Mohammad L; Kampmann, Freja Bach; Mills, James L; Olsen, Sjurdur F; Zhang, Cuilin | Abstract: BackgroundArtificially 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.ObjectiveThe aim of this study was to examine associations of ASB intake and cardiometabolic health among high-risk women with prior gestational diabetes mellitus (GDM).MethodsWe 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 a 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.ResultsIn 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 l1 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.ConclusionsAmong Danish women with a history of GDM, ASB intake was not significantly associated with cardiometabolic profiles.

Aim: The TCF7L2 gene variant rs7903146 has the largest effect on type 2 diabetes risk reported in genome-wide association studies, however its role in adipose tissue development and function is unk...

Offspring of women with gestational diabetes mellitus (GDM) exhibit a high risk of developing type 2 diabetes later in life, potentially as a result of developmental programming by epigenetic mechanisms (1,2). We read with great interest the meta-analysis by Howe et al. (3) integrating results of differential cord blood DNA methylation changes from seven epigenome-wide association studies (EWAS) including in total 3,677 mother-newborn pairs. Pregnancies complicated with GDM were associated with significantly lower cord blood methylation levels within the promoter region of the OR2L13 gene, as well as within the gene body of the CYP2E1 gene (3). At single CpG site levels, the authors reported GDM to be associated with differential methylations at six distinct CpG sites (3). As pointed out by Howe et al., replication of EWAS analyses is extremely important due to 1 ) high risk of confounders; 2 ) in general, small absolute methylation differences; and 3 ) analytical uncertainties related to multiple comparisons and adjustment for cell …

ObjectiveNut intake has been associated with reduced cardiometabolic risk, but few studies have examined its association with renal function. We examined associations between nut intake and renal function among women with previous gestational diabetes mellitus (GDM), a population with an increased risk for renal dysfunction.Design and methodsThis study included 607 women with a history of GDM who participated in the Diabetes & Women's Health Study (2012-2014) follow-up clinical examination in Denmark. At the clinic, biospecimens were collected, and habitual intake of nuts (9 types) in the past year was assessed using a food frequency questionnaire. A total of 330 women free of major chronic diseases were included in the analysis. Total nut intake was classified as none (≤1 serving/month), monthly (2-3 servings/month), weekly (1-6 servings/week), and daily (≥1 serving/day). One serving was defined as 28 g. Renal function markers included estimated glomerular rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), calculated based on plasma creatinine (mg/dL), and urinary albumin (mg/L), and creatinine (mg/dL) measurements, respectively. We estimated percent differences with 95% confidence intervals for each outcome by nut intake, adjusted for current body mass index, age, physical activity, energy intake, alcohol consumption, and vegetables intake.ResultsWe observed a nonlinear association between total nut intake and UACR with lowest UACR values among women with weekly intake. Compared to women with weekly intake (n=222), the adjusted UACR values were higher by 86% [95% confidence interval: 15%, 202%], 24% [-1%, 54%], and 117% [22%, 288%] among women with no (n=13), monthly (n=86), and daily (n=9) intake, respectively. Compared to weekly consumers, daily nut consumers also had 9% [0%, 19%] significantly higher eGFR values, but eGFR values were similar among women with no and monthly intake.ConclusionModerate nut consumption may be beneficial to kidney health among women with prior GDM.

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&ndash, 34 of gestation. Gestational diabetes mellitus was diagnosed according to the WHO 2013 guidelines. Out of 392 women screened, 39% (95% CI: 34.2&ndash, 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.

Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational-age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) n = 1470) and NGA as BW between 10 and 90th percentile (n = 14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3–12%, P = 0.002) higher intake of added sugar and a 2–8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n−6, compared with NGA girls (P < 0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded.

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.

Objective Fetal exposure to gestational diabetes mellitus (GDM) increases the risk of metabolic diseases in the offspring. Leptin, adiponectin, and fibroblast growth factor 21 (FGF21) may play potential roles in the underlying disease mechanisms. We investigated the impact of fetal exposure to GDM on leptin, adiponectin, and FGF21 concentrations and their associations with measures of adiposity and metabolic traits during childhood/adolescence. Design and methods The follow-up study included 504 GDM and 540 control offspring aged 9–16 from the Danish National Birth Cohort. Anthropometric measurements, fasting blood samples, puberty status and fat percentages by dual-energy X-ray absorptiometry were examined. Serum concentrations of leptin, adiponectin, and FGF21 were measured by validated immune assays. Results GDM offspring had 38% (95% CI: 22–55%) higher leptin, 0.6 mg/L (95% CI: −1.2, −0.04 mg/L) lower adiponectin, and 32% (95% CI: −47%, −12%) lower FGF21 concentrations than control offspring (P P = 0.06) and significantly lower FGF21 concentrations (P = 0.006). When accounting for offspring BMI z-score, GDM exposure had no significant independent effect on leptin or adiponectin concentrations, whereas FGF21 was still significant. In univariate analyses, leptin and adiponectin were associated with fasting insulin, HOMA-IR, and adiposity, and FGF21 with total fat percentage. Conclusions GDM offspring had higher leptin, lower adiponectin and FGF21 concentrations than control offspring. Elevated leptin and decreased adiponectin concentrations associated with adverse metabolic traits and were most likely driven by higher obesity prevalence among GDM offspring. The functional implications of decreased FGF21 concentrations among GDM offspring need to be further explored.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication which has substantial short- and long-term adverse health implications for women and their children. However, large-scale studies on genetic risk loci for GDM remain sparse. METHODS: We conducted a case-control study among 2,636 GDM cases and 6,086 non GDM controls from the Nurses’ Health Study II (NHSII) and the Danish National Birth Cohort (DNBC). One hundred and twelve susceptibility genetic variants confirmed by genome-wide association studies for type 2 diabetes (T2D) were selected and measured. A weighted genetic risk score (GRS) was created based on variants that were significantly associated with risk of GDM after correcting for false discovery rate (FDR). RESULTS: For the first time, we identified eight variants associated with GDM, namely rs7957197 (HNF1A), rs10814916 (GLIS3), rs3802177 (SLC30A8), rs9379084 (RREB1), rs34872471 (TCF7L2), rs7903146 (TCF7L2), rs11787792 (GPSM1), and rs7041847 (GLIS3). Additionally, we confirmed three variants, rs10830963 (MTNR1B), rs1387153 (MTNR1B), and rs4506565 (TCF7L2), that were previously significantly associated with GDM risk. Furthermore, compared to participants in the first (lowest) quartile of weighted GRS based on these 11 SNPs, the odds ratios of GDM were 1.07 (95% CI: 0.93, 1.22), 1.23 (95% CI 1.07, 1.41), and 1.53 (95% CI 1.34, 1.74) in the second, third, and fourth (highest) quartile, respectively. The significant positive associations between the weighted GRS and risk of GDM persisted across most of the strata of major risk factors for GDM including family history of type 2 diabetes, smoking status, body mass index, and age. CONCLUSION: In this large-scale case-control study with women from two independent populations, eight novel GDM SNPs were identified, which offers potential to improve our understanding on GDM etiology, particularly biological mechanisms related to beta cell function.

Shortened telomere length is a marker of cell damage and is associated with oxidative stress, chronic inflammation and metabolic disease. We hypothesised that the offspring of women with gestational diabetes mellitus (GDM) with increased risk of cardiovascular and metabolic diseases might exhibit shorter telomere length. We investigated telomere length in 439 GDM and 469 control group offspring, aged between 9 and 16 years, recruited from the Danish National Birth Cohort. Relative telomere length was measured in peripheral blood DNA (n = 908) using a quantitative PCR approach. Multivariate regression analysis was used to investigate the association between mothers’ GDM status and telomere length in the offspring. Female offspring had longer telomeres than males. Offspring of mothers with GDM had significantly shorter telomere length than control offspring, but this difference was observed only in girls. There was a negative association between telomere length and GDM exposure among the female offspring (14% shorter telomeres, p = 0.003) following adjustment for the age of the offspring. Telomere length in female offspring was negatively associated with fasting insulin levels and HOMA-IR (p = 0.03). Maternal age, smoking, gestational age, birthweight and the offspring’s anthropometric characteristics were not associated with telomere length (p ≥ 0.1). The 9- to 16-year-old girls of mothers with GDM had shorter telomeres than those from the control population. Further studies are needed to understand the extent to which shortened telomere length predicts and/or contributes to the increased risk of disease later in life among the offspring of women with GDM.

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.

OBJECTIVE We examined the association of lactation duration with incident type 2 diabetes among women with a history of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We monitored 4,372 women with a history of GDM participating in the Nurses’ Health Study II for incident type 2 diabetes over 25 years up to 2017. Lactation history was obtained through follow-up questionnaires to calculate lactation duration. Follow-up blood samples were collected from a subset of these women at median age of 58 years through the Diabetes & Women’s Health Study. RESULTS We documented 873 incident cases of type 2 diabetes during 87,411 person-years of follow-up. Longer duration of lactation was associated with lower risk of type 2 diabetes for both total lactation (hazard ratio 1.05 [95% CI 0.83–1.34] for up to 6 months, 0.91 [0.72–1.16] for 6–12 months, 0.85 [0.67–1.06] for 12–24 months, and 0.73 [0.57–0.93] for >24 months, compared with 0 months; P-trend = 0.003) and exclusive breastfeeding (P-trend = 0.002) after adjustment for age, ethnicity, family history of diabetes, parity, age at first birth, smoking, diet quality, physical activity, and prepregnancy BMI. Longer duration of lactation was also associated with lower HbA1c, fasting plasma insulin, and C-peptide concentrations among women without type 2 diabetes at follow-up (all adjusted P-trend ≤0.04). CONCLUSIONS Longer duration of lactation is associated with a lower risk of type 2 diabetes and a favorable glucose metabolic biomarker profile among women with a history of GDM. The underlying mechanisms and impact on diabetes complications, morbidity, and mortality remain to be determined.

Supplemental Digital Content is available in the text., Background: Road traffic is a major source of air pollution and noise. Both exposures may contribute to increased blood pressure and metabolic disease; however, few studies have examined these relationships in children. Objectives: We aimed to investigate whether long-term exposures to air pollution and noise from road traffic were associated with increased blood pressure and insulin resistance in children. Methods: Cardiometabolic outcomes were derived from a follow-up examination of 629 children (10–15 years old) enrolled in the Danish National Birth Cohort. We evaluated associations with prenatal and postnatal residential exposure to nitrogen dioxide (NO2) and noise from road traffic (Lden) using historical addresses and linear regression models. Results: A 10-unit increase in postnatal exposure to NO2 and Lden was associated with a 0.31 (−0.87, 1.48) and 0.18 (−0.61, 0.96) mmHg changes in diastolic blood pressure, respectively. In contrast, both exposures were associated with decreased systolic blood pressure. After adjustment and mutual adjustment for NO2, exposure to Lden was associated with a statistical significant decrease in systolic blood pressure both during prenatal and postnatal life, but the majority of the associations evaluated did not reach statistical significance. Inverse associations were observed for plasma fasting glucose, insulin, and HOMA of insulin resistance for both exposures, exposure windows, before and after adjustment. Conclusions: The findings do not support evidence of associations between long-term exposures to air pollution and road traffic noise, increased blood pressure, and a metabolic profile characteristic of increased risk for glucose intolerance or type 2 diabetes later in life.

Abdominal subcutaneous and visceral adipose tissue thickness was examined by ultrasound in 17 men with low birth weight (LBW) and 26 with normal BW control individuals to determine if abdominal obesity in LBW individuals is due to increased visceral or subcutaneous fat mass/thickness, or both. Men born with LBW had an increased waist-to-hip ratio (P = 0.04), greater abdominal fat thickness (P = 0.05) and increased visceral (VAT) and subcutaneous adipose tissue (SAT) thickness compared with controls, however the latter not statistically significant (P = 0.08, P = 0.10). A significant difference between birth weight groups in both SAT (P = 0.04) and VAT (P = 0.03) was found after adjustment for weight, whereas no significant difference in either SAT (P = 0.93) or VAT (P = 0.30) was found after adjustment for BMI. Increased waist-to-hip ratio in LBW individuals is due to increased total abdominal fat including both subcutaneous and visceral fat.

Telomeres are protein-bound regions of repetitive nucleotide sequences (TTAGGG) at the end of human chromosomes, and their length is a marker of cellular aging. Intrauterine growth restriction is associated with shorter blood cell telomeres at birth and individuals with type 2 diabetes have shorter telomeres. Individuals with a low birth weight (LBW) have an increased risk of metabolic disease and type 2 diabetes. Therefore, we aimed to investigate the relationship between birth weight and telomere length and the association between birth weight, telomere length and cardiometabolic phenotype in adulthood. Young, healthy men with LBW (n = 55) and normal birth weight (NBW) (n = 65) were examined including blood pressure, blood samples and body composition. Leukocyte telomere length was determined using a high-throughput qPCR method. The LBW men were more insulin resistant as determined by the HOMA-IR index. There was no difference in telomere length between LBW and NBW subjects. When adjusting for birth weight and cohort effect, significant negative associations between telomere length and fasting glucose (P = 0.003) and HbA1c (P = 0.0008) were found. In conclusion, no significant difference in telomere length was found between LBW and NBW men. The telomere length was negatively associated with glucose concentrations and HbA1c levels within the normal non-diabetic range independent of birth weight.

OBJECTIVES: Women with gestational diabetes (GDM) are at increased risk for renal complications later in life. Nut intake has been associated with reduced cardiometabolic risk, but few studies have examined its association with renal function. We examined associations of nut intake and renal function among women with prior GDM. METHODS: We studied 330 women from the Danish National Birth Cohort (1996–2002) with a GDM pregnancy who participated in a clinical exam 9 to 16 years after the index pregnancy as part of the Diabetes & Women's Health Study (2012–2014) and were free of major chronic diseases at follow-up. Habitual past year intake of nine types of nuts was ascertained at follow-up using a food frequency questionnaire. Total nut intake was classified as none (1 serving/d). Estimated glomerular filtration rate (eGFR) via CKD-EPI equation and urine albumin-to-creatinine ratio (UACR) were calculated based on serum creatinine (mg/dL) and urine albumin (mg/L), and creatinine (mg/dL) measurements respectively. We estimated % differences with 95% confidence intervals (CI) in these outcomes by nut intake adjusted for current body mass index, age, physical activity, energy intake, and dietary variables. We explored possible non-linear relations using restricted cubic splines. RESULTS: A significant non-linear U-shaped association was detected between total nut consumption and UACR (P = 0.001) with lowest UACR levels among women with weekly consumption. Compared to women with weekly intake (n = 222), adjusted UACR levels were 86% [95% CI: 15%, 200%] and 23% [−1%, 54%] higher among women with no or monthly nut intake, respectively, while UACR levels were 118% [22%, 286%] higher among women with daily intake. Compared to weekly consumers, adjusted eGFR levels were 9% [0%, 19%] higher among daily consumers. CONCLUSIONS: Moderate nut consumption may be beneficial to kidney health among women with prior GDM. FUNDING SOURCES: Intramural Research Program of the NICHD, March of Dimes Birth Defects Foundation, Innovation Fund Denmark, Health Foundation, Heart Foundation, EU, Danish Diabetes Academy supported by Novo Nordisk Foundation, and NIH Building Interdisciplinary Research Careers in Women's Health Program.

Background: Offspring of mothers with gestational diabetes mellitus (GDM) are at increased risk of developing metabolic diseases. Adipokines such as adiponectin and leptin may be involved in the underlying mechanisms. Fibroblast growth factor 21 (FGF-21) has recently been identified as a potent metabolic regulator. Therefore, we investigated the impact of fetal exposure to GDM on adiponectin, leptin and FGF-21 levels and their associations with metabolic and adiposity traits during adolescence. Methods: A prospective study comparing 502 offspring of GDM exposed mothers and 535 offspring of non-exposed mothers. During a clinical exam of offspring, aged 9-16 years old, metabolic traits were measured and fasting blood samples collected and assayed for serum concentrations of leptin, adiponectin and FGF-21. Results: GDM exposed offspring had 34% (95% CI: 18-51%) higher leptin levels, and 34% (95% CI: -48, -15%) lower FGF-21 concentrations than non-exposed offspring (p Conclusion: GDM exposed offspring had higher leptin and lower FGF-21 concentrations than non-exposed controls, but this was driven by higher prevalence of adiposity among GDM offspring. The differential adipokine concentration does not seem to be the major driver behind the dysmetabolic phenotype among GDM offspring. Disclosure F.B. Kampmann: None. A. Thuesen: None. L. Hjort: None. M. Bjerre: None. J. Frystyk: None. I. Tetens: None. A.A. Bjerregaard: None. J.E. Chavarro: None. S.F. Olsen: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. A.A. Vaag: Employee; Self; AstraZeneca. L. Grunnet: None. Funding Danish Council for Strategic Research; Innovation Fund, Denmark (09-067124, 11-115923); Novo Nordisk Foundation (NNF160C0022518); Danish Diabetes Academy

Background: Women with prior gestational diabetes (GDM) are at exceptionally high risk for type 2 diabetes (T2D). Yet, little is known about genetic determinants for the progression to T2D from GDM. Further, inference from existing data is hindered by small sample size. In a large study based on two independent populations, we examined a genetic risk score (GRS) for T2D in relation to the progression risk. Methods: This study included white women in the Diabetes and Women’s Health Study, which followed women with GDM from the Nurses’ Health Study II (NHSII, N = 1998) and the Danish National Birth Cohort (DNBC, N = 550). A GRS of T2D was calculated using 59 T2D SNPs (GRS59) from genome-wide association studies in European populations. GRS scores for beta-cell function (GRSBC) and insulin resistance (GRSIR) were derived based on subsets of these SNPs. The relative risks (RRs) of progression to T2D were estimated using log-binomial regression. RRs from the two cohorts were meta-analyzed using fixed effects models. Results: During the study follow-ups of more than 10 years after the index pregnancy, 416 (20.8%) in NHSII and 155 (28.2%) women in DNBC developed T2D. GRS59 was positively related to the risk of progression to T2D. RRs (95% CI) for increasing quartiles of GRS59 were 1.00, 0.99 (0.79, 1.23), 1.26 (1.03, 1.55), and 1.25 (1.01, 1.53), respectively (p-trend = 0.008). The associations were significantly stronger among lean (pre-pregnant BMI < 25 kg/m2) than overweight or obese women (p-interaction < 0.001). Further, GRSIR, but not GRSBC, was related to the risk of T2D. RRs (95% CI) for increasing quartiles of GRSIR were 1.00, 1.25 (1.02, 1.55), 1.32 (1.07, 1.64), and 1.29 (1.05, 1.58), respectively (p-trend = 0.02). The results were generally consistent across the two cohorts. Conclusion: In this large prospective study of women with prior GDM, greater GRS of T2D, especially GRS of insulin resistance, was associated with greater risk of progression to T2D. Disclosure M. Li: None. M.L. Rahman: None. J. Wu: None. M. Ding: None. J.E. Chavarro: None. Y. Lin: None. S.H. Ley: None. L. Grunnet: None. S. Hinkle: None. A. Thuesen: None. E. Yeung: None. R.E. Gore-Langton: None. S.J. Sherman: None. L. Hjort: None. F.B. Kampmann: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. F. Tekola-Ayele: None. A. Liu: None. J. Mills: None. A.A. Vaag: Employee; Self; AstraZeneca. S.F. Olsen: None. F. Hu: None. C. Zhang: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; March of Dimes Birth Defects Foundation; Innovation Fund Denmark; Health Foundation; Heart Foundation; European Union

Background and Aims: The prevalence of gestational diabetes mellitus (GDM) is increasing world-wide and it complicates around 1-10% of all pregnancies. GDM is associated with increased risk of long-term metabolic health consequences for both mother and child. In Tanzania, GDM prevalence increased from 0% in 1991 to 19.5% in 2016. Furthermore, the prevalence seems to be dependent on the living conditions, thus an overall GDM prevalence of 5.9% was found in urban areas and 1.0% in rural areas in Tanzania. We aimed to examine the prevalence of GDM in a rural district of North-Eastern Tanzania based upon an oral glucose tolerance test (OGTT) with subsequent fasting blood samples. Methods: The participants were included in a large population-based pre-pregnancy study named ”FOETALforNCD - Foetal Exposure and Epidemiological Transition: The Role of Anaemia in Early Life for Non-Communicable Diseases in Later Life." In total, 538 women were included in the pregnancy study; hereof 403 women were screened with an OGTT at week 32-34 of gestation, after 12 hours of fasting. GDM was diagnosed according to the WHO 2013 guidelines. Results: The OGTT results showed that 153 women had GDM, i.e., a prevalence of 39.0%. The majority (94.1%) were diagnosed based on the fasting blood sample. When examine the blood samples from the follow-up of the 153 women diagnosed with GDM, 41 had a confirmed GDM diagnosis (39 had repeated fasting blood sample and 2 had a repeated OGTT. In the remaining 112 women. GDM could not be validated. 40 women had repeated fasting blood samples, 43 had random blood samples, 3 had a repeated OGTT and 26 had no further blood samples taken. Conclusion: A very high prevalence of GDM was found in this part of Tanzania. In view of the laborious, costly and patient unfriendly OGTT, in low and middle-income countries alternative methods should be considered to be used to diagnose GDM. Disclosure L. Grunnet: None. L. Hjort: None. B.B. Nielsen: None. D.T. Minja: None. O.A. Msemo: None. J.P. Lusingu: None. R.B. Prasad: None. L. Groop: None. T.G. Theander: None. C. Schmiegelow: None. I.C. Bygbjerg: None. D.L. Christensen: None. Funding Danish Council for Strategic Research (1309-00003B)

PurposeLow-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.ParticipantsThe 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 dateAt 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 Future plansThe 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.

Women with gestational diabetes mellitus (GDM) may be at an increased risk of liver complications because chronic hyperglycemia is a risk factor for liver fat accumulation and potential liver dysfunction. Large prospective studies examining liver fat accumulation following a GDM pregnancy are lacking.The DiabetesWomen's Health Study (2012-2014) examined the association between GDM and subsequent fatty liver scores among 607 women with and 619 women without GDM in the Danish National Birth Cohort. Nine to 16 years postpartum, a clinical examination was performed, with measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase, from which fatty liver scoring indices were calculated to assess liver fat score, fatty liver index, hepatic steatosis index, and liver fat percentage. Relative risks (RR) with 95% confidence intervals (CI) for elevated liver scoring indices by GDM status were assessed adjusting for major risk factors, including prepregnancy body mass index.Women with prior GDM had higher adjusted ALT and AST levels than women without GDM (by 6.7% [95% CI 1.7-12.0] and 4.8% [95% CI 0.6-9.1], respectively). Women with GDM also had adjusted increased risks for elevated liver fat score (RR 2.34; 95% CI 1.68-3.27), fatty liver index (RR 1.59; 95% CI 1.27-1.99), and hepatic steatosis index (RR 1.44; 95% CI 1.21-1.71).Women with GDM during pregnancy were at an increased risk for fatty liver 9 to 16 years postpartum. Gestational diabetes mellitus may serve as another risk indicator for the early identification and prevention of liver fat accumulation.背景: 妊娠期糖尿病(gestational diabetes mellitus，GDM)女性发生肝脏并发症的风险可能增加，因为慢性高血糖是肝脏脂肪蓄积及潜在肝功能异常的危险因素。目前评估GDM患者产后肝脏脂肪蓄积的大型前瞻性研究不足。 方法: 糖尿病与女性健康研究(The DiabetesWomen's Health Study, 2012-2014)使用丹麦国家出生队列，在607例合并GDM的女性和619例无GDM的女性中调查了GDM与后续脂肪肝评分之间的相关性。在产后9-16年进行临床检查，测定丙氨酸氨基转移酶(alanine aminotransferase，ALT)、天冬氨酸氨基转移酶(aspartate aminotransferase，AST)和γ-谷氨酰转移酶，由此计算脂肪肝评分指标，评估肝脏脂肪评分、脂肪肝指数、肝脏脂肪变性指数以及肝脏脂肪百分比。校正主要风险因素(包括妊娠前体重指数)后，根据GDM状态评估导致肝脏评分指标升高的相对风险(relative risk，RR)及其95%可信区间(confidence interval，CI)。 结果: 既往患GDM的女性校正的ALT及AST水平均高于无GDM的女性(分别高出6.7%[95% CI: 1.7-12.0]与4.8%[95% CI: 0.6-9.1])。GDM女性的校正后肝脏脂肪评分(RR 2.34；95% CI: 1.68-3.27)、脂肪肝指数(RR 1.59；95% CI: 1.27-1.99)及肝脏脂肪变性指数(RR 1.44；95% CI: 1.21-1.71)升高的风险也增加。 结论: 妊娠期合并GDM的女性在产后9-16年发生脂肪肝的风险增加。GDM可作为早期发现和预防肝脏脂肪蓄积的另一个风险指标。.

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.

Diabetes in pregnancy is not only associated with increased risk of pregnancy complications and subsequent maternal metabolic disease, but also increases the risk of long-term metabolic disease in the offspring. At the interface between genetic and environmental factors, epigenetic variation established in utero represents a plausible link between the in utero environment and later disease susceptibility. The identification of an epigenetic fingerprint of diabetes in pregnancy linked to the metabolic health of the offspring might provide novel biomarkers for the identification of offspring most at risk, before the onset of metabolic dysfunction, for targeted monitoring and intervention. In this Personal View, we (1) highlight the scale of the problem of diabetes in pregnancy, (2) summarise evidence for the variation in offspring epigenetic profiles following exposure to diabetes in utero, and (3) outline potential future approaches to further understand the mechanisms by which exposure to maternal metabolic dysfunction in pregnancy is transmitted through generations.

Background Given the long-term adverse sequelae of childhood obesity, identification of early life factors related to fetal growth and childhood obesity is warranted. Investigation on growth and obesity in early life in association with intrauterine exposure to maternal hyperglycemia, a common metabolic pregnancy complication, is of public health significance and clinical implications. Objective We investigated the association of fasting plasma glucose (FPG) concentrations during pregnancy with offspring growth and risk of overweight/obesity through age 7 y, after adjustment for confounders, including maternal prepregnancy obesity status. Design FPG concentrations at 28 gestational weeks (IQR: 22-32 wk) were extracted from medical records for 661 pregnancies complicated by gestational diabetes mellitus in the Danish National Birth Cohort (1996-2002). Offspring's ponderal index was derived from birth weight and length; age- and sex-specific body mass index (BMI) z scores at 5 mo, 12 mo, and 7 y were calculated based on WHO reference data. Relations between FPG and offspring growth and obesity were assessed by linear and Poisson regression with robust standard errors, adjusting for maternal prepregnancy BMI and sociodemographic and perinatal factors. Results At birth, maternal FPG during pregnancy was significantly associated with offspring ponderal index (β = 0.46; 95% CI: 0.14, 0.78 per 1-mmol/L increase) and risk of macrosomia (birth weight >4000 g) (RR = 1.21; 95% CI: 1.07, 1.38 per 1-mmol/L increase). At 7 y, higher maternal FPG concentrations were significantly associated with increased BMI z scores (β = 0.20; 95% CI: 0.04, 0.36) and elevated risk of overweight/obesity (RR = 1.21; 95% CI: 1.01, 1.50). Additional adjustment for birth weight and childhood lifestyle factors did not appreciably alter results. No associations were observed at 5 or 12 mo. Conclusion Among women with gestational diabetes mellitus, maternal FPG concentrations during pregnancy were significantly and positively associated with offspring birth size and overweight/obesity risk at 7 y, adjusting for maternal prepregnancy BMI.

ObjectiveWomen with a history of gestational diabetes mellitus (GDM) have an exceptionally high risk for type 2 diabetes (T2D). Yet, little is known about genetic determinants for T2D in this population. We examined the association of a genetic risk score (GRS) with risk of T2D in two independent populations of women with a history of GDM and how this association might be modified by non-genetic determinants for T2D.Research design and methodsThis cohort study included 2434 white women with a history of GDM from the Nurses’ Health Study II (NHSII, n=1884) and the Danish National Birth Cohort (DNBC, n=550). A GRS for T2D was calculated using 59 candidate single nucleotide polymorphisms for T2D identified from genome-wide association studies in European populations. An alternate healthy eating index (AHEI) score was derived to reflect dietary quality after the pregnancy affected by GDM.ResultsWomen on average were followed for 21 years in NHSII and 13 years in DNBC, during which 446 (23.7%) and 155 (28.2%) developed T2D, respectively. The GRS was generally positively associated with T2D risk in both cohorts. In the pooled analysis, the relative risks (RRs) for increasing quartiles of GRS were 1.00, 0.97, 1.25 and 1.19 (p trend=0.02). In both cohorts, the association appeared to be stronger among women with poorer (AHEI ConclusionsAmong white women with a history of GDM, higher GRS for T2D was associated with an increased risk of T2D.

Publisher's version (útgefin grein), Oily fish, an important source of marine n-3 long-chain polyunsaturated fatty acids (LCPUFA), has shown to reduce cardiometabolic risk in adults. Whether maternal fish intake affects offspring metabolic health is less established, especially among high-risk pregnancies. We aimed to examine the association of fish intake in pregnancy with offspring metabolic health who were either exposed or unexposed to gestational diabetes mellitus (GDM). Our study included 1234 mother-offspring dyads (608 with a GDM index pregnancy and 626 control dyads) nested within the Danish National Birth Cohort, which is a prebirth cohort. Maternal seafood and marine n-3 LCPUFA consumption was quantified by a food frequency questionnaire (gestational week 25) and a sub-sample with interview data (weeks 12 and 30). The offspring were clinically examined at 9–16 years, including a Dual energy X-ray Absorptiometry (DXA) scan and a fasting blood sample. We calculated multivariable effect estimates and 95% confidence intervals (CI) for anthropometric, adiposity, and metabolic parameters. The median (IQR) intake of total seafood was 23(24) g/day. We found largely no association for total seafood and marine n-3 LCPUFA with offspring metabolic parameters in either group. Using interview data, GDM-exposed women reporting no fish in week 12 and 30 (versus intake >2 times/week) had offspring with a higher Body Mass Index (BMI) (ratio of geometric means (RGM): 1.28, 95% CI: 1.06, 1.55), waist circumference (RGM: 1.22, 95% CI: 1.05, 1.40), triglycerides (RGM: 1.77, 95% CI: 1.03, 3.03), and homeostatic model assessment of insulin resistance HOMA-IR (RGM: 2.16, 95% CI: 1.17, 3.97). We found no associations of n-3 LCPUFA and seafood intake with offspring metabolic outcomes. However, GDM-exposed women who consistently reported eating no fish had offspring with a poorer metabolic profile. Fish intake in pregnancy may mitigate some adverse effects of intrauterine hyperglycemia, however, these findings need replication in better powered studies., This work was part of the project “Long-term effects of early nutrition on later health” supported by the European Commission (Project No.: FP7-289346-EarlyNutrition). E.M. was supported by a fellowship grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation. Further funding for the data collections was provided by grants from the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming) and 09-075611); the Innovation Fund Denmark (11-115923) and Rigshospitalet, Copenhagen University Hospital.

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.

Lactation is associated with reduced postpartum weight retention and a lower risk of several cardiometabolic disorders in population-based studies. We examined the association between lactation and long-term thyroid function among women with history of gestational diabetes mellitus (GDM), a high-risk population for subsequent metabolic complications. The study included 550 women who developed GDM in the Danish National Birth Cohort (1996&ndash, 2002) and followed-up in the Diabetes &amp, Women&rsquo, s Health Study (2012&ndash, 2014). We assessed adjusted associations between cumulative lactation duration and concentrations of thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) measured at follow-up. Women with longer cumulative lactation duration tended to have higher fT3 levels (adjusted &beta, and 95% confidence interval (CI) for &ge, 12 months vs. none: 0.19 (0.03&ndash, 0.36), p-trend = 0.05). When restricted to women with a single lifetime pregnancy to control for parity (n = 70), women who lactated for &gt, 6 months (vs. none) had higher fT3 levels (0.46 pmol/L (0.12&ndash, 0.80), p-trend = 0.02) and a higher fT3:fT4 ratio (0.61 (0.17&ndash, 1.05), p-trend = 0.007). Our findings suggested that a longer duration of lactation may be related to greater serum fT3 levels and fT3:fT4 ratio 9&ndash, 16 years postpartum among Danish women with a history of GDM. The association was particularly pronounced among women who only had one lifetime pregnancy.

Objectives: To determine risk factors of pre-hypertension and hypertension in a cohort of 1247 rural Tanzanian women before conception. Methods: Demographic and socioeconomic data, anthropometric measurements, past medical and obstetric history and other risk factors for pre-hypertension and hypertension were collected using a structured questionnaire. Multiple logistic regression analysis was used to evaluate the associations between anthropometric indices and other risk factors of pre-hypertension and hypertension. The predictive power of different anthropometric indicators for identification of pre-hypertension and hypertension patients was determined by Receiver Operating Characteristic curves (ROC). Results: The median (range) age was 28.0 (18–40) years. The age-standardised prevalences of pre-hypertension and hypertension were 37.2 (95% CI 34.0–40.6) and 8.5% (95%CI 6.7–10.8), respectively. Of hypertensive patients (n = 98), only 20 (20.4%) were aware of their condition. In multivariate analysis, increasing age, obesity and haemoglobin levels were significantly associated with pre-hypertension and hypertension. Conclusion: Despite a low prevalence of hypertension, over one third of the women had pre-hypertension. This poses a great challenge ahead as pre-hypertensive women may progress into hypertension as they grow older without appropriate interventions. Obesity was the single most important modifiable risk factor for pre-hypertension and hypertension.

OBJECTIVE To examine whether gestational diabetes mellitus (GDM), independent of subsequent diabetes, is an early risk factor for renal impairment long term after the index pregnancy. RESEARCH DESIGN AND METHODS In the Diabetes & Women’s Health (DWH) study (2012–2016), we examined the independent and joint associations of GDM and subsequent diabetes with long-term renal function among 607 women with and 619 women without GDM in the Danish National Birth Cohort (DNBC) index pregnancy (1996–2002). At median follow-up of 13 years after the index pregnancy, serum creatinine (mg/dL) and urinary albumin (mg/L) and creatinine (mg/dL) were measured, from which estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) and urinary albumin-to-creatinine ratio (UACR) (mg/g) were derived. RESULTS Compared with women without GDM or subsequent diabetes, women with a GDM history had significantly higher eGFR even if they had not subsequently developed diabetes (adjusted β-coefficient [95% CI] = 3.3 [1.7, 5.0]). Women who had a GDM history and later developed diabetes (n = 183) also had significantly higher UACR [exponent β = 1.3 [95% CI 1.1, 1.6]) and an increased risk of elevated UACR (≥20 mg/g) [adjusted relative risk [95% CI] = 2.3 [1.1, 5.9]) compared with women with neither. After adjusting for potential confounders including prepregnancy BMI and hypertension, GDM without subsequent diabetes was not related to UACR. CONCLUSIONS Women who develop GDM in pregnancy were more likely to show increased eGFR levels 9–16 years postpartum, which could indicate early stages of glomerular hyperfiltration and renal damage. However, only those who subsequently developed diabetes showed overt renal damage as evidenced by elevated UACR.

Aims To assess young healthy men from rural India, who had normal or low birth weights, using magnetic resonance spectroscopy to determine the potential differences in ectopic fat storage between birth weight groups, and to determine if ectopic fat storage was associated with insulin resistance in this population. Methods A total of 54 lean men with normal birth weight and 49 lean men with low birth weight (age range 18–22 years) from rural India were recruited. All the men underwent anthropometry, magnetic resonance spectroscopy, a hyperinsulinaemic-euglycaemic clamp and a dual-energy X-ray absorptiometry. Results The median (interquartile range) values for hepatic cellular lipids, intramyocellular lipids and extramyocellular lipids, measured using magnetic resonance spectroscopy were 0.76 (0.1–1.8)%, 1.27 (1.0–2.3)% and 1.89 (1.3–3.2)%, respectively, for the normal birth weight group and 0.4 (0.1–1.3)%, 1.38 (0.9–2.2)% and 2.07 (1.2–2.8)%, respectively, for the low birth weight group (P > 0.05). No difference in ectopic fat storage was observed between the low and normal birth weight groups, with or without adjustment for age and total fat percentage. Homeostatic model assessment of insulin resistance values were not associated with hepatic cellular, intramyocellular or extramyocellular lipid content in any of the groups. Total fat percentage was the only independent predictor of intramyocellular and extramyocellular lipid content. Conclusion Young and lean men from rural India with low birth weight were not observed to have ectopic fat storage in the liver or muscle, and the amount of liver and muscle fat was unrelated to insulin resistance. Older age and/or an urban affluent lifestyle may be required to show a potential role of ectopic fat storage on insulin resistance in Indian people with low or normal birth weight.

Women with a history of gestational diabetes mellitus (GDM) are advised to control their weight after pregnancy. We aimed to examine how adiposity and weight change influence the long-term risk of developing type 2 diabetes after GDM.We included 1,695 women who had incident GDM between 1991 and 2001, as part of the DiabetesWomen's Health study, and followed them until the return of the 2009 questionnaire. Body weight and incident type 2 diabetic cases were reported biennially. We defined baseline as the questionnaire period when women reported an incident GDM pregnancy. We estimated HRs and 95% CIs using Cox proportional hazards models.We documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. The adjusted HRs of type 2 diabetes associated with each 1 kg/m(2) increase in BMI were 1.16 (95% CI 1.12, 1.19) for baseline BMI and 1.16 (95% CI 1.13, 1.20) for most recent BMI. Moreover, each 5 kg increment of weight gain after GDM development was associated with a 27% higher risk of type 2 diabetes (adjusted HR 1.27; 95% CI 1.04, 1.54). Jointly, women who had a BMI ≥30.0 kg/m(2) at baseline and gained ≥5 kg after GDM had an adjusted HR of 43.19 (95% CI 13.60, 137.11), compared with women who had a BMI25.0 kg/m(2) at baseline and gained5 kg after GDM.Baseline BMI, most recent BMI and weight gain after GDM were significantly and positively associated with risk of progression from GDM to type 2 diabetes.

Physical inactivity and low birth weight (LBW) may lead to an increased risk for developing type 2 diabetes. The extent to which LBW individuals may benefit from physical exercise training when compared with those with normal birth weight (NBW) controls is uncertain. We assessed the impact of an outdoor exercise intervention on body composition, insulin secretion and action in young men born with LBW and NBW in rural India. A total of 61 LBW and 56 NBW healthy young men were recruited into the study. The individuals were instructed to perform outdoor bicycle exercise training for 45 min every day. Fasting blood samples, intravenous glucose tolerance tests and bioimpedance body composition assessment were carried out. Physical activity was measured using combined accelerometry and heart rate monitoring during the first and the last week of the intervention. Following the exercise intervention, the LBW group displayed an increase in physical fitness [55.0 ml (O2)/kg min (52.0−58.0)−57.5 ml (O2)/kg min (54.4−60.5)] level and total fat-free mass [10.9% (8.0−13.4)−11.4% (8.0−14.6)], as well as a corresponding decline in the ratio of total fat mass/fat-free mass. In contrast, an increase in total fat percentage as well as total fat mass was observed in the NBW group. After intervention, fasting plasma insulin levels, homoeostasis model assessments (HOMA) of insulin resistance (HOMA-IR) and insulin secretion (HOMA-IS), improved to the same extent in both the groups. In summary, young men born with LBW in rural India benefit metabolically from exercise training to an extent comparable with NBW 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.

Background Artificial sweeteners are widely replacing caloric sweeteners. Data on long-term impact of artificially sweetened beverage (ASB) consumption during pregnancy on offspring obesity risk are lacking. We prospectively investigated intake of ASBs and sugar-sweetened beverages (SSBs) during pregnancy in relation to offspring growth through age 7 years among high-risk children born to women with gestational diabetes. Methods In a prospective study of 918 mother-singleton child dyads from the Danish National Birth Cohort, maternal dietary intake was assessed by a food frequency questionnaire during pregnancy. Offspring body mass index z-scores (BMIZ) and overweight/obesity status were derived using weight and length/height at birth, 5 and 12 months and 7 years. Linear regression and Poisson regression with robust standard errors were used, adjusting for major risk factors. Results Approximately half of women reported consuming ASBs during pregnancy and 9% consumed daily. Compared to never consumption, daily ASB intake during pregnancy was positively associated with offspring large-for-gestational age [adjusted relative risk (aRR) 1.57; 95% CI: 1.05, 2.35 at birth], BMIZ (adjusted β 0.59; 95% CI: 0.23, 0.96) and overweight/obesity (aRR 1.93; 95% CI; 1.24, 3.01) at 7 years. Per-serving-per-day substitution of ASBs with water during pregnancy was related to a lower overweight/obesity risk at 7 years (aRR 0.83; 95% CI: 0.76, 0.91), whereas SSB substitution with ASBs was not related to a lower risk (aRR 1.14; 95% CI: 1.00, 1.31). Conclusions Our findings illustrated positive associations between intrauterine exposure to ASBs and birth size and risk of overweight/obesity at 7 years. Data with longer follow-up are warranted.

OBJECTIVE Offspring of pregnancies affected by gestational diabetes mellitus (GDM) are at increased risk of the development of type 2 diabetes. However, the extent to which these dysmetabolic traits may be due to offspring and/or maternal adiposity is unknown. We examined body composition and associated cardiometabolic traits in 561 9- to 16-year-old offspring of mothers with GDM and 597 control offspring. RESEARCH DESIGN AND METHODS We measured anthropometric characteristics; puberty status; blood pressure; and fasting glucose, insulin, C-peptide, and lipid levels; and conducted a DEXA scan in a subset of the cohort. Differences in the outcomes between offspring of mothers with GDM and control subjects were examined using linear and logistic regression models. RESULTS After adjustment for age and sex, offspring of mothers with GDM displayed higher weight, BMI, waist-to-hip ratio (WHR), systolic blood pressure, and resting heart rate and lower height. Offspring of mothers with GDM had higher total and abdominal fat percentages and lower muscle mass percentages, but these differences disappeared after correction for offspring BMI. The offspring of mothers with GDM displayed higher fasting plasma glucose, insulin, C-peptide, HOMA-insulin resistance (IR), and plasma triglyceride levels, whereas fasting plasma HDL cholesterol levels were decreased. Female offspring of mothers with GDM had an earlier onset of puberty than control offspring. Offspring of mothers with GDM had significantly higher BMI, WHR, fasting glucose, and HOMA-IR levels after adjustment for maternal prepregnancy BMI, and glucose and HOMA-IR remained elevated in the offspring of mothers with GDM after correction for both maternal and offspring BMIs. CONCLUSIONS In summary, adolescent offspring of women with GDM show increased adiposity, an adverse cardiometabolic profile, and earlier onset of puberty among girls. Increased fasting glucose and HOMA-IR levels among the offspring of mothers with GDM may be explained by the programming effects of hyperglycemia in pregnancy.

Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared with nongenetic and epigenetic risk determinants and disease mechanisms.

PurposeWomen 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.ParticipantsThe 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 dateProgression 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 plansPrimary 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.

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.

Twenty years ago, Hales and Barker along with their co-workers published some of their pioneering papers proposing the ‘thrifty phenotype hypothesis’ in Diabetologia (4;35:595–601 and 3;36:62–67). Their postulate that fetal programming could represent an important player in the origin of type 2 diabetes, the metabolic syndrome and cardiovascular disease (CVD) was met with great scepticism. More recently, their observations have been confirmed and expanded in many epidemiological and animal experimental studies, and human integrative physiological studies have provided insights into some of the underlying molecular mechanisms. Type 2 diabetes is a multiple-organ disease, and developmental programming, with its idea of organ plasticity, is a plausible hypothesis for a common basis for the widespread organ dysfunctions in type 2 diabetes and the metabolic syndrome. Only two among the 45 known type 2 diabetes susceptibility genes are associated with low birthweight, indicating that the association between low birthweight and type 2 diabetes is mainly non-genetic. Prevention programmes targeting adult lifestyle factors seems unable to stop the global propagation of type 2 diabetes, and intensive glucose control is inadequate to reduce the excess CVD mortality in type 2 diabetic patients. Today, the thrifty phenotype hypothesis has been established as a promising conceptual framework for a more sustainable intergenerational prevention of type 2 diabetes.

Several studies suggest a link between increased activity of the inflammatory inhibitor-kappaB kinase/nuclear factor-kappaB (IKK/NF-kappaB) pathway in skeletal muscle and insulin resistance.We aimed to study the regulation of skeletal muscle IKK/NF-kappaB pathway activity as well as the association with glucose metabolism and skeletal muscle insulin signaling.The study population included a metabolically well-characterized cohort of young and elderly predominantly nondiabetic twins (n = 181). Inhibitor-kappaBbeta (IkappaBbeta) protein levels are negatively associated with IKK/NF-kappaB pathway activity and were used to evaluate pathway activity with p65 levels included as loading control. This indirect measure for IKK/NF-kappaB pathway activity was validated by a p65 binding assay.Evaluating the effects of heritability, age, sex, obesity, aerobic capacity, and several hormonal factors (eg insulin and TNF-alpha), only sex and age were significant predictors of IkappaBbeta to p65 ratio (28% decreased ratio in the elderly, P0.01, and 49% increased in males P0.01). IkappaBbeta to p65 ratio was unrelated to peripheral insulin sensitivity (P = 0.51) and in accordance with this also unrelated to proximal insulin signaling (P = 0.81). Although no association was seen with plasma glucose after oral glucose challenge, there was a tendency for lower IkappaBbeta to p65 ratio (adjusted for age and sex) in subjects with impaired as opposed to normal glucose tolerance (P = 0.055).Altogether the subtle elevated IKK/NF-kappaB pathway activity seen in glucose-intolerant subjects suggests that IKK/NF-kappaB pathway activation may be secondary to impaired glucose tolerance and that skeletal muscle IKK/NF-kappaB pathway activity is unlikely to play any major role in the control of skeletal muscle insulin action in nondiabetic subjects.

We hypothesized a nongenetic influence of birth weight (BW) and twin and zygosity status on dual-energy x-ray absorptiometry determined adult total and regional body composition and a quantitative equal, although independent, importance of adult body composition and BW for insulin sensitivity.This was a clinical study of 110 young (aged 22-31 yr) and 86 elderly twins (aged 57-66 yr) and 32 age-matched controls with measures of BW, adult body composition, and insulin sensitivity.BW was nongenetically, positively associated with height, weight, and total and regional (trunk, arm, and leg) fat mass and percentages in the young twins. In the elderly twins, BW was persistently nongenetically related to height as well as leg fat mass and percentage. Insulin sensitivity was nongenetically influenced by total fat percentage as well as arm and trunk fat percentages, all leading to a decrease in insulin sensitivity by 20% per sd increase in the elderly twins. Conversely, a sd increase in BW led to an increase of 16% in insulin sensitivity. Total body fat and regional fat was similarly associated with insulin sensitivity in the younger twins, whereas no influence of BW was seen.BW was nongenetically, positively associated with adult height and total and regional fat mass in an age-dependent manner. BW and total and regional body fat percentages were nongenetically associated with insulin sensitivity in the elderly subjects, supporting an influence of the fetal environment on insulin sensitivity that is quantitatively similar to and independent of the effect of adult adiposity.