Development and feasibility testing of a time-restricted eating intervention for women living with overweight/obesity and HIV in a resource-limited setting of South Africa.

BACKGROUND: Human Immunodeficiency Virus (HIV) and type 2 diabetes (T2D) are amongst the leading causes of death in South Africa. The preferred first-line anti-retroviral treatment contains dolutegravir (DTG), shown to increase body weight, may compound the already high rates of obesity and associated risk for T2D. South Africa has widespread food insecurity, making traditional dietary strategies difficult to implement. Time-restricted eating (TRE) may be an appropriate intervention in resource-limited communities. METHODS: This article outlines the development and feasibility testing of a TRE intervention to inform the design of a TRE randomised controlled trial in women (20-45 years old) living with overweight/obesity and HIV, receiving DTG-based treatment from a resource-limited community in Cape Town, South Africa. Factors influencing TRE adoption were identified using the Capability, Opportunity, Motivation - Behaviour model and the Theoretical Domains Framework, combining in-depth interviews (IDIs) and focus group discussions. Participants from the IDIs went on to participate in a single arm 4-week TRE pilot trial where feasibility was explored in terms of reach, acceptability, applicability, and implementation integrity. An iterative, thematic analysis approach was employed to analyse the qualitative data. RESULTS: Participants included 33 isiXhosa-speaking women (mean age 37.1 years, mean BMI 35.9 kg/m2). Thematic analysis identified psychological capability (knowledge of fasting), social influences (cultural preferences, family support), and reflective motivation (awareness of weight, health impact, motivation for TRE) as key factors influencing adoption of TRE for weight management. In a 4-week TRE pilot trial (n = 12), retention was 100%. Positive outcomes perceived included improved energy, appetite control and weight loss. TRE was perceived as acceptable, easy, and enjoyable. Family support facilitated adherence, while habitual and social eating and drinking practices were barriers. Compliance was high, aided by self-selected eating times, reminders, and weekly calls. Recommendations included the incorporation of dietary education sessions and text messages to provide additional support and reminders. CONCLUSIONS: This study indicates that TRE is a feasible weight management strategy in women living with overweight/obesity and HIV, receiving DTG-based treatment in a resource-limited community. These findings will ensure that the forthcoming TRE randomised controlled trial is adapted and optimised to the local South African context.

Nut Consumption and Renal Function Among Women With a History of Gestational Diabetes.

OBJECTIVE: Nut 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 METHODS: This 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. RESULTS: We 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. CONCLUSION: Moderate nut consumption may be beneficial to kidney health among women with prior GDM.

TCF7L2 Expression Is Regulated by Cell Differentiation and Overfeeding in Human Adipose Tissue.

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 unknown. We investigate the association between gene variant rs7903146 and metabolic parameters and examine in vitro and ex vivo gene expression of TCF7L2 in human adipose tissue and progenitor cells from two independent populations of young healthy men with increased risk of type 2 diabetes due to low birth weight (LBW). Design: Adipose tissue biopsies were excised from 40 healthy young men with low and normal birth weights (NBW) after a control and 5-day high-fat overfeeding diet. In another cohort including 13 LBW and 13 NBW men, adipocyte progenitor cells were isolated and cultivated. Transcriptome-wide expression was performed on RNA extracted from biopsies or cell cultures. Results: Diet-induced peripheral insulin resistance is more pronounced in carriers of the T-risk allele rs7903146, whereas no association with hepatic insulin resistance was shown. TCF7L2 expression increased during adipogenesis in isolated preadipocytes from both LBW and NBW men (p < 0.001) and correlated positively with markers of progenitor cell proliferation and maturation capacity. In the mature adipose tissue, LBW men had lower expression of TCF7L2 compared to NBW men at baseline (p = 0.03) and TCF7L2 expression was suppressed by short-term overfeeding in NBW men (p = 0.005). Conclusions: The results suggest a regulation of TCF7L2 expression during adipogenesis and in mature adipose tissue upon overfeeding, and further that young men exposed to an adverse intrauterine environment have reduced mature adipose tissue TCF7L2 expression.

Telomere length is reduced in 9- to 16-year-old girls exposed to gestational diabetes in utero.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS/INTERPRETATION: 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.

Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is a common complication of pregnancy that 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 2636 women with GDM and 6086 non-GDM control women from the Nurses' Health Study II and the Danish National Birth Cohort. A total of 112 susceptibility genetic variants confirmed by genome-wide association studies for type 2 diabetes 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 the false discovery rate. 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). In addition, we confirmed three variants, rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs4506565 (TCF7L2), that had previously been significantly associated with GDM risk. Furthermore, compared with participants in the first (lowest) quartile of weighted GRS based on these 11 SNPs, the ORs for 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) for participants in the second, third and fourth (highest) quartiles, 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, BMI and age. CONCLUSIONS/INTERPRETATION: In this large-scale case-control study with women from two independent populations, eight novel GDM SNPs were identified. These findings offer the potential to improve our understanding of the aetiology of GDM, and particularly of biological mechanisms related to beta cell function.

Risk factors of pre-hypertension and hypertension among non-pregnant women of reproductive age in northeastern Tanzania: a community based cross-sectional study.

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.

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding.

AIMS/HYPOTHESIS: Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. METHODS: mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. RESULTS: We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes- and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. CONCLUSIONS/INTERPRETATION: Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes.

AIMS/HYPOTHESIS: We aimed to identify microRNAs (miRNAs) associated with type 2 diabetes and risk of developing the disease in skeletal muscle biopsies from phenotypically well-characterised twins. METHODS: We measured muscle miRNA levels in monozygotic (MZ) twins discordant for type 2 diabetes using arrays. Further investigations of selected miRNAs included target prediction, pathway analysis, silencing in cells and association analyses in a separate cohort of 164 non-diabetic MZ and dizygotic twins. The effects of elevated glucose and insulin levels on miRNA expression were examined, and the effect of low birthweight (LBW) was studied in rats. RESULTS: We identified 20 miRNAs that were downregulated in MZ twins with diabetes compared with their non-diabetic co-twins. Differences for members of the miR-15 family (miR-15b and miR-16) were the most statistically significant, and these miRNAs were predicted to influence insulin signalling. Indeed, miR-15b and miR-16 levels were associated with levels of key insulin signalling proteins, miR-15b was associated with the insulin receptor in non-diabetic twins and knockdown of miR-15b/miR-16 in myocytes changed the levels of insulin signalling proteins. LBW in twins and undernutrition during pregnancy in rats were, in contrast to overt type 2 diabetes, associated with increased expression of miR-15b and/or miR-16. Elevated glucose and insulin suppressed miR-16 expression in vitro. CONCLUSIONS: Type 2 diabetes is associated with non-genetic downregulation of several miRNAs in skeletal muscle including miR-15b and miR-16, potentially targeting insulin signalling. The paradoxical findings in twins with overt diabetes and twins at increased risk of the disease underscore the complexity of the regulation of muscle insulin signalling in glucose homeostasis.

Long-term risk of type 2 diabetes mellitus in relation to BMI and weight change among women with a history of gestational diabetes mellitus: a prospective cohort study.

AIMS/HYPOTHESIS: 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. METHODS: We included 1,695 women who had incident GDM between 1991 and 2001, as part of the Diabetes & Women'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. RESULTS: 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 BMI <25.0 kg/m(2) at baseline and gained <5 kg after GDM. CONCLUSIONS/INTERPRETATION: 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.

Genetic, nongenetic and epigenetic risk determinants in developmental programming of type 2 diabetes.

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.

Rationale, design, and method of the Diabetes & Women's Health study--a study of long-term health implications of glucose intolerance in pregnancy and their determinants.

Women who develop gestational diabetes mellitus or impaired glucose tolerance during pregnancy are at substantially increased risk for type 2 diabetes and comorbidities after pregnancy. Little is known about the role of genetic factors and their interactions with environmental factors in determining the transition from gestational diabetes mellitus to overt type 2 diabetes mellitus. These critical data gaps served as the impetus for this Diabetes & Women's Health study with the overall goal of investigating genetic factors and their interactions with risk factors amenable to clinical or public health interventions in relation to the transition of gestational diabetes mellitus to type 2 diabetes mellitus. To achieve the goal efficiently, we are applying a hybrid design enrolling and collecting data longitudinally from approximately 4000 women with a medical history of gestational diabetes mellitus in two existing prospective cohorts, the Nurses' Health Study II and the Danish National Birth Cohort. Women who had a medical history of gestational diabetes mellitus in one or more of their pregnancies are eligible for the present study. After enrollment, we follow study participants for an additional 2 years to collect updated information on major clinical and environmental factors that may predict type 2 diabetes mellitus risk as well as with biospecimens to measure genetic and biochemical markers implicated in glucose metabolism. Newly collected data will be appended to the relevant existing data for the creation of a new database inclusive of genetic, epigenetic and environmental data. Findings from the study are critical for the development of targeted and more effective strategies to prevent type 2 diabetes mellitus and its complications in this high-risk population.

Differential dietary intake and contribution of ultra-processed foods during pregnancy according to nutritional status.

Introduction: Frequent consumption of ultra-processed foods (UPFs) during pregnancy is linked to excess intake of added sugar, fat, and sodium and inadequacy of several micronutrients. Diet quality during pregnancy should be maximized as inadequate levels of key nutrients and excessive intake of energy and added sugar might influence mother-child health. We aimed to estimate the contribution (% of total calories) of ultra-processed products to the total energy intake by pre-gestational body mass index (BMI) categories and Hb status during pregnancy in participants from the MAS-Lactancia Cohort. Methods: Pre-gestational weight, hemoglobin levels, 24-h dietary intake recall interviews, and sociodemographic data were collected during the second and third trimesters of pregnancy. Reported consumed foods were categorized using the NOVA classification, and the contribution of calories from each NOVA category was estimated using the Mexican Food Database. We estimated medians and interquartile ranges (p25 and p75) for dietary intake and energy contributions. The comparison of intake between the second and third trimesters was done using the Wilcoxon test. In addition, a quantile regression model with an interaction between pre-gestational BMI and Hb levels status in tertiles over the percentage of energy from UPFs was adjusted by age and socioeconomic status. Results: The contribution to total energy intake from UPFs was 27.4% in the second trimester and 27% in the third trimester (with no statistical difference). The percentage of energy intake from UPFs was higher in women who started pregnancy with obesity and presented the lowest levels of Hb (1st tertile), 23.1, 35.8, and 44.7% for the 25th, 50th, and 75th percentiles, respectively, compared to those with normal BMI and the highest tertile of Hb levels: 18, 29.0, and 38.6% for the 25th, 50th, and 75th percentiles, respectively. Conclusion: In conclusion, UPF intake in pregnant women is similar to the general population and was higher for those with pre-gestational obesity and the lowest tertile of Hb levels. UPF contributes also to sugar, saturated fat, and sodium, which may adversely affect the health of mothers and their offspring.

Skeletal muscle fibre type and enzymatic activity in adult offspring following placental and peripheral malaria exposure in foetal life.

Background: Maternal malaria may restrict foetal growth. Impaired utero-placental blood flow due to malaria infection may cause hypoxia-induced altered skeletal muscle fibre type distribution in the offspring, which may contribute to insulin resistance and impaired glucose metabolism. This study assessed muscle fibre distribution 20 years after placental and/or peripheral in-utero malaria exposure compared to no exposure, i.e., PPM+, PM+, and M-, respectively. Methods: We traced 101 men and women offspring of mothers who participated in a malaria chemosuppression study in Muheza, Tanzania. Of 76 eligible participants, 50 individuals (29 men and 21 women) had skeletal muscle biopsy taken from m. vastus lateralis in the right leg. As previously reported, fasting and 30 min post-oral glucose challenge plasma glucose values were higher, and insulin secretion disposition index was lower, in the PPM+ group. Aerobic capacity (fitness) was estimated by an indirect VO2max test on a stationary bicycle. Muscle fibre sub-type (myosin heavy chain, MHC) distribution was analysed, as were muscle enzyme activities (citrate synthase (CS), 3-hydroxyacyl-CoA dehydrogenase, myophosphorylase, phosphofructokinase, lactate dehydrogenase, and creatine kinase activities. Between-group analyses were adjusted for MHC-I %. Results: No differences in aerobic capacity were found between groups. Despite subtle elevations of plasma glucose levels in the PPM+ group, there was no difference in MHC sub-types or muscle enzymatic activities between the malaria-exposed and non-exposed groups. Conclusion: The current study did not show differences in MHC towards glycolytic sub-types or enzymatic activity across the sub-groups. The results support the notion of the mild elevations of plasma glucose levels in people exposed to placental malaria in pregnancy being due to compromised pancreatic insulin secretion rather than insulin resistance.

Influence of placental and peripheral malaria exposure in fetal life on cardiometabolic traits in adult offspring.

INTRODUCTION: Fetal 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 METHODS: We 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. RESULTS: Offspring 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. CONCLUSIONS: Using 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.

Independent phenotypic plasticity axes define distinct obesity sub-types.

Studies in genetically 'identical' individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this 'unexplained' phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either 'normal' or 'overgrown'. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent ß-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.

Cumulative Lactation and Clinical Metabolic Outcomes at Mid-Life among Women with a History of Gestational Diabetes.

Lactation is associated with a lower risk of subsequent cardiometabolic disease among parous women; however, the underlying mechanisms are unknown. Further, the potential protective effects of lactation on cardiometabolic risk markers at mid-life among high-risk women with past gestational diabetes (GDM) are not established. Using data from the Diabetes & Women's Health Study (2012−2014; n = 577), a longitudinal cohort of women with past GDM from the Danish National Birth Cohort (1996−2002), we assessed associations of cumulative lactation duration (none, <6 months, 6−12 months, ≥12−24 months, and ≥24 months) with clinical metabolic outcomes (including type 2 diabetes [T2D], prediabetes, and obesity) and cardiometabolic biomarkers (including biomarkers of glucose/insulin metabolism, fasting lipids, inflammation, and anthropometrics) 9−16 years after enrollment when women were at mid-life. At follow-up, women were 43.9 years old (SD 4.6) with a BMI of 28.7 kg/m2 (IQR 24.6, 33.0); 28.6% of participants had T2D, 39.7% had prediabetes, and 41.2% had obesity. Relative risks (95% CI) of T2D for 0−6, 6−12, 12−24, and ≥24 months of cumulative lactation duration compared to none were 0.94 (0.62,1.44), 0.88 (0.59,1.32), 0.73 (0.46,1.17), and 0.71 (0.40,1.27), respectively. Cumulative lactation duration was not significantly associated with any other clinical outcome or continuous biomarker. In this high-risk cohort of middle-aged women with past GDM, T2D, prediabetes, and obesity were common at follow-up, but not associated with history of cumulative lactation duration 9−16 years after the index pregnancy. Further studies in diverse populations among women at mid-age are needed to understand associations of breastfeeding with T2D.

Lactation Duration and Long-term Risk for Incident Type 2 Diabetes in Women With a History of Gestational Diabetes Mellitus.

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.

Genetic factors and risk of type 2 diabetes among women with a history of gestational diabetes: findings from two independent populations.

OBJECTIVE: Women 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 METHODS: This 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. RESULTS: Women 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

Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibers and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609.

OBJECTIVE: Recent studies identified the rs9939609 A-allele of the FTO (fat mass and obesity associated) gene as being associated with obesity and type 2 diabetes. We studied the role of the A-allele in the regulation of peripheral organ functions involved in the pathogenesis of obesity and type 2 diabetes. METHODS: Forty-six young men underwent a hyperinsulinemic euglycemic clamp with excision of skeletal muscle biopsies, an iv glucose tolerance test, 31phosphorous magnetic resonance spectroscopy, and 24-h whole body metabolism was measured in a respiratory chamber. RESULTS: The FTO rs9939609 A-allele was associated with elevated fasting blood glucose and plasma insulin, hepatic insulin resistance, and shorter recovery half-times of phosphocreatine and inorganic phosphate after exercise in a primarily type I muscle. These relationships--except for fasting insulin--remained significant after correction for body fat percentage. The risk allele was not associated with fat distribution, peripheral insulin sensitivity, insulin secretion, 24-h energy expenditure, or glucose and fat oxidation. The FTO genotype did not influence the mRNA expression of FTO or a set of key nuclear or mitochondrially encoded genes in skeletal muscle during rest. CONCLUSION: Increased energy efficiency--and potentially increased mitochondrial coupling--as suggested by faster recovery rates of phosphocreatine and inorganic phosphate in oxidative muscle fibers may contribute to the increased risk of obesity and type 2 diabetes in homozygous carriers of the FTO A-risk allele. Hepatic insulin resistance may represent the key metabolic defect responsible for mild elevations of fasting blood glucose associated with the FTO phenotype.

Diabetes in pregnancy and epigenetic mechanisms-how the first 9 months from conception might affect the child's epigenome and later risk of disease.

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.