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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 VO 2max 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.

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.

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.

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

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 5 0.003) and exclusive breastfeeding (P-trend 5 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.

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: 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

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.

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.

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.

Low birth weight (LBW) is common in the Indian population and may represent an important predisposing factor for type 2 diabetes (T2D) and the metabolic syndrome. Intensive metabolic examinations in ethnic LBW Asian Indians have been almost exclusively performed in immigrants living outside India. Therefore, we aimed to study the metabolic impact of being born with LBW in a rural non-migrant Indian population.