The potential impact of the fetal genotype on maternal blood pressure during pregnancy.

The heritability of pregnancy-induced hypertension (encompassing both gestational hypertension and preeclampsia) is around 0.47, suggesting that there is a genetic component to its development. However, the maternal genetic risk variants discovered so far only account for a small proportion of the heritability. Other genetic variants that may affect maternal blood pressure in pregnancy arise from the fetal genome, for example wild-type pregnant mice carrying offspring with Cdkn1c or Stox1 disrupted develop hypertension and proteinuria. In humans, there is a higher risk for preeclampsia in women carrying fetuses with Beckwith-Wiedemann syndrome (including those fetuses with CDKN1C mutations) and a lower risk for women carrying babies with trisomy 21. Other risk may be associated with imprinted fetal growth genes and genes that are highly expressed in the placenta such as GCM1. This article reviews the current state of knowledge linking the fetal genotype with maternal blood pressure in pregnancy.MRCThis is the Author Accepted Manuscript of Petry CJ, Beardsall K, Dunger DB. "The potential impact of the fetal genotype on maternal blood pressure during pregnancy". published in the Journal of Hypertension. The published version is available at http://dx.doi.org/10.1097/HJH.000000000000021

Gestational diabetes mellitus in Africa: a systematic review.

BACKGROUND: Gestational diabetes mellitus (GDM) is any degree of impaired glucose tolerance first recognised during pregnancy. Most women with GDM revert to normal glucose metabolism after delivery of their babies; however, they are at risk of developing type 2 diabetes later in life as are their offspring. Determining a country's GDM prevalence can assist with policy guidelines regarding GDM screening and management, and can highlight areas requiring research. This systematic review assesses GDM prevalence in Africa. METHODS AND FINDINGS: Three electronic databases were searched without language restrictions; PubMed, Scopus and the Cochrane Library. Thirty-one search terms were searched. Eligible articles defined GDM, stated what GDM screening approaches were employed and reported GDM prevalence. The reporting quality and risk of bias within each study was assessed. The PRISMA guidelines for systematic reviews were followed. The literature search identified 466 unique records. Sixty full text articles were reviewed of which 14 were included in the systematic review. One abstract, for which the full text article could not be obtained, was also included. Information regarding GDM classification, screening methods and prevalence was obtained for six African countries; Ethiopia (n = 1), Morocco (n = 1), Mozambique (n = 1), Nigeria (n = 6), South Africa (n= 4) and Tanzania (n = 1). Prevalence figures ranged from 0% (Tanzania) to 13.9% (Nigeria) with some studies focussing on women with GDM risk factors. Most studies utilised the two hour 75 g oral glucose tolerance test and applied the World Health Organization's diagnostic criteria. CONCLUSIONS: Six countries, equating to 11% of the African continent, were represented in this systematic review. This indicates how little is known about GDM in Africa and highlights the need for further research. Considering the increasing public health burden of obesity and type 2 diabetes, it is essential that the extent of GDM is understood in Africa to allow for effective intervention programmes.This is the final published version of the article. It was originally published here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0097871

Associations between Maternal Iron Supplementation in Pregnancy and Changes in Offspring Size at Birth Reflect Those of Multiple Micronutrient Supplementation.

It was previously observed that in a population of a high-income country, dietary multiple micronutrient supplementation in pregnancy was associated with an increased risk of gestational diabetes (GDM) and increased offspring size at birth. In this follow-up study, we investigated whether similar changes are observed with dietary iron supplementation. For this we used the prospective Cambridge Baby Growth Study with records of maternal GDM status, nutrient supplementation, and extensive offspring birth size measurements. Maternal iron supplementation in pregnancy was associated with GDM development (risk ratio 1.67 (1.01-2.77), p = 0.048, n = 677) as well as offspring size and adiposity (n = 844-868) at birth in terms of weight (β' = 0.078 (0.024-0.133); p = 0.005), head circumference (β' = 0.060 (0.012-0.107); p = 0.02), body mass index (β' = 0.067 (0.014-0.119); p = 0.01), and various skinfold thicknesses (β' = 0.067-0.094; p = 0.03-0.003). In a subset of participants for whom GDM statuses were available, all these associations were attenuated by adjusting for GDM. Iron supplementation also attenuated the associations between multiple micronutrient supplementation and these same measures. These results suggest that iron supplementation may mediate the effects associated with multiple micronutrient supplementation in pregnancy in a high-income country, possibly through the increased risk of developing GDM

Persisting benefits 12-18 months after discontinuation of pubertal metformin therapy in low birthweight girls.

BACKGROUND: Discontinuation of metformin therapy, if started beyond menarche in adolescents or young women with hyperinsulinaemia following low birthweight, is rapidly followed by rebound deteriorations in body fat, insulin resistance and blood lipid profile. OBJECTIVE: We hypothesized that early commencement of metformin and its continuation throughout puberty might have more persisting benefits. PATIENTS AND MEASUREMENTS: We followed up on a previously reported randomized study cohort at 12 months and 18 months after treatment discontinuation, including body composition by absorptiometry, fasting insulin, glucose and blood lipids. In that open-labelled, prospective study, 22 low birthweight girls with early normal puberty (Stage 2 breast development at age 8-9 years) were randomized to remain untreated (N = 12] or to receive metformin (850 mg/day; N = 10) for 36 months (between time -36 months to 0 month). RESULTS: The significant improvements previously reported at the end of the 36-month active treatment period in per cent body fat, abdominal fat mass, fasting insulin sensitivity, high density lipoprotein (HDL) cholesterol and triglyceride levels all persisted at follow-up 12 months after treatment discontinuation. Further anthropometry at 18 months off therapy confirmed the persistence of benefits in height, body mass index (BMI) and waist circumference in the previously metformin-exposed girls. CONCLUSION: In low birth weight girls with early normal onset of puberty, metformin treatment for 3 years across puberty resulted in auxological, endocrine and metabolic benefits that persisted for at least 1 year after metformin withdrawal. Further follow-up and longer-term studies are needed to explore the possibility that insulin sensitization therapy during puberty might reprogramme predisposition to metabolic disease

Simple and effective exercise design for assessing in vivo mitochondrial function in clinical applications using (31)P magnetic resonance spectroscopy.

The growing recognition of diseases associated with dysfunction of mitochondria poses an urgent need for simple measures of mitochondrial function. Assessment of the kinetics of replenishment of the phosphocreatine pool after exercise using (31)P magnetic resonance spectroscopy can provide an in vivo measure of mitochondrial function; however, the wider application of this technique appears limited by complex or expensive MR-compatible exercise equipment and protocols not easily tolerated by frail participants or those with reduced mental capacity. Here we describe a novel in-scanner exercise method which is patient-focused, inexpensive, remarkably simple and highly portable. The device exploits an MR-compatible high-density material (BaSO4) to form a weight which is attached directly to the ankle, and a one-minute dynamic knee extension protocol produced highly reproducible measurements of post-exercise PCr recovery kinetics in both healthy subjects and patients. As sophisticated exercise equipment is unnecessary for this measurement, our extremely simple design provides an effective and easy-to-implement apparatus that is readily translatable across sites. Its design, being tailored to the needs of the patient, makes it particularly well suited to clinical applications, and we argue the potential of this method for investigating in vivo mitochondrial function in new cohorts of growing clinical interest.We are grateful to all the participants. This work was funded by the Clinical Research Infrastructure Grant. We thank the National Institute for Health Research (NIHR) Cambridge BioResource and S. Nutland, for facilitating the recruitment of the 24 BioResource volunteers. We thank the NIHR Cambridge Biomedical Research Centre for funding the BioResource and we also acknowledge research grants from Addenbrooke's Charitable Trust and the British Society for Pediatric Endocrinology and Diabetes. D.B.S. is supported by the Wellcome Trust [091551] and the U.K. National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. A.S. and the Siemens MAGNETOM 3T Verio scanner are funded by the NIHR via an award to the Cambridge NIHR/Wellcome Trust Clinical Research Facility. A.T. and D.B.D. are supported by the U.K. NIHR Cambridge Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep19057

Abdominal fat depots associated with insulin resistance and metabolic syndrome risk factors in black African young adults

Abstract Background Individuals of black African ethnicity tend to have less visceral adipose tissue (VAT) but more subcutaneous-abdominal adipose tissue (SCAT) than white Caucasians. However, it is unclear whether such distribution of abdominal fat is beneficial for metabolic disease risk in black individuals. Here we compared the associations between these specific abdominal fat depots, insulin sensitivity and metabolic syndrome risk. Methods A cross-sectional analysis of 76 black South African young adults (36 men; 40 women) aged 18–19 years participating in the Birth to Twenty Cohort Study had VAT and SCAT measured by MRI. The metabolic syndrome traits (blood pressure, lipid profile, fasting glucose and insulin) were measured and the values were combined into a metabolic syndrome risk score. Fasting glucose and insulin were used to derive the HOMA-index of insulin resistance (HOMA-IR). Results Compared to men, women had greater VAT (mean: 16.6 vs. 12.5 cm2) and SCAT (median 164.0 vs. 59.9 cm2). In men, SCAT (r = 0.50) was more strongly correlated to the metabolic syndrome score (MetS) than was VAT (r = 0.23), and was associated with both MetS (P = 0.001) and HOMA-IR (P = 0.001) after adjustment for VAT and total fat mass. In women, both abdominal fat compartments showed comparable positive correlations with MetS (r = 0.26 to 0.31), although these trends were weaker than in men. Conclusions In young black South African adults, SCAT appears to be more relevant than VAT to metabolic syndrome traits

The association between age at menarche and later risk of gestational diabetes is mediated by insulin resistance.

AIMS: Associations have been reported between age at menarche and the later risk of gestational diabetes. However, it is not known whether these associations reflect differences in insulin sensitivity and/or pancreatic β-cell function in pregnancy. METHODS: We examined this question in women enrolled in the prospective Cambridge Baby Growth Study who recalled their age at menarche in questionnaires during pregnancy. Polynomial logistic and linear regression models were used to relate menarche timing to the risk of gestational diabetes, both unadjusted and adjusted for the Homeostasis Model Assessments of insulin resistance (HOMA IR) and pancreatic β-cell function (HOMA B) at week 28 of pregnancy. RESULTS: Age at menarche showed a U-shaped association with gestational diabetes risk (linear term: p = 9.5 × 10-4; quadratic term: p = 1.0 × 10-3; n = 889; overall model p = 8.1 × 10-3). Age at menarche showed a negative linear association with insulin resistance (HOMA IR: β = -0.13, p = 5.2 × 10-4, n = 771), which explained the relationship between age at menarche and gestational diabetes risk (adjusted linear term going from p = 0.03-0.08; adjusted quadratic term going from p = 0.04-0.08; n = 771). Age at menarche also showed a negative linear association with β-cell function (HOMA B: β = -0.11, p = 2.8 × 10-3, n = 771) but this did not attenuate the relationship between age at menarche and gestational diabetes (adjusted linear term p = 0.02; adjusted quadratic term p = 0.03, n = 771). CONCLUSIONS: These results suggest that the associations between age at menarche and risk of gestational diabetes and raised pregnancy glucose concentrations may be mediated by insulin resistance.Funding for this study has come from the Wellbeing of Women (the Royal College of Obstetricians and Gynaecologists, UK) (RG1644). Other core funding has come from the Medical Research Council (7500001180, G1001995, U106179472), European Union Framework 5 (QLK4-1999-01422), the Mothercare Charitable Foundation (RG54608), Newlife Foundation for Disabled Children (07/20), and the World Cancer Research Fund International (2004/03). In addition, there has been support from National Institute for Health Research Cambridge Biomedical Research Centre. KO is supported by the Medical Research Council (Unit Programme number: MC_UU_12015/2)

Compositional marker in vivo reveals intramyocellular lipid turnover during fasting-induced lipolysis

Intramyocellular lipid (IMCL) is of particular metabolic interest, but despite many proton magnetic resonance spectroscopy (¹H MRS) studies reporting IMCL content measured by the methylene (CH₂) resonance signal, little is known about its composition. Here we validated IMCL CH₃:CH₂ ratio as a compositional marker using ¹H MRS at short echo time, and investigated IMCL content and composition during a 28-hour fast in 24 healthy males. Increases in IMCL CH₂ relative to the creatine and phosphocreatine resonance (Cr) at 3.0 ppm (an internal standard) correlated with circulating free fatty acid (FA) concentrations, supporting the concept of increased FA influx into IMCL. Significant decreases in IMCL CH₃:CH₂ ratio indicated a less unsaturated IMCL pool after fasting, and this compositional change related inversely to IMCL baseline composition, suggesting a selective efflux of unsaturated shorter-chain FA from the IMCL pool. This novel in vivo evidence reveals IMCL turnover during extended fasting, consistent with the concept of a flexible, responsive myocellular lipid store. There were also differences between soleus and tibialis anterior in basal IMCL composition and in response to fasting. We discuss the potential of this marker for providing insights into normal physiology and mechanisms of disease.We thank the participants, staff at the Cambridge NIHR/Wellcome Trust Clinical Research Facility and the Wolfson Brain Imaging Centre, Sarah Nutland (NIHR Cambridge BioResource, Cambridge, UK) for facilitating participant recruitment and Edwina French (MRC Laboratory of Molecular Biology, Cambridge, UK) for help with phantoms. We acknowledge grants from Addenbrooke’s Charitable Trust and the British Society for Pediatric Endocrinology and Diabetes. LH is a British Heart Foundation Senior Fellow in Basic Science. DBS is supported by the Wellcome Trust (107064). AT, AK and DBD are funded by the UK NIHR Cambridge Biomedical Research Centre and Medical Research Council (UD99999906), and AS by the NIHR via the NIHR Cambridge Clinical Research Facility

Lipidomic analyses, breast- and formula-feeding, and growth in infants.

OBJECTIVE: To evaluate lipidomic differences between breast- and formula-fed infants. STUDY DESIGN: We utilized high-resolution mass-spectrometry methods to analyze 3.2 mm dried blood spot samples collected at ages 3 months (n = 241) and 12 months (n = 144) from a representative birth cohort study. Lipidomic profiles were compared between infants exclusively breast-fed, formula-fed, or mixed-fed, and related to 12-month infancy weight. Data analysis included supervised multivariate statistics (partial least squares discriminant analysis), and univariate analysis with correction for multiple testing. RESULTS: Distinct differences in 3-month lipidomic profiles were observed between exclusively breast-fed and formula-fed infants; mixed-fed infants showed intermediate profiles. Principle lipidomic characteristics of breast-fed infants were lower total phosphatidylcholines (PCs), with specifically lower short chain unsaturated PC but higher long chain polyunsaturated PC; higher cholesterol esters; and variable differences in sphingomyelins. At 12 months, lipidomic profiles were markedly different to those at 3 months, and differences between the earlier breast/formula/mixed-feeding groups were no longer evident. However, several specific lipid species, associated with breast-feeding at 3 months, also correlated with differences in 3- to 12-month weight. CONCLUSIONS: State-of-the-art dried blood spot sample lipidomic profiling demonstrated striking differences between breast-fed and formula-fed infants. Although these changes diminished with age, breast-fed lipidomic profiles at 3 months were associated with infancy weight and could potentially represent biomarkers of infant nutrition.PP was supported by a UK MRC Clinical Training Fellowship (G1001995). The Cambridge Baby Growth Study has been supported by the European Union, the World Cancer Research Foundation International, the Medical Research Council (including a centenary award), and the NIHR Cambridge Comprehensive Biomedical Research Centre. The lipidomics assays were supported by the Medical Research Council (UD99999906 and Cambridge Lipidomics Biomarker Research Initiative G0800783).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.jpeds.2014.10.02