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Glycogen metabolism in β-cells may affect downstream metabolic pathways controlling insulin release. We examined glycogen metabolism in human islets and in the rodent-derived INS-1 832/13 β-cells and found them to express the same isoforms of key enzymes required for glycogen metabolism. Our findings indicate that glycogenesis is insulin-independent but influenced by extracellular glucose concentrations. Levels of glycogen synthase decrease with increasing glucose concentrations, paralleling accumulation of glycogen. We did not find cAMP-elicited glycogenolysis and insulin secretion to be causally related. In conclusion, our results reveal regulated glycogen metabolism in human islets and insulin-secreting cells. Whether glycogen metabolism affects insulin secretion under physiological conditions remains to be determined. [ABSTRACT FROM AUTHOR]

Our aim was to determine the effect of exposure to maternal obesity or to maternal weight loss around conception on the programming of hepatic insulin signaling in the offspring. We used an embryo transfer model in sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for 1 wk after conception on the expression of hepatic insulin-signaling and gluconeogenic factors and key miRNAs involved in insulin signaling in the offspring. We found that exposure to maternal obesity resulted in increased hepatic miR-29b (P<0.05), miR-103 (P<0.01), and miR-107 (P<0.05) expression, a decrease in IR (P<0.05), phopsho-Akt (P<0.01), and phospho-FoxO1 (P<0.01) abundance, and a paradoxical decrease in 11βHSD 1 (P< 0.05), PEPCK-C (P<0.01), and PEPCK-M (P<0.05) expression in lambs. These changes were ablated by a period of moderate dietary restriction imposed during the periconceptional period. Maternal dietary restriction alone also resulted in decreased abundance of a separate subset of hepatic insulin-signaling molecules, namely, IRS1 (P<0.05), PDK1 (P<0.01), phospho-PDK1 (P<0.05), and aPKCζ (P<0.05) and in decreased PEPCK-C (P<0.01) and G6Pase (P<0.01) expression in the lamb. Our findings highlight the sensitivity of the epigenome to maternal nutrition around conception and the need for dietary interventions that maximize metabolic benefits and minimize metabolic costs for the next generation. [ABSTRACT FROM AUTHOR]

There is mounting evidence that nutrition plays an important role in the aetiology and management of many diseases affecting Australians. Nutrition counseling provides a strategy for not only reducing patient suffering, but also for reducing the health care costs associated with these illnesses. At the forefront of providing nutrition counseling to Australians are General Practitioners (GPs) and Dietitians. Australian data shows that GPs encounter many patients with the chronic diseases that have nutrition in their aetiology and management. Although this presents opportunities to provide nutrition counseling, overseas literature suggests that often nutrition counseling opportunities are not taken up. At present, there is little evidence to support whether this problem exists in Australia, or the magnitude of the problem. Whilst evidence suggests there are barriers for GPs in providing nutrition counseling, there is conflicting evidence on how these influence the GP's decision to provide such counseling. Overseas studies have also identified barriers for GPs to refer to dietitians to provide nutrition counseling, however there is no evidence to identify whether these barriers exist in Australia. Whilst various strategies have been implemented to aid in the provision of effective nutrition management to the Australian public, there is little evidence on the efficacy of these. Research is needed in the above areas if effective patient nutrition management is to be implemented in Australia. [ABSTRACT FROM AUTHOR]

There is increasing evidence linking bitter taste receptor (BTR) signaling to gut hormone secretion and glucose homeostasis. However, its effect on islet hormone secretion has been poorly characterized. This study investigated the effect of the bitter substance, denatonium benzoate (DB), on hormone secretion from mouse pancreatic islets and INS-1 832/13 cells. DB (0.5-1 mM) augmented insulin secretion at both 2.8 mM and 16.7 mM glucose. This effect was no longer present at 5 mM DB likely due to the greater levels of cellular apoptosis. DB-stimulated insulin secretion involved closure of the KATP channel, activation of T2R signaling in beta-cells, and intraislet glucagon-like peptide-1 (GLP-1) release. DB also enhanced glucagon and somatostatin secretion, but the underlying mechanism was less clear. Together, this study demonstrates that the bitter substance, DB, is a strong potentiator of islet hormone secretion independent of glucose. This observation highlights the potential for widespread off-target effects associated with the clinical use of bitter-tasting substances. [ABSTRACT FROM AUTHOR]

In 2020, the COVID-19 pandemic forced unprecedented disruptions in higher education operations. While the adverse mental health effects experienced by college students due to these changes are well documented, less is known about the impact on their sexual and reproductive health (SRH), and the reciprocal relationships between SRH and mental health among adolescents and emerging adults. This position paper reviews existing literature on the effects of the COVID-19 pandemic on SRH, sexual violence, unintended pregnancy, sexually transmitted illness and human immunodeficiency virus rates and highlights issues specific to college-aged males, females, racial/ethnic and sexual minorities, and individuals with disabilities. The need to conceptualize SRH as an integral component of normal development, overall health, and well-being in the context of COVID-19 is discussed. The need to prioritize the design and implementation of developmentally appropriate, evidence-based SRH interventions specifically targeting college students is identified. Furthermore, an intergenerational approach to SRH that includes parents/caregivers and/or college faculty and staff (e.g., coaches, trainers) could facilitate comprehensive SRH prevention programming that enhances sexual violence prevention training programs currently mandated by many colleges. Policies and programs designed to mitigate adverse pandemic-related exacerbations in negative SRH outcomes are urgently needed and should be included in mainstream clinical psychology, not only focused on preventing unwanted outcomes but also in promoting rewarding interpersonal relationships and overall well-being. Recommendations for clinical psychologists and mental health researchers are made. [ABSTRACT FROM AUTHOR]

Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off‐target effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta on cardiovascular structure and function, and underlying molecular mechanism using the chicken embryo, an established model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta. Fertilized eggs were treated with Dex (0.1 mg kg−1), Beta (0.1 mg kg−1), or water vehicle (Control) on embryonic day 14 (E14, term = 21 days). At E19, biometry, cardiovascular function, stereological, and molecular analyses were determined. Both glucocorticoids promoted growth restriction, with Beta being more severe. Beta compared with Dex induced greater cardiac diastolic dysfunction and also impaired systolic function. While Dex triggered cardiomyocyte hypertrophy, Beta promoted a decrease in cardiomyocyte number. Molecular changes of Dex on the developing heart included oxidative stress, activation of p38, and cleaved caspase 3. In contrast, impaired GR downregulation, activation of p53, p16, and MKK3 coupled with CDK2 transcriptional repression linked the effects of Beta on cardiomyocyte senescence. Beta but not Dex impaired NO‐dependent relaxation of peripheral resistance arteries. Beta diminished contractile responses to potassium and phenylephrine, but Dex enhanced peripheral constrictor reactivity to endothelin‐1. We conclude that Dex and Beta have direct differential detrimental effects on the developing cardiovascular system. [ABSTRACT FROM AUTHOR]

Exposure to maternal obesity before and/or throughout pregnancy may increase the risk of obesity and insulin resistance in the offspring in childhood and adult life, therefore, resulting in its transmission into subsequent generations. We have previously shown that exposure to maternal obesity around the time of conception alone resulted in increased adiposity in female lambs. Changes in the abundance of insulin signalling molecules in skeletal muscle and adipose tissue precede the development of insulin resistance and type 2 diabetes. It is not clear, however, whether exposure to maternal obesity results in insulin resistance in her offspring as a consequence of the impact of increased adiposity on skeletal muscle or as a consequence of the programming of specific changes in the abundance of insulin signalling molecules in this tissue. We have used an embryo transfer model in the sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for one week after conception on the expression and abundance of insulin signalling molecules in muscle in the offspring. We found that exposure to maternal obesity resulted in lower muscle GLUT-4 and Ser 9 phospho-GSK3α and higher muscle GSK3α abundance in lambs when compared to lambs conceived in normally nourished ewes. Exposure to maternal weight loss in normal or obese mothers, however, resulted in lower muscle IRS1, PI3K, p110β, aPKCζ, Thr 642 phospho-AS160 and GLUT-4 abundance in the offspring. In conclusion, maternal obesity or weight loss around conception have each programmed specific changes on subsets of molecules in the insulin signalling, glucose transport and glycogen synthesis pathways in offspring. There is a need for a stronger evidence base to ensure that weight loss regimes in obese women seeking to become pregnant minimize the metabolic costs for the next generation. [ABSTRACT FROM AUTHOR]

Mitochondria-derived oxidative stress during fetal development increases cardiovascular risk in adult offspring of pregnancies complicated by chronic fetal hypoxia. We investigated the efficacy of the mitochondria-targeted antioxidant MitoQ in preventing cardiovascular dysfunction in adult rat offspring exposed to gestational hypoxia, integrating functional experiments in vivo, with those at the isolated organ and molecular levels. Rats were randomized to normoxic or hypoxic (13%-14% O2) pregnancy ± MitoQ (500 μM day-1) in the maternal drinking water. At 4 months of age, one cohort of male offspring was chronically instrumented with vascular catheters and flow probes to test in vivo cardiovascular function. In a second cohort, the heart was isolated and mounted onto a Langendorff preparation. To establish mechanisms linking gestational hypoxia with cardiovascular dysfunction and protection by MitoQ, we quantified the expression of antioxidant system, β-adrenergic signaling, and calcium handling genes in the fetus and adult, in frozen tissues from a third cohort. Maternal MitoQ in hypoxic pregnancy protected offspring against increased α1-adrenergic reactivity of the cardiovascular system, enhanced reactive hyperemia in peripheral vascular beds, and sympathetic dominance, hypercontractility and diastolic dysfunction in the heart. Inhibition of Nfe2l2-mediated oxidative stress in the fetal heart and preservation of calcium regulatory responses in the hearts of fetal and adult offspring link molecular mechanisms to the protective actions of MitoQ treatment of hypoxic pregnancy. Therefore, these data show the efficacy of MitoQ in buffering mitochondrial stress through NADPH-induced oxidative damage and the prevention of programmed cardiovascular disease in adult offspring of hypoxic pregnancy. [ABSTRACT FROM AUTHOR]

Antenatal glucocorticoid therapy reduces mortality in the preterm infant, but evidence suggests off‐target adverse effects on the developing cardiovascular system. Whether deleterious effects are direct on the offspring or secondary to alterations in uteroplacental physiology is unclear. Here, we isolated direct effects of glucocorticoids using the chicken embryo, a model system in which the effects on the developing heart and circulation of therapy can be investigated, independent of effects on the mother and/or the placenta. Fertilized chicken eggs were incubated and divided randomly into control (C) or dexamethasone (Dex) treatment at day 14 out of the 21‐day incubation period. Combining functional experiments at the isolated organ, cellular and molecular levels, embryos were then studied close to term. Chicken embryos exposed to dexamethasone were growth restricted and showed systolic and diastolic dysfunction, with an increase in cardiomyocyte volume but decreased cardiomyocyte nuclear density in the left ventricle. Underlying mechanisms included a premature switch from tissue accretion to differentiation, increased oxidative stress, and activated signaling of cellular senescence. These findings, therefore, demonstrate that dexamethasone treatment can have direct detrimental off‐target effects on the cardiovascular system in the developing embryo, which are independent of effects on the mother and/or placenta. [ABSTRACT FROM AUTHOR]

Heritable trait variation within a population of organisms is largely governed by DNA variations that impact gene transcription and protein function. Identifying genetic variants that affect complex functional traits is a primary aim of population genetics studies, especially in the context of human disease and agricultural production traits. The identification of alleles directly altering mRNA expression and thereby biological function is challenging due to difficulty in isolating direct effects of cis-acting genetic variations from indirect trans-acting genetic effects. Allele specific gene expression or allelic imbalance in gene expression (AI) occurring at heterozygous loci provides an opportunity to identify genes directly impacted by cis-acting genetic variants as indirect trans-acting effects equally impact the expression of both alleles. However, the identification of genes showing AI in the context of the expression of all genes remains a challenge due to a variety of technical and statistical issues. The current study focuses on the discovery of genes showing AI using single nucleotide polymorphisms as allelic reporters. By developing a computational and statistical process that addressed multiple analytical challenges, we ranked 5,809 genes for evidence of AI using RNA-Seq data derived from brown adipose tissue samples from a cohort of late gestation fetal lambs and then identified a conservative subgroup of 1,293 genes. Thus, AI was extensive, representing approximately 25% of the tested genes. Genes associated with AI were enriched for multiple Gene Ontology (GO) terms relating to lipid metabolism, mitochondrial function and the extracellular matrix. These functions suggest that cis-acting genetic variations causing AI in the population are preferentially impacting genes involved in energy homeostasis and tissue remodelling. These functions may contribute to production traits likely to be under genetic selection in the population. [ABSTRACT FROM AUTHOR]

Objectives The goals of interconception care are to optimize women's health and encourage adequate spacing between pregnancies. Our study calculated trends in interpregnancy interval (IPI) patterns and measured the association of differing intervals with birth outcomes in California. Methods Women with 'non-first birth' deliveries in California hospitals from 2007 to 2009 were identified in a linked birth certificate and patient discharge dataset and divided into three IPI birth categories: <6, 6-17, and 18-50 months. Trends over the study period were tested using the Cochran-Armitage two-sided linear trend test. Chi square tests were used to test the association between IPI and patient characteristics and selected singleton adverse birth outcomes. Results Of 645,529 deliveries identified as non-first births, 5.6 % had an IPI <6 months, 33.1 % had an IPI of 6-17 months, and 61.3 % had an IPI of 18-50 months. The prevalence of IPI <6 months declined over the 3-year period (5.8 % in 2007 to 5.3 % in 2009, trend p value <0.0001).Women with an IPI <6 months had a significantly higher prevalence of early preterm birth (<34 weeks), low birthweight (<2500 g), neonatal complications, neonatal death and severe maternal complications than women with a 6-17 month or 18-50 month IPI (p < 0.005). Comparing those with a 6-17 month vs 18-50 month IPI, there were increased early preterm births and decreased maternal complications, complicated delivery, and stillbirth/intrauterine fetal deaths among those with a shorter IPI. Conclusions for Practice In California, women with an IPI <6 months were at increased risk for several birth outcomes, including composite morbidity measures. [ABSTRACT FROM AUTHOR]

There is a need to understand the separate or interdependent contributions of maternal prepregnancy BMI, gestational weight gain, glycaemic control, and macronutrient intake on the metabolic outcomes for the offspring. Experimental studies highlight that there may be separate influences of maternal obesity during the periconceptional period and late gestation on the adiposity of the offspring. While a period of dietary restriction in obese mothers may ablate the programming of obesity, it is associated with an activation of the stress axis in the offspring. Thus, maternal obesity may result in epigenetic changes which predict the need for efficient fat storage in postnatal life, while maternal weight loss may lead to epigenetic changes which predict later adversity. Thus, development of dietary interventions for obese mothers during the periconceptional period requires a greater evidence base which allows the effective weighing up of the metabolic benefits and costs for the offspring. [ABSTRACT FROM AUTHOR]