Impact of maternal overweight and obesity on milk composition and infant growth

Overweight and obesity (OW/OB) impact half of the pregnancies in the United States and can have negative consequences for offspring health. Studies are limited on human milk alterations in the context of maternal obesity. Alterations in milk are hypothesized to impact offspring development during the critical period of lactation. We aimed to evaluate the relationships between mothers with OW/OB (body mass index [BMI] ≥25 kg/m2), infant growth, and selected milk nutrients. We recruited mother–infant dyads with pre‐pregnancy OW/OB and normal weight status. The primary study included 52 dyads with infant growth measures through 6 months. Thirty‐two dyads provided milk at 2 weeks, which was analysed for macronutrients, long‐chain fatty acids, and insulin. We used multivariable linear regression to examine the association of maternal weight status with infant growth, maternal weight status with milk components, and milk components with infant growth. Mothers with OW/OB had infants with higher weight‐for‐length (WFL) and BMI Z‐scores at birth. Mothers with OW/OB had higher milk insulin and dihomo‐gamma‐linolenic, adrenic, and palmitic acids and reduced conjugated linoleic and oleic acids. N6 long‐chain polyunsaturated fatty acid (LC‐PUFA)‐driven factor 1 was associated with higher WFL, lower length‐for‐age (LFA), and lower head circumference‐for‐age Z‐scores change from 2 weeks to 2 months in human milk‐fed infants, whereas N6 LC‐PUFA‐driven factor 5 was associated with lower LFA Z‐score change. Human milk composition is associated with maternal pre‐pregnancy weight status and composition may be a contributing factor to early infant growth trajectory.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155909/1/mcn12979.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155909/2/mcn12979-sup-0003-Figure_S2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155909/3/mcn12979_am.pd

Comparative lipidome study of maternal plasma, milk, and lamb plasma in sheep

Lipids play a critical role in neonate development and breastmilk is the newborn\u27s major source of lipids. Milk lipids directly influence the neonate plasma lipid profile. The milk lipidome is dynamic, influenced by maternal factors and related to the maternal plasma lipidome. The close inter-relationship between the maternal plasma, milk and neonate plasma lipidomes is critical to understanding maternal-child health and nutrition. In this exploratory study, lipidomes of blood and breast milk from Suffolk sheep and matched lamb blood (n = 13), were profiled on day 34 post birth by untargeted mass spectrometry. Comparative multivariate analysis of the three matrices identified distinct differences in lipids and class of lipids amongst them. Paired analysis identified 346 differential lipids (DL) and 31 correlated lipids (CL) in maternal plasma and milk, 340 DL and 32 CL in lamb plasma and milk and 295 DL and 16 CL in maternal plasma and lamb plasma. Conversion of phosphatidic acid to phosphatidyl inositol was the most active pathway in lamb plasma compared to maternal plasma. This exploratory study illustrates the partitioning of lipids across maternal plasma, milk and lamb plasma and the dynamic relationship between them, reiterating the need to study these three matrices as one biological system

A randomised controlled trial of a tele-based lifestyle intervention for colorectal cancer survivors ('CanChange'): study protocol

Background Colorectal cancer survivors may suffer from a range of ongoing psychosocial and physical problems that negatively impact on quality of life. This paper presents the study protocol for a novel telephone-delivered intervention to improve lifestyle factors and health outcomes for colorectal cancer survivors. Methods/Design Approximately 350 recently diagnosed colorectal cancer survivors will be recruited through the Queensland Cancer Registry and randomised to the intervention or control condition. The intervention focuses on symptom management, lifestyle and psychosocial support to assist participants to make improvements in lifestyle factors (physical activity, healthy diet, weight management, and smoking cessation) and health outcomes. Participants will receive up to 11 telephone-delivered sessions over a 6 month period from a qualified health professional or 'health coach'. Data collection will occur at baseline (Time 1), post-intervention or six months follow-up (Time 2), and at 12 months follow-up for longer term effects (Time 3). Primary outcome measures will include physical activity, cancer-related fatigue and quality of life. A cost-effective analysis of the costs and outcomes for survivors in the intervention and control conditions will be conducted from the perspective of health care costs to the government. Discussion The study will provide valuable information about an innovative intervention to improve lifestyle factors and health outcomes for colorectal cancer survivors

Fractalkine signaling in regulation of insulin secretion

Fractalkine is a chemokine, which has been shown to play important roles in metabolic disease in both animal models and humans. Fractalkine is a key player in the accumulation of atherosclerotic plaques, and fractalkine receptor (CX3CR1) mutations have been implicated in obesity. Serum fractalkine levels have been found to be elevated in type 2 diabetic patients, but the role of fractalkine signaling on the pancreatic β cell was unclear. Recently published findings in April 2013 issue of the journal Cell by Lee and Olefsky et al. have implicated fractalkine in β-cell insulin secretion. They demonstrate that Cx3cr1 knockout mice have impaired glucose tolerance resulting from decreased insulin secretion. In addition, fractalkine administration improved glucose tolerance and induced insulin secretion. This modulation of insulin secretion was proposed to result from an increase in intracellular calcium and potentiation of insulin secretion, which occurs in a Gαi and MEK-dependent manner. They also found that Cx3cr1 knockout animals had transcriptional repression of genes important for β-cell function, specifically NeuroD, via induction of ICER-1. One important issue that remains unresolved is how CX3CR1 signaling regulates the potentiation of calcium influx and the distal events in insulin exocytosis. Finally, testing the effects of fractalkine treatment on proliferation and survival in vivo during regenerative conditions would be critical to determine the potential use of this chemokine in diabetes. While these exciting results open the possibility for new therapeutics, there are some concerns about a potential risk for exacerbation of atherosclerosis

Natural history of β-cell adaptation and failure in type 2 diabetes

Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure, and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure

Islet Dysfunction in a Novel Transgenic Model of T Cell Insulitis

The newly established CD3FLAG-mIR transgenic mouse model on a C57Bl/6 background has a FLAG tag on the mouse Insulin Receptor (mIR), specifically on T cells, as the FLAG-tagged mIR gene was engineered behind CD3 promoter and enhancer. The IR is a chemotactic molecule for insulin and the Flag-tagged mIR T cells in the BL/6-CD3FLAGmIR transgenic mice can migrate into the pancreas, as shown by immunofluorescent staining. While the transgenic mice do not become diabetic, there are phenotypic and metabolic changes in the islets. The transgenic islets become enlarged and disorganized by 15 weeks and those phenotypes continue out to 35 weeks of age. We examined the islets by RT-PCR for cell markers, ER stress markers, beta cell proliferation markers, and cytokines, as well as measuring serum insulin and insulin content in the pancreas at 15, 25, and 35 weeks of age. In transgenic mice, insulin in serum was increased at 15 weeks of age and glucose intolerance developed by 25 weeks of age. Passage of transgenic spleen cells into C57Bl/6 RAG−/− mice resulted in enlarged and disorganized islets with T infiltration by 4 to 5 weeks post-transfer, replicating the transgenic mouse studies. Therefore, migration of non-antigen-specific T cells into islets has ramifications for islet organization and function

Programming effects of metformin exposure during gestation on offspring pancreatic β‐cell mass and glucose homeostasis (910.5)

Background: Epidemiologic studies have linked abnormal maternal nutrition to increased offspring susceptibility to type 2 diabetes (T2D). The developing pancreas is extremely sensitive to metabolic stressors, and exposure to energy or nutrient imbalances during gestation impacts its development leading to long‐term changes in β‐cell mass and function (β‐cell programming). How nutrients affect developing β‐cells to induce long‐lasting consequences is unclear, but signaling pathways that convey information about energy and nutrient status are prime candidates. The AMP‐activated protein kinase (AMPK) is a nutrient sensor that it is indirectly activated by metformin, the most widely used oral agent for T2D. Objective: To establish how metformin administration during pregnancy impacts β‐cell mass and susceptibility to diabetes later in life in a rodent model. Methods: Metformin was delivered in drinking water to c57bl/6 mice from embryonic day 0.5 (E0.5) and continued throughout gestation (Met group). Animals were examined during embryonic stages, at birth and as adults. Results: Pancreatic buds were examined at E14 by staining for markers of pancreatic and endocrine progenitor populations, Pancreatic and duodenal homeobox 1 (Pdx‐1) and neurogenin 3 (Ngn3) respectively. Met embryos had an increase in Ngn3 and Pdx‐1 number. The Met offspring did not differ from controls in terms of birth weight or length but had a lower random glucose. Met neonates were found to have increased β‐cell mass at birth when compared to controls. On examining offspring for adult metabolic phenotype, the Met animals displayed improved glucose tolerance and insulin secretion compared to controls. Conclusions: In utero exposure to metformin may have a positive impact on regulation of endocrine cell development. Metformin is currently in clinical trials for use in gestational diabetes. Thus, careful characterization of the effect of in utero exposure to metformin on offspring metabolic phenotype is essential. Grant Funding Source: Supported by DK‐084236‐03‐S

Maternal High-Fat Diet During Pre-Conception and Gestation Predisposes Adult Female Offspring to Metabolic Dysfunction in Mice

The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring's metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood

Maternal diet–induced microRNAs and mTOR underlie β cell dysfunction in offspring

A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in β cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in β cell programming during fetal development. Here, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, a lower β cell fraction, and reduced mTOR signaling. Adult offspring of LP0.5-exposed mothers exhibited glucose intolerance as a result of an insulin secretory defect and not β cell mass reduction. The β cell insulin secretory defect was distal to glucose-dependent Ca(2+) influx and resulted from reduced proinsulin biosynthesis and insulin content. Islets from offspring of LP0.5-fed dams exhibited reduced mTOR and increased expression of a subset of microRNAs, and blockade of microRNA-199a-3p and -342 in these islets restored mTOR and insulin secretion to normal. Finally, transient β cell activation of mTORC1 signaling in offspring during the last week of pregnancy of mothers fed a LP0.5 rescued the defect in the neonatal β cell fraction and metabolic abnormalities in the adult. Together, these findings indicate that a maternal low-protein diet alters microRNA and mTOR expression in the offspring, influencing insulin secretion and glucose homeostasis