Metformin; a review of its history and future: from lilac to longevity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135516/1/pedi12473_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135516/2/pedi12473.pd

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

Human Milk Retains Important Immunologic Properties After Defatting

BackgroundIn neonatal chylothorax, thoracic lymphatic drainage is ineffective. The resultant effusions often require drainage, leading to a loss of immune components. Affected infants can be managed with formula or defatted human milk feedings low in long‐chain triglycerides to decrease lymph production. We hypothesized that there is no significant difference in the immunological profile or antibacterial effect of full‐fat and defatted human milk.MethodsMilk from lactating mothers was divided into 1 aliquot that was defatted via centrifugation with the full‐fat aliquot as control. Macronutrient content was analyzed with mid‐infrared spectroscopy. Flow cytometry was used to measure immune cell populations. Lactoferrin, lysozyme, immunoglobulin (Ig)A, and IgG values were determined using enzyme‐linked immunosorbent assay. The antibacterial properties were determined by inoculating paired full‐fat and defatted milk samples with Escherichia coli or Streptococcus pneumoniae bacteria and performing colony counts.ResultsCompared with full‐fat milk, defatted milk demonstrated decreased total energy and fat and increased carbohydrate concentrations. Defatted milk demonstrated a significant decrease in all immune cell populations. There was no difference in IgA, IgG, lysozyme, or lactoferrin concentrations. Both aliquots demonstrated equivalent growth inhibition of E. coli and S. pneumoniae.ConclusionsUnexpectedly, defatted human milk contained significantly less leukocytes than full‐fat milk. IgA, IgG, lysozyme, and lactoferrin concentrations were preserved. The ability of defatted milk to inhibit bacterial growth was unaffected, suggesting that the antibacterial benefits of human milk remain after the defatting process. Further investigation regarding the clinical effect of leukocyte loss in defatted milk is warranted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156146/3/jpen1722-supl-0001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156146/2/jpen1722_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156146/1/jpen1722.pd

The Role of Preproglucagon Peptides in Regulating β-Cell Morphology and Responses to Streptozotocin-induced Diabetes

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in β-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (GcgNull) mice and mice with Gcg expression either specifically within the pancreas (GcgΔPanc) or the intestine (GcgΔIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in GcgNull mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, GcgNull mice had increased pancreas mass via both α- and β-cell hyperplasia and reactivation of Gcg in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. GcgNull and GcgΔIntest mice maintained higher β-cell mass after treatment with STZ compared with control and GcgΔPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of β-cell mass in the GcgNull mice compensated for decreased individual β-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes. NEW & NOTEWORTHY We examined the role of Gcg on β-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased β-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized β-cell mass and glucose-stimulated insulin secretion. Increased β-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes

Vitamin D status in youth with type 1 and type 2 diabetes enrolled in the Pediatric Diabetes Consortium (PDC) is not worse than in youth without diabetes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134500/1/pedi12340.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134500/2/pedi12340_am.pd

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