Promoting healthy eating in early pregnancy in individuals at risk of gestational diabetes mellitus: does it improve glucose homeostasis? A study protocol for a randomized control trial

BackgroundHealthy eating during pregnancy has favorable effects on glycemic control and is associated with a lower risk of gestational diabetes mellitus (GDM). According to Diabetes Canada, there is a need for an effective and acceptable intervention that could improve glucose homeostasis and support pregnant individuals at risk for GDM.AimsThis unicentric randomized controlled trial (RCT) aims to evaluate the effects of a nutritional intervention initiated early in pregnancy, on glucose homeostasis in 150 pregnant individuals at risk for GDM, compared to usual care.MethodsPopulation: 150 pregnant individuals ≥18 years old, at ≤14 weeks of pregnancy, and presenting ≥1 risk factor for GDM according to Diabetes Canada guidelines. Intervention: The nutritional intervention initiated in the first trimester is based on the health behavior change theory during pregnancy and on Canada’s Food Guide recommendations. It includes (1) four individual counseling sessions with a registered dietitian using motivational interviewing (12, 18, 24, and 30 weeks), with post-interview phone call follow-ups, aiming to develop and achieve S.M.A.R.T. nutritional objectives (specific, measurable, attainable, relevant, and time-bound); (2) 10 informative video clips on healthy eating during pregnancy developed by our team and based on national guidelines, and (3) a virtual support community via a Facebook group. Control: Usual prenatal care. Protocol: This RCT includes three on-site visits (10–14, 24–26, and 34–36 weeks) during which a 2-h oral glucose tolerance test is done and blood samples are taken. At each trimester and 3 months postpartum, participants complete web-based questionnaires, including three validated 24-h dietary recalls to assess their diet quality using the Healthy Eating Food Index 2019. Primary outcome: Difference in the change in fasting blood glucose (from the first to the third trimester) between groups. This study has been approved by the Ethics Committee of the Centre de recherche du CHU de Québec-Université Laval.DiscussionThis RCT will determine whether a nutritional intervention initiated early in pregnancy can improve glucose homeostasis in individuals at risk for GDM and inform Canadian stakeholders on improving care trajectories and policies for pregnant individuals at risk for GDM.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05299502, NCT0529950

Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells

INTRODUCTION: Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemotherapy alone. In order to improve the antineoplastic activity of gefitinib, we investigated the effects of blocking the signalling of the insulin-like growth factor 1 receptor (IGF-1R), a tyrosine kinase with a crucial role in malignancy that is coexpressed with EGFR in most human primary breast carcinomas. METHODS: AG1024 (an inhibitor of IGF-1R) was used with gefitinib for treatment of MDA468, MDA231, SK-BR-3, and MCF-7 breast cancer lines, which express similar levels of IGF-1R but varying levels of EGFR. Proliferation assays, apoptosis induction studies, and Western blot analyses were conducted with cells treated with AG1024 and gefitinib as single agents and in combination. RESULTS: Gefitinib and AG1024 reduced proliferation in all lines when used as single agents, and when used in combination revealed an additive-to-synergistic effect on cell growth inhibition. Flow cytometry measurements of cells stained with annexin V-propidium iodide and cells stained for caspase-3 activation indicated that adding an IGF-1R-targeting strategy to gefitinib results in higher levels of apoptosis than are achieved with gefitinib alone. Gefitinib either reduced or completely inhibited p42/p44 Erk kinase phosphorylation, depending on the cell line, while Akt phosphorylation was reduced by a combination of the two agents. Overexpression of IGF-1R in SK-BR-3 cells was sufficient to cause a marked enhancement in gefitinib resistance. CONCLUSION: These results indicate that IGF-1R signaling reduces the antiproliferative effects of gefitinib in several breast cancer cell lines, and that the addition of an anti-IGF-1R strategy to gefitinib treatment may be more effective than a single-agent approach

Glycosyltransferases from pea membranes : glucose and fucose incorporation into cell wall polysaccharides

Synthesis from UDP-($sp{14}$C) glucose of charged lipid-linked glucosyl compounds by pea membranes was short-lived, and of very limited magnitude compared to the synthesis of 1,4- and 1,3-linked B-glucans. Lipid-linked monophosphoryl glucose was the only charged lipid formed at initial stages, and had properties similar to that of dolichol-monophosphoryl glucose. It exhibited no turnover during pulse-chase experiments. Lipid-linked pyrophosphoryl-glucose or -oligosaccharides were not detected. Coumarin inhibited the synthesis of SDS-soluble products and glucans, but not of the lipid-P-glucose. Transfer of the label from endogeneous lipid-P-($sp{14}$C) glucose or from dolichol-P-($sp3$H) glucose into non-lipid products was minimal. It was concluded that the lipid-linked phosphoryl saccharide formed from UDP-glucose was not an obligate intermediate in the formation of B-glucans in pea membranes.Fucose-containing lipid-linked intermediates were not involved in the biosynthesis of xyloglucans. However, pea microsomal membranes catalysed the transfer of $lbrack sp{14}{ rm C} rbrack$-fucose from GDP-$lbrack sp{14}$C) fucose, with or without added unlabelled UDP-glucose, UDP-xylose or UDP-galactose, to an insoluble product with properties characteristic of xyloglucan. After digestion of the ethanol-insoluble pellet with Streptomyces griseus endocellulase, $lbrack sp{14}$C) fucose residues occurred exclusively in a fragment identified as the xyloglucan nonasaccharide, Glc$sb4$ Xyl$sb3$ Gal Fuc. By comparison, in incubations with UDP-$lbrack sp3$H) xylose, the maximum size of labeled oligosaccharide found following cellulase digestion of products was an octasaccharide. In the presence of both GDP-$lbrack sp{14}$C) -fucose and UDP-$lbrack sp3$H) xylose, a nonasaccharide containing both labels was produced. Fucose and xylose residues were transferred rapidly to acceptor molecules of MW up to 300,000. Such products did not elongate detectably over 60 min of incubation. We concluded that the nonasaccharide subunit of xyloglucan was generated in vitro by transfucosylation to preformed acceptor chains, and that its synthesis was dependent on exogenous GDP-fucose.Microsomal membranes were separated by rate-zonal centrifugation on renografin gradients. Transfer to xyloglucan of labelled fucose and xylose from GDP- ($sp{14}$C) fucose and UDP- ($sp{14}$C) xylose occurred mainly in dictyosome-enriched fractions. No transferase activity was detected in secretory vesicle fractions. Pulse-chase experiments using pea stem slices incubated with ($sp3$H) fucose suggested that xyloglucan chains are fucosylated and their structure completed within the dictyosomes, before being transported to the cell wall by secretory vesicles