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Dissertations / Theses on the topic 'Glucagon-like peptide 1'

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Published: 4 June 2021

Last updated: 14 March 2023

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1

Armstrong, Matthew James. "Glucagon-like peptide-1 in nonalcoholic steatohepatitis." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/4987/.

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Nonalcoholic fatty liver disease (NAFLD), and in particular its inflammatory component steatohepatitis (NASH), are associated with significant risk of liver/cardiovascular morbidity and death. My findings highlight that NAFLD is now the commonest cause of liver disease in primary care, yet significant numbers with advanced fibrosis remain undetected. Application of simple non-invasive scoring systems could aid with identifying those in greatest need of intervention. By adopting an integrative physiological approach with functional measures of lipid and carbohydrate flux, I demonstrated that patients with NASH (vs. healthy controls) have marked adipose tissue dysfunction (especially in abdominal subcutaneous adipose tissue), alongside increased hepatic and muscle insulin resistance (IR). Targeting adipose-derived lipotoxicity should be the mainstay of therapy in NASH. Glucagon-like peptide-1 (GLP-1) based therapy (liraglutide) appears to be safe and well tolerated in patients at risk of underlying NAFLD. My prospective randomised-controlled study highlighted that liraglutide reduces metabolic dysfunction, hepatic lipogenesis, hepatic/adipose IR and inflammation in patients with NASH. My in vitro studies in human hepatocytes indicate that the anti-steatotic effects are not solely reliant on improvements in weight and/or glycaemic control. Taken together, my findings highlight that GLP-1 based therapies have all the metabolic and clinical attributes to make them a promising therapeutic option in patients with NASH. However, the safety and histological efficacy of such awaits the completion of my 48-week Phase II ‘LEAN’ trial, which is integral as to whether larger clinical trials are warranted.

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2

Adamczyk, Malgorzata. "The glucoregulatory action of glucagon-like peptide-1 (GLP-1)." Thesis, University of Ottawa (Canada), 1995. http://hdl.handle.net/10393/9612.

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Glucagon-like peptide-1 (GLP-1) has been shown to improve tolerance to glucose. It has been suggested that this could be mediated by an incretin effect--the enhancement of insulin secretion in response to glucose, as well as by alterations in the sensitivity of the body to insulin. In order to evaluate the effect of GLP-1 on the improvement of glucose tolerance, the systemic as well as tissue-specific (the liver, intestine and muscle) effects of this hormone have been determined. The study has been conducted on animal model (the pig). Following an overnight fast and baseline measurements, glucose was infused (set point = 150 mg/dl), alone or supplemented with GLP-1 (4 ng/kg/min) and GLP-1 (8 ng/kg/min) in 90 min steps. The levels of metabolites (glucose, lactate) and hormones (insulin, glucagon, GLP-1) were then determined in arterial blood as well as in portal, hepatic and femoral venous blood. Tissue balances were then calculated. Levels of metabolites and hormones, glucose infusion rates and tissue balances were compared using statistical analysis (general linear models procedure, SAS Institute). (Abstract shortened by UMI.)

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3

Brynes, Audrey. "Dietary intake, glucagon like peptide-1 and insulin sensitivity." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326161.

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4

Paternoster, Silvano. "Lysophosphatidylinositol-glucagon like peptide 1 crosstalk in metabolic diseases." Thesis, Curtin University, 2020. http://hdl.handle.net/20.500.11937/81689.

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This PhD thesis discusses the study of a novel class of drugs for the treatment of metabolic diseases. We have characterized the pharmacology and biology of the lipid Oleoyl-lysophosphatidylinositol (Oleoyl-LPI), and we show that some synthetic molecules mimicking its structure, are efficient glucagon-like peptide-1 (GLP-1) secreting drugs in vitro and in vivo in diabetic mice. We have also dissected the pharmacology of Cannabis-derived drugs and demonstrated that they can also modulate GLP-1 secretion.

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5

Khatib, Oussama-Mohmad. "Peripheral and central effect of glucagon-like peptide-1 (GLP-1)." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244094.

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6

Bose, Amal Krishna. "Glucagon like peptide-1 (GLP-1) in myocardial ischaemia-reperfusion injury." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445399/.

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Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone released by enteroendocrine cells lining the intestine in response to the presence of nutrients. GLP-1 is known to cause increased secretion of insulin from the pancreas and has been identified as one of the crucial components of insulin and in turn glucose homeostasis. GLP-1 has a very short half life of 1-2 minutes, being rapidly degraded by a ubiquitous enzyme called dipeptidyl dipeptidase IV and also undergoing renal excretion. Interestingly GLP-1 mRNA transcripts have been identified in several organs outside of the expected enteropancreatic axis including the heart. Insulin has been shown to reduce cell death in the ischemic-reperfused rat myocardium and in isolated rat myocytes via its ability to activate prosurvival kinase signalling pathways. We propose that GLP-1 could protect the myocardium against ischaemia-reperfusion injury by activating similar prosurvival signalling pathways. Both in-vivo (open chest) and in-vitro (Langendorff perfused) rat heart models of regional ischaemia and reperfusion were used. In-vivo treatment with GLP-1 produced a significant reduction in infarction (% infarct/risk zone) compared to valine pyrrolidide (VP), (an inhibitor of the enzyme dipeptidyl peptidase), and control groups (20.0 2.8, vs. 47.3 4.3, and 44.3 2.4, respectively PO.001). In isolated perfused hearts (where there is no circulating insulin) GLP-1 significantly reduced infarct size compared to VP and control (26.7 2.7 vs. 52.6 4.7 and 58.7 4.1, PO.001) groups respectively. Protection was abolished in the presence of the PI3kinase inhibitor, LY294002 (58.6 4.1), the ERK 1/2 MAPK inhibitor, U0126 (48.3 8.6), the p70s6K inhibitor, Rapamycin (57.1 4.9%) and by the GLP-1 receptor antagonist exendin-9-39 (57.3 3.8). GLP-1 protects the myocardium against ischaemic - reperfusion injury when given throughout ischaemia - reperfusion or when given just five minutes prior to the onset of reperfusion or as a preconditioning mimetic. To further elucidate the mechanism of GLP-1 mediated myocardial preservation we carried out Western blot studies examining the phosphorylation of components of the RISK pathway which showed an increase in the phosphorylation of BAD. The increased phosphorylation of the pro-death peptide BAD, confirmed the potential anti- apoptotic effect of GLP-1. In conclusion we have demonstrated for the first time that GLP-1 protects the rat myocardium against ischaemia-reperfusion injury, both in vivo and in vitro. GLP-1 appears to protect via the up regulation of specific prosurvival kinase pathways. This may represent a new therapeutic potential for this class of drugs currently undergoing trials in the treatment of non-insulin dependent diabetes.

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7

Sinclair, Elaine M. "GLP-1 effects on pancreatic b-cell lines." Thesis, University of Aberdeen, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252142.

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The aims of this thesis were to establish a suitable model system for the study of glucose and nutrient regulation of insulin secretion and biosynthesis. This would serve as a basis for investigating the GLP-1 effects on pancreatic b-cell biology. This thesis shows that two b-cell model systems, namely MIN6 and INS-1 cells, respond to increasing concentrations of glucose, by increasing insulin secretion and cell proliferation in a physiological manner. The MIN6 cell line also responds to other cellular nutrients, L-arginine and L-leucine in a manner similar to primary islet cells. The MIN6 cells however, fail to consistently increase insulin secretion in response to GLP-1, a known potentiator of insulin secretion in b-cells, despite the presence of the GLP-1 receptor. Incubation of GLP-1 with INS-1 cells, increases insulin secretion in a glucose-dependent manner, and causes a small increase in cell proliferation. GLP-1 is also known to increase cAMP levels within the cell and interact with cAMP response elements (CRE) via activation protein kinase A (PKA). Using a luciferase reporter gene construct containing 4 copies of the CRE, glucose, GLP-1 and forskolin failed to increase luciferase activity in MIN6 cells, suggesting that a defect in cAMP signalling may explain the inconsistent effect of GLP-1 in MIN6 cells. A stimulatory effect of GLP-1 and forskolin was observed in the INS-1 cells. Using both a rat insulin I and human insulin gene promoter construct, a stimulatory effect of GLP-1 on insulin gene transcription was observed in INS-1 cells. An insight into the signalling pathways involved in GLP-1 stimulation of the rat insulin I gene was gained through the use of protein kinase inhibitors, which inhibit signalling of known signal transduction cascades. It was found that an inhibitor of protein kinase A (H-89) was effective in blocking the increase in insulin promoter activity induced by GLP-1 using the rat insulin I promoter construct. Interestingly, the p38/SAPK2 inhibitor, SB203580, further increased the GLP-1 stimulation of rat insulin I promoter activity, indicating that this pathway usually invokes an inhibitory effect on insulin promoter activity.

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8

Lu, Jing. "Signalling and regulation of the glucagon-like peptide-1 receptor." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/28974.

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Following nutrient ingestion, glucagon-like peptide 1 (GLP-1) secreted from intestinal L-cells mediates anti-diabetic effects, most notably stimulating glucose-dependent insulin release from pancreatic β-cells but also inhibiting glucagon release, promoting satiety and weight reduction and potentially enhancing or preserving β-cell mass. These effects are through the GLP-1 receptor (GLP-1R) which is a therapeutic target in type 2 diabetes. The present study focused on desensitisation and re-sensitisation of GLP-1R-mediated signalling and interactions of orthosteric and allosteric ligands. Data demonstrate GLP-1R desensitisation and subsequent re-sensitisation following removal of extracellular ligand with ligand-specific features. Following GLP-1-mediated desensitisation, re-sensitisation is dependent on receptor internalisation, endosomal acidification and receptor recycling. Re-sensitisation is also dependent on endothelin converting enzyme-1 (ECE-1) activity, possibly through proteolysis of GLP-1 in endosomes, facilitating disassociation of receptor-β-arrestin complexes leading to GLP-1R recycling and re-sensitisation. ECE-1 activity also regulates GLP-1-induced activation of extracellular signal regulated kinase (ERK) and generation of cAMP possibly through a G protein independent/β-arrestin dependent mechanism. By contrast, following GLP-1R activation by the orthosteric agonist, exendin-4, or allosteric agonist, compound 2, re-sensitisation was slow and independent of ECE-1 activity. Thus, different ligands depend on different events during GLP-1R trafficking which could be important for re-sensitisation and signalling, particularly that mediated by scaffolding around β-arrestin. As the GLP-1R is targeted therapeutically at orthosteric and allosteric sites, this study examined activation of the GLP-1R by orthosteric and allosteric agonists and in particular interactions between ligands of these sites. Challenging the GLP-1R with the allosteric ligand, compound 2, along with GLP-1 9-36 amide, a low affinity, low efficacy metabolite of GLP-1 7-36 amide, results in synergistic receptor activation. This may be important for therapeutic approaches with allosteric ligands, as metabolites of GLP-1 may be present in vivo at concentrations higher than the classic endogenous ligand. Indeed this could present a novel therapeutic approach.

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9

KINZIG, KIMBERLY PEACOCK. "MULTIPLE ROLES OF THE CNS GLUCAGON-LIKE PEPTIDE-1 SYSTEM." University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1037717933.

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10

Wishart, Clare. "The activation of the glucagon-like peptide-1 (GLP-1) receptor by peptide and non-peptide ligands." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/5775/.

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The glucagon-like peptide-1 receptor (GLP-1R) potentiates glucose-stimulated insulin release from pancreatic β cells and promotes correct β cell function, as such it is a validated target for the treatment of type 2 diabetes (T2D). GLP-1R is a Family B GPCR, activated by the cognate ligand GLP-1(7-36), a 30 residue peptide hormone secreted after eating, and Exendin4 (Ex4), a 39-residue synthetic peptide. Peptide ligands interact with both the large extracellular domain and core domain of GLP-1R. Core domain interaction is thought to activate the receptor. Whilst the interaction between the receptor extracellular domain and ligand is well characterised, the ligand-core domain interaction and subsequent activation is not fully understood. Herein, a combination of mutant peptides and non-peptide ligands based on a pyrimidine scaffold (Pm compounds) are used in HTR-FRET cAMP accumulation assays, using recombinant FlpIn-HEK293 cells expressing human GLP-1R, to characterise the activation profiles of these ligands to decipher the underlying activation mechanism at the GLP-1R core domain. Structure-function studies of Pm compounds showed a trifluoromethyl and sulphur dioxide group are essential for GLP-1R activation, and that they allosterically enhance GLP-1(9-36) and Ex4(9-39) cAMP signalling profiles independently from their own cAMP response. Insulin secretion assays showed Pm compounds potentiate insulin release from INS-1 832/13 cells in combination with truncated GLP-1(9-36), implicating the use of allosteric modulators as treatment for T2D. Truncated GLP-1(15-36) was capable of binding and activating GLP-1R with low affinity and low potency, yet analogously truncated Ex4(9-39) was an antagonist with high affinity. Previous studies had demonstrated GLP-1(15-36) was an antagonist, and peptide-mediated activity had been attributed to the amino-terminus. Furthermore, the Pm compound-mediated cAMP response at GLP-1R was potentiated by Ex4(9-39). Mutant peptide activation data suggest activating residues D15, V16 and S17 are situated more centrally within the peptide ligand, and an extension to the currently accepted GLP-1R activation model is proposed.

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11

Giblett, Joel Peter. "Cardioprotective effects of Glucagon-like Peptide 1 (GLP-1) and their mechanisms." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/263201.

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Background: Glucagon-like Peptide 1 (GLP-1) is a human incretin hormone that has been demonstrated to protect against non-lethal ischaemia reperfusion injury in the left ventricle in humans. It has been suggested from some animal research that this protection may be mediated through the pathway of ischaemic conditioning, of which the opening of the mKATP channel is a key step. Furthermore, it is uncertain whether the protection applies to the right ventricle. Finally, there is limited human evidence of a protective effect against lethal ischaemia reperfusion injury. Methods: Two studies use non-lethal ischaemia to test whether GLP-1 protection is maintained despite blockade of the mKATP channel with the sulfonylurea, glibenclamide. A demand ischaemia study uses dobutamine stress echo to compare LV function. The other uses transient coronary balloon occlusion to generate supply ischaemia during GLP-1 infusion, assessed by conductance catheter. A further transient balloon occlusion is also used to assess the effect of supply ischaemia on RV function. Finally, the GOLD PCI study assesses whether GLP-1 protects against periprocedural myocardial infarction when administered during elective PCI in a randomised, placebo controlled double blind trial. Results: Glibenclamide did not affect GLP-1 cardioprotection in either supply of demand ischaemia suggesting that GLP-1 protection is not mediated through the mKATP channel. The RV experienced stunning with RCA balloon occlusion but there was little evidence of cumulative ischaemic dysfunction with further occlusions. GOLD PCI is continuing to recruit patients. The nature of the study means results cannot be assessed until recruitment is complete. Conclusions: GLP-1 is an agent with potential for clinical use as a cardioprotective therapy. It’s mechanism of action in the heart remains uncertain.

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12

Adriaenssens, A. Elizabeth. "Regulatory mechanisms in glucagon-like peptide-1-and somatostatin-producing cells." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648668.

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13

Wallis, Katharina. "Studies into the intestinal growth factor glucagon-like peptide-2." Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/5581.

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Glucagon-like peptide-2 (GLP-2) is a peptide hormone, secreted postprandially from enteroendocrine L-cells. GLP-2 has emerged as a central physiological mediator of intestinal growth and integrity and has recently shown promise as a therapeutic agent in patients with short bowel syndrome and inflammatory bowel disease. Reliable methods for GLP-2 measurement are not widely available. In this work a radioimmunoassay (RIA), using the GLP-2 antiserum (FT-17) has been optimised and validated. Cross-reactivity with GLP-2 precursors and degradation products was investigated using column chromatography. It is shown that accurate estimations of active GLP-2 secretion in response to a physiological stimulus can be made using this RIA. Plasma concentration of GLP-2 and other hormones, secreted from L-cells, were investigated in patients with short bowel syndrome (SBS), morbid obesity and in those following Roux-en-Y gastric bypass (RYGB) surgery. It is shown that, contrary to current thinking, SBS patients with a retained colon can be GLP-2 deficient despite increased L-cell activity as indicated by raised levels of PYY. Differential regulation of peptide generation in L-cells, depending on the residual intestinal anatomy, is a possible explanation. Secretion of PYY and glucagon-like peptides may also differ in obesity. Despite a previously documented attenuated postprandial PYY response in obese compared with normal weight subjects, no difference in glucagon-like peptide secretion was found in a series of test meals. In obese patients undergoing RYGB, an exaggerated postprandial GLP-2 response was noted as early as 2 days following the procedure and persisted for at least 2 years. In diabetic patients this adaptive response was delayed. Enhancing endogenous GLP-2 secretion might serve as a therapeutic strategy for patients in whom intestinal mucosal regeneration is impaired. It is shown that bile acids and glutamine act as effective GLP-2 secretagogues in model L-cells and that diversion of bilio-pancreatic secretions to the distal ileum leads to increased plasma concentration of GLP-2 in rats.

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14

Joseph, Jamie William. "Oral delivery of glucagon-like peptide-1 using PLGA-COOH microspheres." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ46161.pdf.

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15

Moore, Claire E. J. "Investigation into glucagon like peptide-1 signalling in pancreatic β-cells." Thesis, University of Leicester, 2008. http://hdl.handle.net/2381/29965.

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Glucagon like peptide-1 (GLP-1) is a GS-coupled receptor agonist that exerts multiple effects on pancreatic beta-cells, including the stimulation of insulin gene expression and secretion, growth and survival. A number of kinases are activated in response to GLP-1R activation, including extracellular regulated kinases (Erk1/2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB) and mammalian target of rapamycin mTOR, all of which contribute in regulating various aspects of beta-cell function. However, the mechanism by which GLP-1 activates these signalling pathways in pancreatic beta-cells is not fully understood. Therefore, the objectives of this thesis were to investigate how GLP-1 signals to Erk1/2. PI3K/PKB and mTOR. It has previously been reported that GLP-1 stimulated Erk1/2 activation is dependent on the influx of Ca2+ specifically through L-Type VGCC. In this thesis I provide evidence that this increase in Ca2+ activates the Ca2+ dependent phosphatase, calcineurin which in turn activates IKK leading to the activation of the MEK kinase, Tp12. Ca2+ entry through L-Type VGCC also plays a key role in stimulating insulin secretion which I show is responsible for glucose stimulated PI3K activation and PKB phosphorylation. In contrast, GLP-1 can activate PI3K independent of insulin secretion which is unable to couple to PKB. Interestingly, GLP-1 is able to potentiate glucose stimulated mTOR activation via a PI3K leading to the phosphorylation of rpS6 on Ser240/244. Moreover, GLP-1 can stimulate the phosphorylation of rpS6 on Ser235/236 which is not dependent on mTOR activation or the two currently known S6Ks, S6K1/2 or p90RSK.

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16

Jeng, Winnie. "Structural and functional studies of the glucagon-like peptide-1 (GLP-1) receptor." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0025/MQ40866.pdf.

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17

Kim, Julie. "The roles of glucagon-like peptide-1 (GLP-1) in the mouse brain." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0027/MQ40868.pdf.

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18

Tee, Cheng Tai. "The modulation of human dendritic cells by glucagon like peptide-2." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/28252.

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Glucagon-like peptide-2 (GLP-2) is a pleiotropic peptide secreted in the human intestine with known intestinotrophic properties beneficial in conditions like short bowel syndrome (SBS); a condition characterized by malabsorption of both fluid and nutrients. Left untreated, SBS can lead to dehydration, malnutrition, and weight loss. Teduglutide, a long acting analogue of GLP-2, has been used in multiple clinical studies to elucidate its trophic properties. Murine studies however have also shown that GLP-2 inhibits pro-inflammatory cytokines raising the possibility of an anti-inflammatory property and its potential use in intestinal inflammatory conditions; in particular inflammatory bowel disease (IBD). Dendritic cells (DC) play a central role in the initiation and regulation of the immune system. They bridge the innate and adaptive immune systems and are unique in their ability to activate naïve T cells as well as dictate the type of T-cell immunity. We hypothesized that GLP-2 has an immunomodulatory role and exert this action via DC. Toxic effects of GLP-2 peptide on human DC in-vitro have not previously been experimented. Our experiments showed that GLP-2 did not have a toxic effect on DC at 1pM, 1nM and 1μM concentrations and hence we were subsequently able to look at the effects of GLP-2 on human DC phenotype and function. Using whole blood and intestinal biopsies from healthy volunteers, we obtained a population of enriched low density cells (LDC) which offered a novel and 'physiological' model for DC. These cells were labelled with appropriate fluorochromes and assayed by a flow cytometer. We established that DC incubated overnight with GLP-2 had a reduced intensity ratio of HLA DR and an increased expression of CD14 in a dose dependent way compared with controls. The expression of co-stimulatory molecule CD86 was also higher in the treated DC. This phenotypic change suggests that GLP-2 modulated DC into an immature state although still able to stimulate T-cell proliferation. Ongoing cytokine production of IFN-γ and IL-12 from healthy blood DC was inhibited by GLP-2 however only cytokine production of IFN-γ from intestinal lamina propria DC was inhibited. These findings suggest that GLP-2 may induce a 'homeostatic' or 'immuno-tolerant' state and block Th1 cytokines in DC. Functional experiments confirmed that GLP-2 modulated DC enhanced T cell proliferation although this occurred only with intestinal DC. GLP-2 conditioned DC also functionally affected the cytokine profile of T cells by reducing the cytokines IFN-γ in both human blood and intestinal DC and IL-12 in only the latter. Hence our human DC in-vitro findings mirror some of the results found in murine studies showing GLP-2 effects on blocking Th1 cytokines. The results suggest that GLP-2 has an immunoregulatory effect and that the mechanism of action may possibly involve direct effects on DC. GLP-2 therefore is able to modulate DC characteristics and function leading to future application as an immunotherapy for inflammatory diseases.

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19

TAUCHI, MIYUKI. "THE ROLE OF GLUCAGON-LIKE PEPTIDE-1 IN STRESS AND ENERGY HOMEOSTASIS." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148315063.

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20

Klustaitis, Kori M. "Activation of the central nervous system by circulating Glucagon-Like Peptide-1." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243357633.

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21

Lebrun, Lorène. "Lipopolysaccharides et glucagon-like peptide 1 : des mécanismes moléculaires à la physiopathologie." Thesis, Dijon, 2016. http://www.theses.fr/2016DIJOS038/document.

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La prévalence de l’obésité et du diabète de type 2 évolue de façon épidémique. Ces pathologies sont caractérisées par un état inflammatoire à bas bruit dont l’origine moléculaire est inconnue. L’une des pistes qui émerge concerne le microbiote intestinal et plus particulièrement des molécules pro-inflammatoires présentes à la surface des bactéries Gram(-) : les lipopolysaccharides (LPS). Nous avons récemment montré que ces LPS augmentent les taux circulants de glucagon-like peptide 1 (GLP-1), une hormone connue pour stimuler la sécrétion d'insuline. Par ailleurs, un lien existerait entre qualité nutritionnelle de l’alimentation et taux de LPS sanguins. Ainsi, alimentation, LPS et GLP-1 pourraient être liés. Ces travaux de thèse portent sur i) les mécanismes moléculaires reliant LPS et GLP-1 et ii) les conséquences physiopathologiques d’une endotoxémie expérimentale lors d’un régime obésogène. Nous montrons, in vitro, ex vivo et in vivo, que les LPS stimulent la sécrétion de GLP-1 par les cellules entéroendocrines via un mécanisme TLR4-dépendant. Les LPS présents dans l’intestin déclenchent cette sécrétion lors de situations pathologiques de dégradation de la muqueuse, faisant du GLP-1 un potentiel marqueur précoce d’altération de la barrière intestinale. Chez des souris sauvages, une endotoxémie expérimentale n’aggrave pas les conséquences métaboliques généralement observées lors d’un régime obésogène, certains paramètres sont même améliorés. Enfin, des souris présentant un défaut de détoxification des LPS nourries avec un régime obésogène prennent plus de masse corporelle que les souris contrôles. Les origines moléculaires de ces différences sont également recherchées
Obesity and type 2 diabetes are metabolic diseases which have reached epidemic proportions worldwide. These metabolic disorders are related to a low grade inflammation whose molecular origin is still unknown. Previous studies have highlighted the involvement of the gut microbiota and especially components of the cell wall of Gram(-) bacteria: lipopolysaccharides (LPS). We have recently shown that LPS enhance glucagon-like peptide 1 (GLP-1) plasma levels, a hormone which is known to stimulate insulin secretion. Moreover there would be a link between the nutritional qualities of food and LPS plasma levels. Thus diet, LPS and GLP-1 may be closely related. The present work focuses on i) the molecular mechanisms linking LPS to GLP-1 and ii) the pathophysiological consequences of an experimental endotoxemia under obesogenic diet conditions. In vitro, ex vivo and in vivo experiments highlight LPS as potent secretagogues of GLP-1. They are able to induce GLP-1 secretion from enteroendocrine cells through a direct TLR4-dependent mechanism. Luminal LPS trigger GLP-1 secretion only under pathological conditions leading to intestinal mucosal damages. Therefore GLP-1 could be a promising early biomarker for diagnosing gut barrier injuries. Experimentally-induced endotoxemia in wild-type mice does not worsen the usually observed metabolic consequences of an obesogenic diet but rather seems to improve some of them. In addition, under high-fat diet, genetically-engineered mice with a defective LPS detoxification process gain more weight than control mice. The purpose of this thesis is also to disentangle the molecular explanation behind this difference

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22

González, Abuín Noemí. "Modulation of active glucagon-like peptide-1 (glp-1) levels by grape-seed procyanidins." Doctoral thesis, Universitat Rovira i Virgili, 2013. http://hdl.handle.net/10803/128942.

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Modulation of active glucagon-like peptide-1 (GLP-1) levels by grape-seed procyanidins Les procianidines del pinyol de raïm (GSPE) poden millorar estats de disrupció de la homeòstasi de la glucosa i es va hipotetitzar que la modulació de GLP-1, incretina que millora la producció d¿insulina i la seva detecció a teixits perifèrics, podria ser un mecanisme de actuació del GSPE. Per demostrar aquesta hipòtesi, s¿ha avaluat, in vivo i in vitro l¿efecte del GSPE en la secreció i producció de GLP-1, així com l¿efecte sobre la activitat de DPP4, enzim que degrada GLP-1. Els resultats obtinguts demostren que el tractament oral amb GSPE millora el nivells de GLP-1 induïts per una càrrega oral de glucosa. A més a més, s¿ha vist que GSPE modula la secreció i producció de GLP-1, així com la activitat de DPP4. En conclusió, la modulació del nivells de GLP-1 activa pot, en part, explicar els efectes antihiperglicèmics del GSPE.

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23

Yeung, Chung-man. "Structure-function studies on the ligand-binding domains of a glucagon-like peptide 1 receptor from Goldfish carassius auratus." Click to view the E-thesis via HKUTO, 2001. http://sunzi.lib.hku.hk/hkuto/record/B42576234.

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Situ, Chen. "Development of region-specific antisera to GLP-1 : physiological and pathological studies." Thesis, Queen's University Belfast, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388192.

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25

Sandhu, Harmanjit Singh. "The effect of GLP-1, glucagon-like peptide 1, on insulin sensitivity in diabetic dogs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0010/MQ29350.pdf.

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Thompson, Aiysha. "Cellular trafficking and functional characterisation of the human glucagon like peptide-1 receptor." Thesis, Swansea University, 2014. https://cronfa.swan.ac.uk/Record/cronfa42586.

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The binding of glucagon like peptide-1 (GLP-1] to its receptor, the GLP-1 receptor (GLP-IR), results in insulin secretion from pancreatic beta-cells. This makes the receptor an important drug target for type 2 diabetes. The GLP-IR is a family B G-protein coupled receptor (GPCR) and functions at the cell surface by coupling to Galphas and Galphaq pathways and causing ERK phosphorylation. The objective of this study was to analyse trafficking, activity and internalisation of GLP-IR at the cellular and molecular level. The human GLP-IR (hGLP-1R) N-terminus is required for trafficking and maturation. This study demonstrated the importance of signal peptide (SP] cleavage, N-linked glycosylation and the hydrophobic region after the SP [HRASP] within the N-terminus of the hGLP-1R for cell surface expression. Due to difficulties in peptide drugs, orally active small molecule agonists of the GLP-IR are of high importance. Small molecule allosteric agonists, compounds 2 and B, were found to cause cAMP production similar to orthosteric GLP-1, but not intracellular Ca2+ accumulation, ERK phosphorylation or internalisation of the receptor. Compounds 2 and B binding to the GLP-IR inhibits GLP-1 internalisation, intracellular Ca2+ accumulation and ERK phosphorylation of the receptor. Agonist induced hGLP-1R internalisation is important for insulin secretion. Inhibition of the G?q pathway but not the Gas pathway reduced hGLP-1R internalisation. Consistent with this, the hGLP-1R T149M mutant and compounds 2 and B, which activate only the Gas pathway, failed to induce hGLP-1R internalisation. Chemical inhibitors of the Galphaq pathway significantly reduced agonist induced hGLP-1R internalisation and suppressed ERK phosphorylation demonstrating phosphorylated ERK acts downstream of the Galphaq pathway in hGLP-1R internalisation. Finally, distinct regions within the C-terminus of hGLP-1R required for its cell surface expression, activity and internalisation were identified. Residues 411- 418, 419-430 and 431-450 are essential for hGLP-1R cell surface expression, activity and internalisation, respectively.

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LACHEY, JENNIFER LYNN. "THE ROLE OF THE CENTRAL GLUCAGON-LIKE PEPTIDE-1 IN MEDIATING VISCERAL ILLNESS." University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1022853734.

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28

Hart, Nathaniel. "Combinatorial Targeting of the Glucagon-Like Peptide-1 And Sulfonylurea-1 Receptors Using a Complimentary Multivalent Glucagon-Like Peptide-1/Glibenclamide Ligand for the Improvement of β-Cell Targeting Agents and Diabetic Treatment." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/311363.

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A scourge of Type I and Type II diabetes impacts the health of hundreds of millions worldwide. The number and prevalence of diabetics are expected to rise dramatically in the next two decades. Diabetes is defined by chronic hyperglycemia which can result in a number of detrimental and costly metabolic, renal, cardiovascular and neurological disorders. Identification of at risk individuals and effective blood glucose management are critical to improving diabetic outcomes and preventing hyperglycemic complications. Diabetes prevention and treatment is limited by the understanding of islet function and mass in the diabetogenic and diabetic state. The islets of Langerhans are dispersed throughout the pancreas and comprise <2% of the pancreatic mass. The reclusive nature of islet cells presents unique challenges understanding disease development. No agent capable of exclusively targeting pancreatic β-cells within the islet has been discovered and the lack of targeting agent specificity impedes efforts to: quantify β-cell mass and develop novel therapeutics. We propose β-cell targeting can be improved by targeting unique combinations of receptors simultaneously with multivalent ligands. A synthetic multivalent agent composed of two β-cell specific diabetic therapeutics, glucagon-like peptide-1 (GLP-1) and glibenclamide (Glb), targeted against the GLP-1R and the sulfonylurea-1 receptor (SUR1) is a lead compound for the development of specific bi-functional islet cell targeting agents for use in the in vivo detection and treatment of β -cells. Herein, we describe the synthesis and initial characterization of a heterobivalent ligand composed of GLP-1 coupled to Glb. The heterobivalent ligand binds to an unaltered β-cell line with increased specificity relative to a human pancreatic exocrine cell line. Additionally, receptor cross-linking modifies β-cell signaling. Exposure of β-cells to the heterobivalent ligand results in antagonism of SUR1-Ca²⁺ signaling and equipotent agonism of GLP-1R-cAMP signaling, in comparison to the cognate monomeric ligands (Glb and GLP-1). Perturbations in intracellular signaling modifies β-cell insulin secretion resulting in decreased basal insulin secretion and with maintained yet reduced ability to potentiate β-cell glucose stimulated insulin secretion. GLP-1/Glb β-cell specificity and functional modulation suggests combinatorial receptor targeting is an effective strategy for the development of bi-functional cell-specific targeting agents, warranting further investigation and optimization.

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Sibthorpe, Poppy E. "Studies on glucagon-like peptide-2 (GLP-2) and the equine gastrointestinal tract." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/232700/1/Poppy_Sibthorpe_Thesis.pdf.

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Glucagon-like peptide-2 (GLP-2) is an important regulator of intestinal growth, but its function is poorly understood in horses. This thesis examined GLP-2 physiology and secretion patterns in ponies to determine whether it could contribute to the development of hyperinsulinaemia, which might increase the risk of the endocrine disorder, insulin dysregulation, and the severe hoof disease, laminitis. This research provides one of the first directed investigations into GLP-2 secretion and glucose uptake in horses and ponies, with studies in vitro and in vivo making a significant contribution to our knowledge of GLP-2 in equine intestinal physiology.

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Edwards, Christopher Mark Beresford. "The role of glucagon-like peptide-1 (GLP-1) in carbohydrate metabolism and body weight regulation." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268871.

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揚重文 and Chung-man Yeung. "Structure-function studies on the ligand-binding domains of aglucagon-like peptide 1 receptor from Goldfish carassius auratus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B42576234.

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Pereira, Marie. "Skeletal effects and signalling mechanisms of glucagon-like peptide-1 receptor agonists in bone." Thesis, Royal Veterinary College (University of London), 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.731289.

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Gunn, Irene. "Central nervous system and peripheral actions of glucagon-like peptide-1 (7-36) amide." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340488.

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34

Huang, Yan. "Exploring the structure, function & regulation of the human glucagon-like peptide-1 receptor." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/8969.

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Glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion and promotes β-cell function via its receptor (GLP-1R), which therefore is a validated target for the treatment of type 2 diabetes. Due to difficulties with peptide therapeutics, it is important to find small-molecule GLP-1R agonists. This leads to a need to understand the structure, function and regulation of the receptor, particularly, differences between agonisms mediated by GLP-1 (orthosteric agonist) and small molecules. The GLP-1R contains a putative N-terminal signal peptide sequence, which is assessed here by recombinantly expressing several epitope-tagged GLP-1R constructs in HEK293 cells. The findings demonstrate that the GLP-1R is expressed predominately at the plasma membrane and also slightly cytosolic. Only fully glycosylated, mature form of the receptor is able to traffic to the cell surface and performs the function. The signal peptide sequence of the GLP-1R is essential for synthesis. After fulfilling the function, this sequence is cleaved and thus not part of the mature protein. The cleavage of signal peptide is critical for processing and trafficking of the GLP-1R. Based on one of these constructs generated here, a cell line (HEK293: GLP-1R-EGFP) with stable expression of the visible GLP-1R is established, which allows observations and determinations for ligand-mediated receptor internalisation in real time. Compound 2 (6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline) has been described as a GLP-1R allosteric modulator and agonist. Findings here that compound 2-mediated agonisms on both the wild-type (WT) GLP-1R and the mutant with removal of the N-terminal domain provide direct evidence for the allosteric agonism. Interestingly, compound 2-mediated cAMP response is enhanced by orthosteric antagonist exendin 9-39, but the latter inhibits receptor internalisation mediated by compound 2. Recently, it has been hypothesised that the binding of GLP-1 allows a sequence of NRTFD (Asn63-Asp67) in the N-terminus of the GLP-1R to interact with another part of the receptor and cause agonism. This was examined here by generating receptor mutants and synthetic peptides. Findings here that Asp67 plays a key role in stabilising the N-terminal structure of the GLP-1R and thus is critical for processing and trafficking of the receptor protein do not support such hypothesis although synthetic NRTFD mediates a weak and partial agonism on the WTGLP-1R.

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35

LoÌpez, de Maturana Garmendia Rakel. "Structure/function studies of the extracellular domains of the glucagon-like peptide-1 receptor." Thesis, University of Leeds, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250867.

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Ranganath, Lakshminarayan Rao. "The role of glucagon-like peptide-1 and lipoprotein lipase in health and obesity." Thesis, University of Surrey, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336988.

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37

Salehi, Marzieh. "The Role of Glucagon-like Peptide 1 in Insulin Secretion after Gastric Bypass Surgery." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282921101.

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38

Nasr, Elsayed Mohammed Nasr. "The binding and activation of the glucagon-like peptide-1 receptor by exendin-4." Thesis, University of Leeds, 2010. http://etheses.whiterose.ac.uk/1691/.

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Background and purpose Exendin-4 (EX4) has the same physiological properties as glucagon-like peptide-1 (7-36)amide (GLP-1). EX4 has 50% identity with GLP-1, with an extra nine amino acids at its C-terminus. The two peptides mediate their functions through coupling to the glucagon like peptide-1 receptor (GLP-1R) with similar affinity and potency. Unlike N-terminally truncated GLP-1, (GLP-1(15-36)amide), the equivalently truncated EX4(9-39) binds GLP-1R without significant loss of affinity; furthermore, GLP-1(15-36) is a partial agonist while EX4(9-39) is an antagonist. Previous binding analysis of either N or C-terminally truncated EX4 at rGLP-1R suggested that the residues responsible for its extra affinity are at its C-terminus, EX4 residues 31-39. Crystal structures supported by mutagenesis showed similar interactions of both GLP-1 and EX4 at the isolated N-terminal domain of human GLP-1R (hGLP-1R-NTD) apart from a subtle hydrogen bond between Ser32 in EX4 and Glu68 in hGLP-1R-NTD. Experimental approach The affinities and activities of GLP-1, EX4 and various analogues were measured at human and rat GLP-1R (hGLP-1R and rGLP-1R, respectively) and various receptor variants. Computer models, molecular dynamics coupled with in silico mutagenesis, were used to model and interpret the data. Key results The membrane-tethered NTDs of hGLP-1R displayed similar affinity for GLP-1 and EX4 in contrast to previous studies using the soluble isolated domain. The selective high affinity at rGLP-1R and the rGLP-1R-like mutant hGLP-1R-Glu68Asp for EX4(9–39) over EX4(9–30) was due to Ser32 in the ligand. This selectivity was not observed with hGLP-1R and the hGLP-1R-like mutant rGLP-1R-Asp68Glu. Gly16-EX4(9–30) was an agonist for rGLP-1R and hGLP-1R-Glu68Asp but was an antagonist for hGLP-1R and rGLP-1R-Asp68Glu. Glu22-GLP-1(15-36) was a partial agonist for all tested receptors. Insertion of (EEEAVRL) of EX4 instead of their equivalent sequence in GLP-1(15-36) prevented its activity and did not enhance its affinity. Substitution of Ser32 in EX4 by similar hydrogen bond donor amino acids did not enhance EX4 affinity or potency. Conclusions and implications GLP-1 and EX4 bind to the NTD of hGLP-1R with similar affinity. A hydrogen bond between Ser32 of EX4 and Asp68 of rGLP-1R is responsible for the improved affinity of EX4 and can play a role in the antagonist/agonist switch of Gly16-EX4(9–30) at the rat receptor. The discovery of the novel antagonist/agonist switch suggests a new mechanism of activation by GLP-1 which does not require its extreme N-terminal residues.

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39

Baraboi, Elena-Dana. "Glucagon-like peptide 1 et peptide YY : activation neuronal et contrôle de la prise alimentaire chez le rat." Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27813/27813.pdf.

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40

Cook, Sonya M. "Characterization of mice with a null mutation in the glucagon-like peptide-1 receptor gene." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0004/MQ40802.pdf.

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41

Ong, Wee Kiat. "Characterisation of cyclic nucleotide phosphodiesterases in the glucagon-like peptide-1-secreting GLUTag cell line." Thesis, University of Strathclyde, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488772.

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42

Read, Philip Alexander. "Investigation of the effect of glucagon-like peptide-1 on left ventricular function during myocardial ischaemia." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609154.

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43

May, Alexander T. "Identification of Expression and Function of the Glucagon-like Peptide-1 Receptor in Gastrointestinal Smooth Muscle." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4886.

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In response to ingestion of nutrients, enteroendocrine L cells secrete the incretin hormone, glucagon-like peptide-1 (GLP-1), to enhance glucose-dependent insulin release. Therapies related to GLP-1 are approved for type 2 diabetes. The GLP-1 receptor (GLP-1R) is expressed in cells of the gastrointestinal tract and elsewhere. In pancreatic beta cells, GLP-1R are coupled to the Gs/cAMP/PKA pathway. The expression and function of GLP-1R in gastrointestinal smooth muscle are not known. Aim. To test the hypothesis that GLP-1 regulates smooth muscle function by acting on GLP-1R expressed on smooth muscle. Methods. Smooth muscle cells (SMC) were isolated and cultured. Expression of GLP-1R mRNA was measured by RT-PCR. Expression of GLP-1R protein was measured by western blot. The effect of GLP-1 (7-36) amide on Gαs activation, cAMP formation, and PKA activity was examined in cultured SMC. The effect of GLP-1 on basal activity and on acetylcholine-induced contraction was measured in intact colon via organ bath. Results. Amplification of GLP-1R mRNA suggested expression of GLP-1R mRNA in mucosal and non-mucosal colon cells, which was confirmed in pure SMC cultures. Similar patterns of protein expression were obtained with western blot. Addition of GLP-1 caused relaxation of phasic activity and agonist-induced tonic contractions in intact colon, suggesting a role of smooth muscle Gs-coupled GLP-1R in mediating relaxation. In SMC, GLP-1 (7-36) amide activated Gas, increased cAMP levels, and stimulated PKA activity. Conclusion. Colonic SMC express GLP-1R, and GLP-1 inhibits both basal and acetylcholine-induced contraction. The GLP1-R is coupled to the heterotrimeric G protein, Gas.

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44

Barrera, Jason G. "The Role of Central Nervous System Glucagon-Like Peptide-1 in the Regulation of Energy Balance." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1258741489.

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45

Catherman, Colin M. "Short and Long Chain Free Fatty Acids Differentially Regulate Glucagon-like Peptide-1 and Peptide YY Transcript Levels in Enteroendocrine Cells (STC-1)." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4797.

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The regulation of glucagon-like peptide-1 and peptide YY hormone levels are regulated based on different influential factors, but primarily levels are dependent upon ingested food content. As meals today become more fat-enriched, there is greater requirement for evaluation of these hormones that regulate insulin and satiety levels within the body. We have shown that the gene expression transcript production of glucagon-like peptide-1 and peptide YY are modulated by different concentrations, and times of short-chain fatty acids and long-chain fatty acids. Although the peptide hormone levels have the influential physiological role on effector tissue, the regulation of these hormones begins at the transcript levels. Recent research indicates that glucagon-like peptide-1 and peptide YY hormones are altered in response to different free-fatty acids. The present investigation generally demonstrated an overall decrease in both hormones after chronic exposure to fatty acids. Intestinal secretin tumor cell line (STC-1 cells) was used as a representative for intestinal L-cells. Quantitative real-time PCR analysis was used to determine the changes in RNA transcripts. Overall, there was a decrease in the 3-hour timeline, which continued to decrease in the 16-hour and 24-hour timelines for glucagon-like peptide-1. Peptide YY transcript expression in 3-hours increased significantly after exposure to propionate, a significant decrease after exposure to acetate, and no significant increase or decrease after exposure to butyrate. However, there was a significant decrease in peptide YY once reaching 24-hour exposure. It was determined there is a threshold for different concentrations of free-fatty acids to influence glucagon-like peptide-1 and peptide YY production, which was present in the different concentrations of butyrate. Lastly, exposure to both concentrations of linolenic acid caused a significant decrease in glucagon-like peptide-1 and peptide YY.

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46

Satkunarajah, Malathy. "Studies of the incretins, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, and their receptors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0004/MQ40875.pdf.

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47

Ward, Caroline Elizabeth. "The regulation of human and mouse pancreatic a-cells by glucose and glucagon-like peptide-1." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533894.

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48

Hower, Michael [Verfasser], and M. [Akademischer Betreuer] Gotthardt. "In vivo Glucagon-like Peptide 1 Rezeptorbildgebung mittels radiometallmarkiertem Exendin 4 / Michael Hower. Betreuer: M. Gotthardt." Marburg : Philipps-Universität Marburg, 2012. http://d-nb.info/1025538587/34.

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49

Green, Brian Desmond. "Amino-terminally modified analogues of glucagon-like peptide-1 (7-36) amide : activity and antidiabetic potential." Thesis, University of Ulster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398986.

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Green, Alastair David. "Investigation of the antidiabetic actions and function of insulin, glucagon and glucagon-like peptide 1 secreting cells for transplantation therapy of diabetes." Thesis, Ulster University, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.676526.

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Diabetic patients who cannot adequately maintain glucose homeostasis using other agents often have to rely on exogenous insulin treatment. This can have side effects such as hypoglycaemia. Islet transplantation has been shown to provide improved glucose management with lower risk of hypoglycaemia in patients with brittle diabetes. Unfortunately this therapy is greatly limited by the lack of availability of primary tissue, and poor long term survival of grafts. Recently, cell therapy has shown great promise as a potential treatment for diabetes. In this project, the effects of cell communication on survival and function of human insulin secreting 1.1 B4 cells in vitro and in vivo were investigated. Additionally, the effects of co-agonism of GLP- 1 and glucagon receptors by cell therapy using mouse L-cell and alpha cell models in diabetic SCID mice were examined. To improve survival and function of grafts, effects of co-culturing mouse GLP-1 secreting GLUTag cells along with mouse insulin secreting MIN6 cells to form heterotypic pseudoislets were also investigated. Such studies might help understand the role of homotypic and heterotypic cellular interactions in maintenance of l3-cell function and survival. The configuration of 1.1 B4 cells as pseudoislets increased insulin secretory function, and enhanced resistance to cytotoxicity. These changes were accompanied by significant increases in the expression of genes for insulin production and secretion, cellcommunication and anti-oxidant defence. Implanted 1.1 B4 cells grew into well vascularised cell masses within approximately 2-3 weeks. As expected, in normoglycaemic animals the cells had no detectable metabolic effects. However, diabetic animals receiving 1.1 B4 cell suspensions or pseudoislet implants also grew cell masses without measurable metabolic effects. It has been shown that 1.1 B4 cells are sensitive to high glucose toxicity, and so the study was repeated, but prior to and during implantation and the cell growth period, hyperglycaemia was ameliorated with intensive insulin therapy. On this occasion both monolayers and pseudoislets yielded well vascularised, insulin positive cell masses which reversed hyperglycaemia in the animals. The therapeutic effect of 1.1 B4 cell suspensions and pseudoislets was similar, though pseudoislet cell masses grew more slowly. Implantation of GLUTag cells and a combination of GLUTag and TC1.9 cells both had profound restorative effects on pancreatic islet beta cells, and caused significant decreases in circulating blood glucose, and increases in glucose tolerance. TC 1.9 cells implanted alone did not form cell masses, and did not significantly affect islet morphology or metabolic parameters. While, GLUTag and TC1.9 combined implants did produce as strong an anti-hyperglycaemic effect as GLUTag alone, half the number of GLUTag cells were implanted in this group, indicating that some degree of dual agonism may have occurred and contributed to the metabolic effects observed. MIN6 and GLUTag pseudoislets were shown to be responsive to glucose and secretagogues and were significantly more resilient to cytotoxic agents than homotypic MIN6 pseudoislets, although the latter were more resistant to glucotoxicity. Additionally, implantation of both types of pseudoislet had profound anti-hyperglycaemic effects on diabetic SCID mice, although the heterotypic pseudoislets appeared to precipitate a more controlled and gradually improvement than MIN6 pseudoislets. Current observations suggest that cell communication greatly enhances human beta cell function and survival. Chronic co-agonism of GLP-1 and glucagon receptors by cell therapy holds significant potential in type diabetes therapy. Lastly, there is clear promise for the improvement of islet function and survival by co-transplantation with GLP-1 secreting cells.

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