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Sample records for 48-hour glucagon-like peptide

  1. Glucagon-like peptide-1

    Deacon, C F; Holst, Jens Juul; Carr, R D

    1999-01-01

    Type 2 diabetes mellitus is a metabolic disease resulting in raised blood sugar which, if not satisfactorily controlled, can cause severe and often debilitating complications. Unfortunately, for many patients, the existing therapies do not give adequate control. Glucagon-like peptide-1 (GLP-1) is...... an incretin hormone which has a spectrum of activities which oppose the symptoms of diabetes. Of particular significance is the fact that these actions are glucose-dependent, meaning that the risk of severe hypoglycemia is practically eliminated. The recent elucidation of the key role of dipeptidyl...

  2. Glucagon-Like Peptide-1 Gene Therapy

    Anne M. Rowzee

    2011-01-01

    Full Text Available Glucagon-like peptide 1 (GLP-1 is a small peptide component of the prohormone, proglucagon, that is produced in the gut. Exendin-4, a GLP-1 receptor agonist originally isolated from the saliva of H. suspectum or Gila monster, is a peptide that shares sequence and functional homology with GLP-1. Both peptides have been demonstrated to stimulate insulin secretion, inhibit glucagon secretion, promote satiety and slow gastric emptying. As such, GLP-1 and Exendin-4 have become attractive pharmaceutical targets as an adjunctive therapy for individuals with type II diabetes mellitus, with several products currently available clinically. Herein we summarize the cell biology leading to GLP-1 production and secretion from intestinal L-cells and the endocrine functions of this peptide and Exendin-4 in humans. Additionally, gene therapeutic applications of GLP-1 and Exendin-4 are discussed with a focus on recent work using the salivary gland as a gene therapy target organ for the treatment of diabetes mellitus.

  3. Glucagon-like peptide 1--a cardiologic dimension

    Treiman, Marek; Elvekjaer, Mikkel; Engstrøm, Thomas;

    2010-01-01

    Recent experimental data suggest glucagon-like peptide 1 (GLP-1) and its analogs to have direct effects on the cardiovascular system, in addition to their classic glucoregulatory actions. These direct effects may be cardioprotective, contractility augmenting, and vasorelaxant. A few preliminary c...

  4. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter;

    2015-01-01

    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to...

  5. Glucagon-like peptides 1 and 2

    Kissow, Hannelouise

    2015-01-01

    healing. The antidiabetic hormone GLP-1, cosecreted with GLP-2, diminished mucositis in an animal model of the condition. Therefore, both peptides could be involved in the pathophysiology of mucositis. SUMMARY: The intestinal GLPs have shown beneficial effects in experimental trials and have potential for...... therapeutic use. In type 2 diabetic and obese patients, GLP secretion is impaired. Elucidating the role of these endogenous hormones could lead to the identification of mucositis risk factors and an alternative preventive therapy for these patients....

  6. Therapeutic strategies based on glucagon-like peptide 1

    Deacon, Carolyn F

    2004-01-01

    Glucagon-like peptide (GLP)-1 is an incretin hormone with potent glucose-dependent insulinotropic and glucagonostatic actions, trophic effects on the pancreatic beta-cells, and inhibitory effects on gastrointestinal secretion and motility, which combine to lower plasma glucose and reduce glycemic...... of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo...

  7. Glucagon-like peptide-1 analogues: An overview

    Vishal Gupta

    2013-01-01

    Full Text Available Abnormalities of the incretin axis have been implicated in the pathogenesis of type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1 and gastroinhibitory intestinal peptide constitutes >90% of all the incretin function. Augmentation of GLP-1 results in improvement of beta cell health in a glucose-dependant manner (post-prandial hyperglycemia and suppression of glucagon (fasting hyperglycemia, amongst other beneficial pleiotropic effects. Native GLP-1 has a very short plasma half-life and novel methods have been developed to augment its half life, such that its anti-hyperglycemic effects can be exploited. They can be broadly classified as exendin-based therapies (exenatide, exenatide once weekly, DPP-4-resistant analogues (lixisenatide, albiglutide, and analogues of human GLP-1 (liraglutide, taspoglutide. Currently, commercially available analogues are exenatide, exenatide once weekly, and liraglutide. This review aims to provide an overview of most GLP-1 analogues.

  8. Glucagon-like peptide-1: glucose homeostasis and beyond.

    Cho, Young Min; Fujita, Yukihiro; Kieffer, Timothy J

    2014-01-01

    Glucagon-like peptide-1 (GLP-1), an incretin hormone secreted primarily from the intestinal L-cells in response to meals, modulates nutrient homeostasis via actions exerted in multiple tissues and cell types. GLP-1 and its analogs, as well as compounds that inhibit endogenous GLP-1 breakdown, have become an effective therapeutic strategy for many subjects with type 2 diabetes. Here we review the discovery of GLP-1; its synthesis, secretion, and elimination from the circulation; and its multiple pancreatic and extrapancreatic effects. Finally, we review current options for GLP-1-based diabetes therapy, including GLP-1 receptor agonism and inhibition of GLP-1 breakdown, as well as the benefits and drawbacks of different modes of therapy and the potential for new therapeutic avenues. PMID:24245943

  9. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists.

    Kang, Yu Mi; Jung, Chang Hee

    2016-06-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID:27118277

  10. Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men

    Nathanson, D; Zethelius, B; Berne, C;

    2011-01-01

    Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest....

  11. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: new advances

    Asmar, Meena; Holst, Jens Juul

    2010-01-01

    This article highlights recent advances in our understanding of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) physiology and their various sites of action beyond the incretin effect....

  12. Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I

    Orskov, C; Poulsen, Steen Seier; Møller, M; Holst, J J

    1996-01-01

    The intestinal incretin hormone glucagon-like peptide I (GLP-I) inhibits gastric motility and secretion in normal, but not in vagotomized subjects, pointing to a centrally mediated effect. Therefore, our aim was to study the availability of rat brain GLP-I receptors to peripherally injected 125I-...

  13. Small-molecule agonists for the glucagon-like peptide 1 receptor

    Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min;

    2007-01-01

    The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been...

  14. Glucagon-like peptide-2 inhibits antral emptying in man, but is not as potent as glucagon-like peptide-1

    Nagell, C F; Wettergren, A; Pedersen, J F;

    2004-01-01

    BACKGROUND: GLP-1 (glucagon-like peptide-1) and GLP-2 (glucagon-like peptide-2) are released in equimolar amounts in response to meal ingestion. GLP-1 inhibits gastric emptying and reduces postprandial gastric and exocrine pancreatic secretion and may play a physiological regulatory role...... with GLP-1 inhibits gastric emptying and the sensation of hunger in man. METHODS: Eight healthy volunteers were tested in a double-blind, placebo-controlled fashion. Antral emptying of a liquid meal and hunger ratings were determined using ultrasound technology and visual analogue scales scoring during...... in controlling appetite and energy intake in humans. The role of GLP-2 is more uncertain. Based on the results of animal studies, it has been suggested that GLP-2 may induce intestinal epithelial growth and inhibit gastric motility. The aim of this study was to determine to what extent GLP-2 alone or together...

  15. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes

    Madsbad, Sten; Krarup, Thure; Deacon, Carolyn F;

    2008-01-01

    PURPOSE OF REVIEW: To discuss the virtues and shortcomings of the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes. RECENT FINDINGS: The injectable glucagon-like peptide-1 receptor agonists exenatide significantly improves...... glycaemic control, with average reductions in haemoglobin A1c of about 1.0%, fasting plasma glucose of about 1.4 mmol/l, and causes a weight loss of approximately 2-3 kg after 30 weeks of treatment in patients with type 2 diabetes. The adverse effects are transient nausea and vomiting. The long...... weight neutral and without gastrointestinal side-effects. SUMMARY: The benefits and position of the glucagon-like peptide-1 analogues and the dipeptidyl peptidase-4 inhibitors in the diabetes treatment algorithm will be clarified when we have long-term trials with hard cardiovascular endpoints and data...

  16. Determination of Glucagon-Like Peptide-1, Glucagon and Oxyntomodulin in Plasma

    Bak, Monika Judyta

    Glucagon-like peptide-1, glucagon and oxyntomodulin are three peptide hormones which play a significant role in diabetes, however there is a major controversy regarding their exact roles due to difficulties in measuring of these peptides because of molecular heterogeneity, low circulating...... sort out which of the studies from the literature that have provided reliable measurements and thereby help resolve controversies regarding the metabolic roles of the peptides. The improved technology should also provide better reliability of future publications in the field....

  17. Oligomerization of a Glucagon-like Peptide 1 Analog: Bridging Experiment and Simulations

    Frederiksen, Tine Maja; Sønderby, Pernille; Ryberg, Line A.;

    2015-01-01

    The glucagon-like peptide 1 (GLP-1) analog, liraglutide, is a GLP-1 agonist and is used in the treatment of type-2 diabetes mellitus and obesity. From a pharmaceutical perspective, it is important to know the oligomerization state of liraglutide with respect to stability. Compared to GLP-1...

  18. Diabetic intestinal growth adaptation and glucagon-like peptide 2 in the rat

    Thulesen, J; Hartmann, B; Nielsen, C;

    1999-01-01

    Dietary fibre influence growth and function of the upper gastrointestinal tract. This study investigates the importance of dietary fibre in intestinal growth in experimental diabetes, and correlates intestinal growth with plasma levels of the intestinotrophic factor, glucagon-like peptide 2 (GLP-2)....

  19. Intestinal Permeability and Glucagon-Like Peptide-2 in Children with Autism: A Controlled Pilot Study

    Robertson, Marli A.; Sigalet, David L.; Holst, Jens J.; Meddings, Jon B.; Wood, Julie; Sharkey, Keith A.

    2008-01-01

    We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls…

  20. Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects

    Näslund, Erik; King, N; Mansten, S; Adner, N; Holst, Jens Juul; Gutniak, M; Hellström, P M

    2004-01-01

    Recombinant glucagon-like peptide-1 (7-36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was ...

  1. Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes?

    Knop, Filip Krag

    2010-01-01

    glucose metabolism) and the cell surface G protein-coupled receptor TGR5 (modulating energy expenditure in brown fat and muscle cells). It has been shown that TGR5 is expressed in enteroendocrine L cells, which secrete the potent glucose-lowering incretin hormone glucagon-like peptide-1 (GLP-1). Recently...

  2. Glucagon-like peptide-1, glucose homeostasis and diabetes

    Holst, Jens Juul; Deacon, Carolyn F; Vilsbøll, Tina;

    2008-01-01

    pancreatic beta cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and incretin enhancers, which inhibit the incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as...... therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here....

  3. Glucagon and glucagon-like peptides 1 and 2

    Holst, Jens Juul

    2010-01-01

    The glucagon gene is expressed not only in the alpha cells of the pancreatic islets but also in the endocrine cells of the intestinal epithelium (so-called L-cells), and in certain neurons of the brain stem. Whereas in the pancreas, glucagon, the hyperglycaemic hormone, is cleaved out of the 160....... After their release, the hormones are eliminated mainly in the kidneys, but both GLP-2 and in particular GLP-1, but not glucagon, are metabolized both locally and in the circulation and liver by dipeptidyl peptidase 4 (DPP-4) which inactivates the peptides, suggesting that GLP-1 acts locally rather than...

  4. Glucagon-Like Peptide 1 Receptors in Nucleus Accumbens Affect Food Intake

    Dossat, Amanda M.; Lilly, Nicole; Kay, Kristen; Williams, Diana L.

    2011-01-01

    Central glucagon-like peptide 1 receptor (GLP-1R) stimulation suppresses food intake, and hindbrain GLP-1 neurons project to numerous feeding-relevant brain regions. One such region is the nucleus accumbens (NAc), which plays a role in reward and motivated behavior. Using immunohistochemical and retrograde tracing techniques in rats, we identified a robust projection from GLP-1 neurons in the nucleus of the solitary tract to the NAc. We hypothesized that activation of NAc GLP-1Rs suppresses f...

  5. Optimising cardioprotection during myocardial ischaemia: targeting potential intracellular pathways with glucagon-like peptide-1

    Clarke, Sophie J; McCormick, Liam M; Dutka, David P

    2014-01-01

    Coronary heart disease and type-2 diabetes are both major global health burdens associated with an increased risk of myocardial infarction (MI). Following MI, ischaemia-reperfusion injury (IRI) remains a significant contributor to myocardial injury at the cellular level. Research has focussed on identifying a strategy or intervention to minimise IRI to optimise reperfusion therapy, with the aim of delivering a superior clinical outcome. The incretin hormone glucagon-like peptide-1, already an...

  6. Role of Central Glucagon-like Peptide-1 in Stress Regulation

    Ghosal, Sriparna; Myers, Brent; Herman, James P.

    2013-01-01

    Glucagon-like peptide 1 (GLP-1) is best known as an incretin hormone, secreted from L cells in the intestine in response to nutrient ingestion to stimulate glucose-dependent insulin secretion. However, GLP-1 is also expressed in neurons, and plays a major role in regulation of homeostatic function within the central nervous system (CNS). This review summarizes our current state of knowledge on the role GLP-1 plays in neural coordination of the organismal stress response. In brain, the primary...

  7. Cell-based delivery of glucagon-like peptide-1 using encapsulated mesenchymal stem cells

    Wallrapp, Christine; Thoenes, Eric; Thürmer, Frank;

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) CellBeads are cell-based implants for the sustained local delivery of bioactive factors. They consist of GLP-1 secreting mesenchymal stem cells encapsulated in a spherically shaped immuno-isolating alginate matrix. A highly standardized and reproducible encapsulati...... preclinical studies and an ongoing safety trial in humans but further studies have to prove the overall potential of CellBead technology in cell-based regenerative medicine....

  8. Ghrelin and glucagon-like peptide-2 increase immediately following massive small bowel resection

    MUTO, Mitsuru; Kaji, Tatsuru; MUKAI, Motoi; NAKAME, Kazuhiko; Yoshioka, Takako; Tanimoto, Akihide; Matsufuji, Hiroshi; ムトウ, ミツル; カジ, タツル; ムカイ, モトイ; ナカメ, カズヒコ; ヨシオカ, タカコ; タニモト, アキヒデ; マツフジ, ヒロシ; 武藤, 充

    2013-01-01

    Children with short bowel syndrome face life-threatening complications. Therefore, there is an urgent need for a new therapy to induce effective adaptation of the remnant intestine. Adaptation occurs only during feeding. We focused on preprandial acyl ghrelin and des-acyl ghrelin, and postprandial glucagon-like peptide-2 (GLP-2), which are known to have active orexigenic and trophic actions. This study aims to clarify the secretion trends of these hormones after massive small bowel resection ...

  9. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

    Ripken, Dina; Wielen, van der, F.W.M.; Wortelboer, Heleen M.; Meijerink, Jocelijn; Witkamp, Renger F.; Hendriks, Henk F. J.

    2016-01-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects...

  10. Effects of glucagon-like peptide-I on glucose turnover in rats

    VanDijk, G; Lindskog, S; Holst, JJ; Steffens, AB; Ahren, B

    1996-01-01

    The influences of glucagon-like peptide-I-(7-36) amide (GLP-I; 15 pmol . kg(-1). min(-1)) on glucose turnover were studied in freely moving Wistar rats. In fed rats, GLP-I reduced plasma glucose (from 7.3 +/- 0.2 to 5.6 +/- 0.3 mmol/l; P = 0.017), increased plasma insulin (from 20 +/- 3 to 89 +/- 11

  11. Direct Control of Brown Adipose Tissue Thermogenesis by Central Nervous System Glucagon-Like Peptide-1 Receptor Signaling

    Lockie, Sarah H.; Heppner, Kristy M.; Chaudhary, Nilika; Chabenne, Joseph R.; Morgan, Donald A; Veyrat-Durebex, Christelle; Ananthakrishnan, Gayathri; Rohner-Jeanrenaud, Françoise; Drucker, Daniel J.; DiMarchi, Richard; Rahmouni, Kamal; Oldfield, Brian J; Tschöp, Matthias H.; Perez-Tilve, Diego

    2012-01-01

    We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)–deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with incr...

  12. The alpha cell expresses glucagon-like peptide-2 receptors and glucagon-like peptide-2 stimulates glucagon secretion from the rat pancreas

    de Heer, J; Pedersen, J; Orskov, C; Holst, Jens Juul

    2007-01-01

    . MATERIALS AND METHODS: The expression of the GLP-2 receptor gene, Glpr2, and the localisation of the protein were evaluated by real-time PCR on cDNA from isolated rat islets and by immunohistochemistry in rat and human pancreas. The glucagon, insulin and somatostatin responses to 0.1, 1 and 10 nmol/l GLP-2......AIMS/HYPOTHESIS: Glucagon-like peptide-2 (GLP-2) is a gut hormone regulating intestinal growth and nutrient absorption. Recently, GLP-2 has been reported to stimulate glucagon secretion in healthy humans. We sought to clarify the mechanism and physiological significance of this endocrine effect...... and to GLP-1 and GLP-2 given simultaneously were studied in the isolated perfused rat pancreas. RESULTS: Expression of Glp2r transcript was confirmed by PCR. In both human and rat pancreas, GLP-2r immunoreactivity was colocalised with proglucagon. GLP-2 at 10 nmol/l increased glucagon secretion...

  13. The effects of duodenal peptides on glucagon-like peptide-1 secretion from the ileum. A duodeno--ileal loop?

    Hansen, Lene; Holst, Jens Juul

    2002-01-01

    Secretion of the gut hormone glucagon-like peptide-1 (GLP-1) is stimulated by meal ingestion. The response is rapid, suggesting a stimulatory pathway elicited from the upper gastrointestinal area. In pigs, we have been unable to demonstrate a neural stimulatory pathway, but GLP-1 secretion is reg...

  14. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury

    Goto, Hiromasa [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Nomiyama, Takashi, E-mail: tnomiyama@fukuoka-u.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Sportology Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Fujitani, Yoshio; Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Sportology Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan)

    2011-02-04

    Research highlights: {yields} Exendin-4 reduces neointimal formation after vascular injury in a mouse model. {yields} Exendin-4 dose not alter metabolic parameters in non-diabetic, non-obese mouse model. {yields} Exendin-4 reduces PDGF-induced cell proliferation in cultured SMCs. {yields} Exendin-4 may reduces neointimal formation after vascular injury at least in part through its direct action on SMCs. -- Abstract: Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4 weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10 nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

  15. Intestinal permeability and glucagon-like peptide-2 in children with autism

    Robertson, Marli A; Sigalet, David L; Holst, Jens Juul;

    2008-01-01

    feeding. Results were compared with sibling controls and children without developmental disabilities. We enrolled 14 children with autism, 7 developmentally normal siblings of these children and 8 healthy, developmentally normal, unrelated children. Our study did not detect differences in these measures......We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to...... of gastrointestinal function in a group of children with autism....

  16. Ligand binding and activation mechanism og the glucagon-like peptide-1 receptor

    Underwood, Christina Rye

    In recent years, G-protein coupled receptors (GPCRs) have become important drug targets, which makes elucidation of their molecular structure and functional domains increasingly important for designing new and better therapeutic agents. The Glucagon-Like Peptide-1 receptor (GLP-1R) is a GPCR. Its...... molecule-mediated activation of GLP-1R (Study II). A fully functional, cysteine-deprived and Cterminally truncated GLP-1R is developed and characterised in Study III. In Study IV, a cAMP biosensor is used to investigate the cAMP kinetics of GLP-1R upon stimulation with different receptor agonists...

  17. Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates

    Vegge, Andreas; Thymann, Thomas; Lund, Pernille;

    2013-01-01

    Short bowel syndrome (SBS) is a frequent complication after intestinal resection in infants suffering from intestinal disease. We tested whether treatment with the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) increases intestinal volume and function in the period immediately following...... increased the relative absorption of wet weight (46 vs. 22%), energy (79 vs. 64%), and all macronutrients (all parameters P <0.05). These findings were supported by a 200% increase in sucrase and maltase activities, a 50% increase in small intestinal epithelial volume (P <0.05), as well as increased DNA and...

  18. The effect of glucagon-like peptide 1 on cardiovascular risk

    Sivertsen, Jacob; Rosenmeier, Jaya; Holst, Jens Juul;

    2012-01-01

    Glucagon-like peptide 1 (GLP-1) is an incretin hormone responsible for amplification of insulin secretion when nutrients are given orally, as opposed to intravenously, and it retains its insulinotropic activity in patients with type 2 diabetes mellitus. GLP-1-based therapies, such as GLP-1 receptor...... on cardiovascular parameters. These effects, possibly independent of the glucose-lowering activity, include changes in blood pressure, endothelial function, body weight, cardiac metabolism, lipid metabolism, left ventricular function, atherosclerosis, and the response to ischemia-reperfusion injury...

  19. Molecular Physiology of Glucagon-Like Peptide-1 Insulin Secretagogue Action in Pancreatic β Cells

    Leech, Colin A.; Dzhura, Igor; Chepurny, Oleg G.; Kang, Guoxin; Schwede, Frank; Genieser, Hans-G.; Holz, George G.

    2011-01-01

    Insulin secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the β cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM). An additio...

  20. Stability of glucagon-like peptide-1 and glucagon in human plasma

    Albrechtsen, Nicolai Jacob Wewer; Bak, Monika Judyta; Hartmann, Bolette;

    2015-01-01

    To investigate the stability of glucagon-like peptide-1(GLP-1) and glucagon in plasma under short- and long-term storage conditions. Methods: Pooled human plasma (n=20), to which a dipeptidyl peptidase 4 (DPP-4) inhibitor and aprotinin were added, was spiked with synthetic GLP-1 (intact, 7-36NH2 as...... subsequent hormone analysis. Our data support addition of DPP-4 inhibitor for GLP-1 measurement as well as cooling on ice of both GLP-1 and glucagon. Freeze/thaw cycles did not significantly affect stability of GLP-1 or glucagon. Long term storage may affect glucagon levels regardless of storage temperature...

  1. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists

    Madsbad, Sten

    2016-01-01

    Currently, six glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short-acting exenatide twice daily and lixisenatide once daily; and longer-acting liraglutide once daily, exenatide once...... weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP-1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head-to-head trials and one large phase II study have compared the efficacy and safety of these seven...

  2. Pharmacological Actions of Glucagon-Like Peptide-1, Gastric Inhibitory Polypeptide, and Glucagon.

    Sekar, R; Singh, K; Arokiaraj, A W R; Chow, B K C

    2016-01-01

    Glucagon family of peptide hormones is a group of structurally related brain-gut peptides that exert their pleiotropic actions through interactions with unique members of class B1 G protein-coupled receptors (GPCRs). They are key regulators of hormonal homeostasis and are important drug targets for metabolic disorders such as type-2 diabetes mellitus (T2DM), obesity, and dysregulations of the nervous systems such as migraine, anxiety, depression, neurodegeneration, psychiatric disorders, and cardiovascular diseases. The current review aims to provide a detailed overview of the current understanding of the pharmacological actions and therapeutic advances of three members within this family including glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon. PMID:27572131

  3. Characterization of the hypotensive effects of glucagon-like peptide-2 in anesthetized rats.

    Iwai, Takashi; Kaneko, Maki; Sasaki-Hamada, Sachie; Oka, Jun-Ichiro

    2013-08-29

    Glucagon-like peptide-2 (GLP-2) is a proglucagon-derived peptide released from enteroendocrine cells and neurons. We recently reported that GLP-2 induced hypotension. In the present study, we characterized the mechanisms of GLP-2-induced hypotension. GLP-2 was administered peripherally or centrally to male Wistar rats anesthetized with urethane and α-chloralose. The rats were vagotomized or systemically pretreated with atropine, prazosin, or propranolol before the GLP-2 administration. The central and peripheral administration of GLP-2 reduced mean arterial blood pressure (MAP). The maximum change of MAP (maximum ΔMAP) was reduced by vagotomy or prazosin, but not propranolol. The effects of the central but not peripheral administration of GLP-2 were reduced by atropine. These results suggest that GLP-2 modulates vagal afferent inputs and inhibits the sympathetic nervous system in the brain to induce hypotension. PMID:23867714

  4. Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

    Francis S. Willard

    2012-01-01

    Full Text Available The therapeutic success of peptide glucagon-like peptide-1 (GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

  5. Increased expression of glucagon-like peptide-1 receptors in psoriasis plaques

    Faurschou, Annesofie; Pedersen, Jens; Gyldenløve, Mette; Poulsen, Steen Seier; Holst, Jens J; Thyssen, Jacob P; Zachariae, Claus; Vilsbøll, Tina; Skov, Lone; Knop, Filip K

    2013-01-01

    Recent case reports suggest that treatment with glucagon-like peptide-1 (GLP-1) agonists results in clinical improvement of psoriasis. The purpose of this study was to determine whether GLP-1 receptors (GLP-1Rs) are found in the skin of healthy volunteers and psoriasis patients and if so, whether...... GLP-1Rs are located on keratinocytes or immune cells. Three mm-punch skin biopsies were taken for gene expression analysis from six healthy volunteers and from affected and unaffected skin of six psoriasis patients. In addition, a blood sample was obtained from all participants. Cultured human...... keratinocytes were either untreated or incubated with tumor necrosis factor- a (TNF-a), interferon-¿ (IFN-¿) or a combination of TNF-a and IFN-¿ for 48 h. Total RNA was extracted from all the samples, reversely transcribed and analysed for the expression of GLP-1R using real-time PCR. Gene expression analysis...

  6. Glucagon-like peptide-1 analogue, liraglutide, in experimental cerebral malaria

    DellaValle, Brian; Hempel, Casper; Staalsoe, Trine;

    2016-01-01

    BACKGROUND: Cerebral malaria from Plasmodium falciparum infection is major cause of death in the tropics. The pathogenesis of the disease is complex and the contribution of reactive oxygen and nitrogen species (ROS/RNS) in the brain is incompletely understood. Insulinotropic glucagon-like peptide-1...... (GLP-1) mimetics have potent neuroprotective effects in animal models of neuropathology associated with ROS/RNS dysfunction. This study investigates the effect of the GLP-1 analogue, liraglutide against the clinical outcome of experimental cerebral malaria (ECM) and Plasmodium falciparum growth....... Furthermore the role of oxidative stress on ECM pathogenesis is evaluated. METHODS: ECM was induced in Plasmodium berghei ANKA-infected C57Bl/6j mice. Infected Balb/c (non-cerebral malaria) and uninfected C57Bl/6j mice were included as controls. Mice were treated twice-daily with vehicle or liraglutide (200...

  7. Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets.

    Tudurí, Eva; López, Miguel; Diéguez, Carlos; Nadal, Angel; Nogueiras, Rubén

    2016-05-01

    Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors. In this review, we focus on the pancreatic effects exerted by current GLP-1 derivatives used to treat diabetes. Based on the results from in vitro and in vivo studies in humans and animal models, we describe the specific actions of GLP-1 analogs on the synthesis, processing, and secretion of insulin, islet morphology, and β cell proliferation and apoptosis. PMID:27062006

  8. Therapeutic effects of Glucagon-Like Peptide-2 on experimental radiation enteritis in rat

    Radiation enteritis in patients treated by abdominal and pelvic radiotherapy is characterized by acute mucosal disruption and chronic intestinal fibrosis. Using a model of localized intestinal irradiation in the rat, we showed remote intestinal dysfunction outside the irradiation field along the whole gut, probably associated with perturbations in the systems regulating intestinal functions. Based on the hypothesis of consequential late effects, acute administration of Glucagon-Like Peptide-2, a growth factor with specific trophic effect on the intestinal mucosa, limited the apparition of both acute and chronic radiation enteritis. This suggests that therapeutic strategies targeting the severity of acute tissue damage may also limit chronic sequelae. The study of GLP-2 effects on epithelial cells in co-culture with either subepithelial myo-fibroblasts or enteric nervous system emphasized the problem of the modelization of complex systems in vitro, and suggested a synergic action from these different actors in vivo. (author)

  9. Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain

    Ebdrup, Bjørn H; Knop, Filip K; Ishøy, Pelle L;

    2012-01-01

    already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes...... between schizophrenia and overweight patients. DISCUSSION: Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogues used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in...... overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogues are discussed. CONCLUSIONS: We propose that adjunctive treatment with GLP-1 analogues may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in...

  10. Optimising cardioprotection during myocardial ischaemia: targeting potential intracellular pathways with glucagon-like peptide-1.

    Clarke, Sophie J; McCormick, Liam M; Dutka, David P

    2014-01-01

    Coronary heart disease and type-2 diabetes are both major global health burdens associated with an increased risk of myocardial infarction (MI). Following MI, ischaemia-reperfusion injury (IRI) remains a significant contributor to myocardial injury at the cellular level. Research has focussed on identifying a strategy or intervention to minimise IRI to optimise reperfusion therapy, with the aim of delivering a superior clinical outcome. The incretin hormone glucagon-like peptide-1, already an established basis for the treatment of type-2 diabetes, also has the potential to protect against IRI. We explain the physiology and cellular processes involved in IRI, and the intracellular pathways activated by GLP-1, which could intercept IRI and deliver cardioprotection. The review also examines the current preclinical and clinical evidence for GLP-1 in cardioprotection and future directions for research as we look for an effective adjunctive treatment to minimise IRI. PMID:24410815

  11. Glucagon-like peptide-1 inhibits blood-brain glucose transfer in humans

    Lerche, Susanne; Brock, Birgitte; Rungby, Jørgen;

    2008-01-01

    demonstrated that a hormone involved in postprandial glucose regulation also limits glucose delivery to brain tissue and hence provides a possible regulatory mechanism for the link between plasma glucose and brain glucose. Because GLP-1 reduces glucose uptake across the intact blood-brain barrier at normal...... glycemia, GLP-1 may also protect the brain by limiting intracerebral glucose fluctuation when plasma glucose is increased.......OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has many effects on glucose homeostasis, and GLP-1 receptors are broadly represented in many tissues including the brain. Recent research in rodents suggests a protective effect of GLP-1 on brain tissue. The mechanism is unknown. We therefore tested...

  12. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans

    Nauck, Michael A; Kemmeries, Guido; Holst, Jens Juul;

    2011-01-01

    OBJECTIVE: Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1-induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control. RESEARCH...... DESIGN AND METHODS: Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m(2)) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg(-1) · min(-1)) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were...... drawn frequently. RESULTS: GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P

  13. Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia

    Toft-Nielsen, M; Madsbad, Sten; Holst, Jens Juul

    1998-01-01

    The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is...... impossible to induce hypoglycaemia in normal subjects in the basal state by exogenous GLP-1, regardless of dose. To further assess the role of the incretin hormones in reactive hypoglycaemia, we reproduced the glucose and hormone profiles of the patients with reactive hypoglycaemia in 8 healthy volunteers in...... 4 separate protocols: 1) i.v. infusion of glucose (25 g) alone, 2) glucose together with i.v. GLP-1 infusion, and 3) and 4) glucose together with i.v. infusion of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), at two different infusion rates. The plasma glucose, GLP...

  14. Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice

    Thulesen, J; Hartmann, B; Hare, K J;

    2004-01-01

    BACKGROUND: Glucagon-like peptide 2 (GLP-2) is an intestinotrophic mediator with therapeutic potential in conditions with compromised intestinal capacity. However, growth stimulation of the intestinal system may accelerate the growth of existing neoplasms in the intestine. AIMS: In the present...... study, the effects of GLP-2 treatment on the growth of chemically induced colonic neoplasms were investigated. METHODS: In 210 female C57bl mice, colonic tumours were initially induced with the methylating carcinogen 1,2-dimethylhydrazine (DMH) and mice were then treated with GLP-2. Two months after...... growth of mucosal neoplasms. Our findings highlight the need for future investigations on the effects of GLP-2 in conditions needing long time treatment or with increased gastrointestinal cancer susceptibility....

  15. A Safety and Dosing Study of Glucagon-Like Peptide 2 in Children With Intestinal Failure

    Sigalet, David L; Brindle, Mary; Boctor, Dana;

    2016-01-01

    ). Nutritional treatment was directed by the primary caregivers. Patients were followed to 1 year. RESULTS: Seven patients were enrolled (age: 4.0 ± 0.8 years; bowel length, mean ± SEM: 24% ± 4% of predicted). All were parenteral nutrition dependent since birth, receiving 44% ± 5% of calories by parenteral......BACKGROUND AND AIMS: A glucagon-like peptide 2 (GLP-2) analogue is approved for adults with intestinal failure, but no studies of GLP-2 have included children. This study examined the pharmacokinetics, safety, and nutritional effects of GLP-2 in children with intestinal failure. METHODS: Native...... human GLP-2(1-33) was synthesized following good manufacturing practices. In an open-label trial, with parental consent, 7 parenteral nutrition-dependent pediatric patients were treated with subcutaneous GLP-2 (20 µg/kg/d) for 3 days (phase 1) and, if tolerated, continued for 42 days (phase 2...

  16. Glucagon-like peptide-2 (GLP-2) response to enteral intake in children during anti-cancer treatment

    Andreassen, B U; Paerregaard, A; Schmiegelow, K;

    2005-01-01

    BACKGROUND: Intestinal dysfunction is frequent in cancer and during anti-cancer treatment. Glucagon-like peptide-2 (GLP-2) is secreted in a nutrition-dependent manner from the intestinal enteroendocrine L-cells. It accelerates crypt cell proliferation and nutrient absorption, inhibits enterocyte...

  17. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon

    Jeppesen, P B; Hartmann, B; Thulesen, J;

    2001-01-01

    Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a ...

  18. Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon

    Jeppesen, P B; Hartmann, B; Thulesen, J;

    2000-01-01

    The glucagon-like peptides (GLP) 1 and 2 are secreted postprandially from L cells located mainly in the ileum. Both hormones prolong intestinal transit and GLP-2 is intestinotrophic in rodents. Patients with a jejunostomy have poor adaptation, rapid gastric and intestinal transit, and impaired po...

  19. Hyperglycemia acutely lowers the postprandial excursions of glucagon-like Peptide-1 and gastric inhibitory polypeptide in humans

    Vollmer, Kirsten; Gardiwal, Husai; Menge, Bjoern A;

    2009-01-01

    INTRODUCTION: Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes. It is unclear whether this is a primary defect or a consequence of the hyperglycemia in type 2 diabetes. We examined whether acute...

  20. Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s)

    Jorgensen, Rasmus; Kubale, Valentina; Vrecl, Milka;

    2007-01-01

    The glucagon-like peptide (GLP)-1 receptor is a promising target for the treatment of type 2 diabetes and obesity, and there is great interest in characterizing the pharmacology of the GLP-1 receptor and its ligands. In the present report, we have applied bioluminescence resonance energy transfer...

  1. Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs

    Ipharraguerre, Ignacio R; Tedó, Gemma; Menoyo, David; de Diego Cabero, Nuria; Holst, Jens Juul; Nofrarías, Miquel; Mereu, Alessandro; Burrin, Douglas G

    2013-01-01

    Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve...

  2. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action

    Hare, Kristine J; Vilsbøll, Tina; Asmar, Meena; Deacon, Carolyn F; Knop, Filip K; Holst, Jens Juul

    2010-01-01

    Glucagon-like peptide 1 (GLP-1) exerts beneficial antidiabetic actions via effects on pancreatic beta- and alpha-cells. Previous studies have focused on the improvements in beta-cell function, while the inhibition of alpha-cell secretion has received less attention. The aim of this research was to...

  3. Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice

    Kissow, Hannelouise; Hartmann, Bolette; Holst, Jens Juul; Viby, Niels-Erik; Hansen, Lærke Schmidt; Rosenkilde, Mette Marie; Hare, Kristine Juul; Poulsen, Steen Seier

    Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel from the intestinal endocrine cells after nutrient intake. GLP-1 is an incretin hormone and analogues are available for the treatment of type 2 diabetes mellitus (T2DM). GLP-2 is an intestinal growth horm...

  4. Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides

    Rehfeld, J F

    2011-01-01

    and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by...... gastrin and CCK and, hence, their effect on insulin secretion are modest in comparison with the effects of glucose-dependentinsulinotropic polypeptide and glucagon-like peptide 1 (GLP-1). Consequently, the interest of CCK and gastrin in incretin research has for decades been limited. A few years ago...

  5. Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides

    Rehfeld, J F

    2011-01-01

    and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by...... gastrin and CCK and, hence, their effect on insulin secretion are modest in comparison with the effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1). Consequently, the interest of CCK and gastrin in incretin research has for decades been limited. A few years ago...

  6. Glucagon-Like Peptide-1 Formulation--the Present and Future Development in Diabetes Treatment.

    Lee, Chooi Yeng

    2016-03-01

    Type 2 diabetes mellitus is a chronic metabolic disorder that has become the fourth leading cause of death in the developed countries. The disorder is characterized by pancreatic β-cells dysfunction, which causes hyperglycaemia leading to several other complications. Treatment by far, which focuses on insulin administration and glycaemic control, has not been satisfactory. Glucagon-like peptide-1 (GLP1) is an endogenous peptide that stimulates post-prandial insulin secretion. Despite being able to mimic the effect of insulin, GLP1 has not been the target drug in diabetes treatment due to the peptide's metabolic instability. After a decade-long effort to improve the pharmacokinetics of GLP1, a number of GLP1 analogues are currently available on the market. The current Minireview does not discuss these drugs but presents strategies that were undertaken to address the weaknesses of the native GLP1, particularly drug delivery techniques used in developing GLP1 nanoparticles and modified GLP1 molecule. The article highlights how each of the selected preparations has improved the efficacy of GLP1, and more importantly, through an overview of these studies, it will provide an insight into strategies that may be adopted in the future in the development of a more effective oral GLP1 formulation. PMID:26551045

  7. Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications

    Meike eKörner

    2012-12-01

    Full Text Available Peptide hormones of the glucagon-like peptide (GLP family play an increasing clinical role, such as GLP-1 in diabetes therapy. Moreover, GLP receptors are over-expressed in various human tumor types and therefore represent molecular targets for important clinical applications. In particular, virtually all benign insulinomas highly over-express GLP-1 receptors (GLP-1R. Targeting GLP-1R with the stable GLP-1 analogs 111In-DOTA/ DPTA-exendin-4 offers a new approach to successfully localize these small tumors. This non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. Malignant insulinomas, in contrast to their benign counterparts, express GLP-1R in only one third of the cases, while they more often express the somatostatin type 2 receptors. Importantly, one of the two receptors appears to be always expressed in malignant insulinomas. The GLP-1R overexpression in selected cancers is worth to be kept in mind with regard to the increasing use of GLP-1 analogs for diabetes therapy. While the functional role of GLP-1R in neoplasia is not known yet, it may be safe to monitore patients undergoing GLP-1 therapy carefully.

  8. Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2.

    Drucker, Daniel J; Yusta, Bernardo

    2014-01-01

    Glucagon-like peptide-2 (GLP-2) is a 33-amino-acid proglucagon-derived peptide secreted from enteroendocrine L cells. GLP-2 circulates at low basal levels in the fasting period, and plasma levels rise rapidly after food ingestion. Renal clearance and enzymatic inactivation control the elimination of bioactive GLP-2. GLP-2 increases mesenteric blood flow and activates proabsorptive pathways in the gut, facilitating nutrient absorption. GLP-2 also enhances gut barrier function and induces proliferative and cytoprotective pathways in the small bowel. The actions of GLP-2 are transduced via a single G protein-coupled receptor (GLP-2R), expressed predominantly within the gastrointestinal tract. Disruption of GLP-2R signaling increases susceptibility to gut injury and impairs the adaptive mucosal response to refeeding. Sustained augmentation of GLP-2R signaling reduces the requirement for parenteral nutrition in human subjects with short-bowel syndrome. Hence GLP-2 integrates nutrient-derived signals to optimize mucosal integrity and energy absorption. PMID:24161075

  9. Medicinal Plants Qua Glucagon-Like Peptide-1 Secretagogue via Intestinal Nutrient Sensors

    Ki-Suk Kim

    2015-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 participates in glucose homeostasis and feeding behavior. Because GLP-1 is rapidly inactivated by the enzymatic cleavage of dipeptidyl peptidase-4 (DPP4 long-acting GLP-1 analogues, for example, exenatide and DPP4 inhibitors, for example, liraglutide, have been developed as therapeutics for type 2 diabetes mellitus (T2DM. However, the inefficient clinical performance and the incidence of side effects reported on the existing therapeutics for T2DM have led to the development of a novel therapeutic strategy to stimulate endogenous GLP-1 secretion from enteroendocrine L cells. Since the GLP-1 secretion of enteroendocrine L cells depends on the luminal nutrient constituents, the intestinal nutrient sensors involved in GLP-1 secretion have been investigated. In particular, nutrient sensors for tastants, cannabinoids, and bile acids are able to recognize the nonnutritional chemical compounds, which are abundant in medicinal plants. These GLP-1 secretagogues derived from medicinal plants are easy to find in our surroundings, and their effectiveness has been demonstrated through traditional remedies. The finding of GLP-1 secretagogues is directly linked to understanding of the role of intestinal nutrient sensors and their recognizable nutrients. Concurrently, this study demonstrates the possibility of developing novel therapeutics for metabolic disorders such as T2DM and obesity using nutrients that are readily accessible in our surroundings.

  10. Glucagon-like peptide 1 and dysglycemia: Conflict in incretin science

    Awadhesh Kumar Singh

    2015-01-01

    Full Text Available Although GLP-1 (glucagon like peptide-1 based therapies (GLP-1 agonists and dipeptidyl peptidase-4 inhibitors is currently playing a cornerstone role in the treatment of type 2 diabetes, dilemma does exist about some of its basic physiology. So far, we know that GLP-1 is secreted by the direct actions of luminal contents on the L cells in distal jejunum and proximal ileum. However, there is growing evidence now, which suggest that other mechanism via "neural" or "upper gut" signals may be playing a second fiddle and could stimulate GLP-1 secretion even before the luminal contents have reached into the proximities of L cells. Therefore, the contribution of direct and indirect mechanism to GLP-1 secretion remains elusive. Furthermore, no clear consensus exists about the pattern of GLP-1 secretion, although many believe it is monophasic. One of the most exciting issues in incretin science is GLP-1 level and GLP-1 responsiveness. It is not exactly known as to what happens to endogenous GLP-1 with progressive worsening of dysglycemia from normal glucose tolerance to impaired glucose to frank diabetes and furthermore with increasing duration of diabetes. Although, conventional wisdom suggests that there may be a decrease in endogenous GLP-1 level with the worsening of dysglycemia, literature showed discordant results. Furthermore, there is emerging evidence to suggest that GLP-1 response can vary with ethnicity. This mini review is an attempt to put a brief perspective on all these issues.

  11. Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus.

    Moberly, Steven P; Mather, Kieren J; Berwick, Zachary C; Owen, Meredith K; Goodwill, Adam G; Casalini, Eli D; Hutchins, Gary D; Green, Mark A; Ng, Yen; Considine, Robert V; Perry, Kevin M; Chisholm, Robin L; Tune, Johnathan D

    2013-07-01

    Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling. PMID:23764734

  12. Male fertility and obesity: are ghrelin, leptin and glucagon-like peptide-1 pharmacologically relevant?

    Alves, Marco G; Jesus, Tito T; Sousa, Mário; Goldberg, Erwin; Silva, Branca M; Oliveira, Pedro F

    2016-01-01

    Obesity is rising to unprecedented numbers, affecting a growing number of children, adolescents and young adult men. These individuals face innumerous health problems, including subfertility or even infertility. Overweight and obese men present severe alterations in their body composition and hormonal profile, particularly in ghrelin, leptin and glucagon-like peptide-1 (GLP-1) levels. It is well known that male reproductive health is under the control of the individual's nutritional status and also of a tight network of regulatory signals, particularly hormonal signaling. However, few studies have been focused on the effects of ghrelin, leptin and GLP-1 in male reproduction and how energy homeostasis and male reproductive function are linked. These hormones regulate body glucose homeostasis and several studies suggest that they can serve as targets for anti-obesity drugs. In recent years, our understanding of the mechanisms of action of these hormones has grown significantly. Curiously, their effect on male reproductive potential, that is highly dependent of the metabolic cooperation established between testicular cells, remains a matter of debate. Herein, we review general concepts of male fertility and obesity, with a special focus on the effects of ghrelin, leptin and GLP-1 on male reproductive health. We also discuss the possible pharmacological relevance of these hormones to counteract the fertility problems that overweight and obese men face. PMID:26648473

  13. Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis.

    Koehler, Jacqueline A; Baggio, Laurie L; Cao, Xiemin; Abdulla, Tahmid; Campbell, Jonathan E; Secher, Thomas; Jelsing, Jacob; Larsen, Brett; Drucker, Daniel J

    2015-03-01

    Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice. PMID:25277394

  14. Glucagon-like peptide 2 treatment may improve intestinal adaptation during weaning

    Thymann, Thomas; Le Huërou-Luron, I; Petersen, Y M;

    2014-01-01

    ) were kept in a low-sanitary environment, leading to weaning diarrhea, and injected with saline or short-acting GLP-2 (200 µg/(kg BW·12 h); n = 11). Treatment with GLP-2 increased goblet cell density (P < 0.05) and reduced short chain fatty acid concentration in the colon (P < 0.01) but had limited......Transition from sow’s milk to solid feed is associated with intestinal atrophy and diarrhea. We hypothesized that the intestinotrophic hormone glucagon-like peptide 2 (GLP-2) would induce a dose- and health status-dependent effect on gut adaptation. In Exp. 1, weaned pigs (average BW at weaning 4...... effects on diarrhea. In Exp. 3, weaned pigs (average BW at weaning 6.90 ± 0.32 kg) were kept in a low-sanitary environment and injected with saline or a long-acting acylated GLP-2 analogue (25 µg/(kg BW·12 h); n = 8). In this experiment, GLP-2 increased intestinal weight (+22%; P < 0.01) and activity of...

  15. Effects of glucagon-like peptide-1 receptor agonists on renal function

    Theodosios; D; Filippatos; Moses; S; Elisaf

    2013-01-01

    Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

  16. Mutated recombinant human glucagon-like peptide-1 induces differentiation of PC12 cells

    Jin Wu; Lan Zhang; Zhongwei Sun; Gang Huang; Jing Huang; Bing Mei

    2011-01-01

    "Glucagon-like peptide-1 (GLP-1) and its long-acting analogues have neuroprotective and neurotrophic properties and are emerging as potential treatments for neurodegenerative diseases. Its short half-life has limited the application of GLP-1 in the clinic. We generated a mutated form of human GLP-1 (mGLP-1) using site-directed mutagenesis and gene recombination techniques, and found that these modifications significantly prolonged the biological half-life of GLP-1 compared with native GLP-1 (nGLP-1). This study investigated the role of mGLP-1 on inducing PC12 cell differentiation. mGLP-1 induced PC12 cell differentiation with neurite outgrowth and increased the expression of growth-associated protein-43 and neuronal class III ?-tubulin, and significantly increased cyclic adenosine monophosphate level. No significant difference was found between mGLP-1 and nGLP-1. The results indicate that mGLP-1 activates the GLP-1 receptor, induces PC12 cell differentiation, and has neurotrophic effects.

  17. Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis.

    Cameron-Vendrig, Alison; Reheman, Adili; Siraj, M Ahsan; Xu, Xiaohong Ruby; Wang, Yiming; Lei, Xi; Afroze, Talat; Shikatani, Eric; El-Mounayri, Omar; Noyan, Hossein; Weissleder, Ralph; Ni, Heyu; Husain, Mansoor

    2016-06-01

    Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation. Incubation with exenatide also inhibited thrombus formation under flow conditions in ex vivo perfusion chambers using human and mouse whole blood. In a mouse cremaster artery laser injury model, a single intravenous injection of exenatide inhibited thrombus formation in normoglycemic and hyperglycemic mice in vivo. Thrombus formation was greater in mice transplanted with bone marrow lacking a functional GLP-1R (Glp1r(-/-)), compared with those receiving wild-type bone marrow. Although antithrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r(-/-) mice, they were undetectable in mice with a genetic deficiency of endothelial nitric oxide synthase. The inhibition of platelet function and the prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events. PMID:26936963

  18. Glucagon-like peptide 1 improved glycemic control in type 1 diabetes

    McDonald Thomas J

    2003-04-01

    Full Text Available Abstract Background Glucagon-like peptide-1 (GLP-1 and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. Methods Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. Results In 8-hour studies time-averaged incremental (delta areas under the curves(AUC for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 ± 0.9, mean ± se, vs 5.4 ± 0.8 mmol/l, p Conclusion We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs.

  19. Glucagon-like peptide-1 gastrointestinal regulatory role in metabolism and motility.

    Hellström, Per M

    2010-01-01

    Gastrointestinal (GI) motility, primarily gastric emptying, balances the hormonal output that takes place after food intake in order to maintain stable blood sugar. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), work together to reduce postprandial hyperglycemia by glucose-dependent insulin secretion and inhibition of glucagon release, as well as inhibition of GI motility and gastric emptying. GLP-1 is considered the more effective of the two incretins due to its additional inhibitory effects on GI motility. It is observed that patients on treatment with GLP-1 analogues or exenatide achieve a considerable weight loss during treatment. This is of benefit to improve insulin resistance in type 2 diabetes. Furthermore, weight loss per se is of considerable benefit in an even longer health perspective. The weight loss is considered to be due to the inhibition of GI motility. This effect has been studied in animal experimentation, and from there taken to involve studies on GI motility in healthy volunteers and patients with irritable bowel syndrome (IBS). Evolving to a phase II study in IBS, the GLP-1 analogue (ROSE-010) was recently shown to be effective for treatment of acute pain attacks in IBS. Taken together, data speak in favor of GI motility as a central component not only in metabolic disorders but also in IBS, be it due to a direct relaxing effect on GI smooth muscle or a slow emptying of gastric contents resulting in a less outspoken nutritional demand on hormonal regulatory functions in the GI tract. PMID:21094906

  20. Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors.

    Sirohi, Sunil; Schurdak, Jennifer D; Seeley, Randy J; Benoit, Stephen C; Davis, Jon F

    2016-07-01

    Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KD(Nestin) (GLP-1R selectively ablated from the central nervous system) mice (n=13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KD(Nestin) mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders. PMID:27072507

  1. Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia

    Jensen, Michael Gejl; Egefjord, Lærke; Lerche, Susanne;

    2012-01-01

    and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and......Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD...... metabolism during a hyperglycemic clamp with 18fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P=0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P=0.039) but not to the same extent in all regions (P=0.022). The unidirectional glucose...

  2. Glucagon-Like Peptide-1 as Predictor of Body Mass Index and Dentate Gyrus Neurogenesis: Neuroplasticity and the Metabolic Milieu

    Coplan, Jeremy D.; Shariful Syed; Perera, Tarique D.; Sasha L Fulton; Mary Ann Banerji; Dwork, Andrew J.; Kral, John G.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles ...

  3. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects

    Vilsbøll, T; Agersø, H; Krarup, T; Holst, Jens Juul

    2003-01-01

    We have previously shown that type 2 diabetic patients have decreased plasma concentrations of glucagon-like peptide 1 (GLP-1) compared with healthy subjects after ingestion of a standard mixed meal. This decrease could be caused by differences in the metabolism of GLP-1. The objective of this st...... response seen after ingestion of a standard breakfast meal must therefore be caused by a decreased secretion of GLP-1 in type 2 diabetic patients....

  4. Glucagon-Like Peptide-1 Modulates Neurally-Evoked Mucosal Chloride Secretion in Guinea Pig Small Intestine In Vitro.

    Baldassano, S; Wang, GD; Mulè, F; Wood, JD

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA wa...

  5. Comparison Review of Short-Acting and Long-Acting Glucagon-like Peptide-1 Receptor Agonists

    Uccellatore, AnnaChiara; Genovese, Stefano; Dicembrini, Ilaria; Mannucci, Edoardo; Ceriello, Antonio

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) are useful tools for treating type 2 diabetes mellitus. In their recent position statement, the American Diabetes Association and European Association for the Study of Diabetes recommend GLP1-RAs as add-on to metformin when therapeutic goals are not achieved with monotherapy, particularly for patients who wish to avoid weight gain or hypoglycemia. GLP1-RAs differ substantially in their duration of action, frequency of administratio...

  6. Plasma glucagon-like peptide 1 and peptide YY levels are not altered in symptomatic fructose-sorbitol malabsorption

    Valeur, Jørgen; Øines, Eliann; Morken, Mette Helvik; Holst, Jens Juul; Berstad, Arnold

    2008-01-01

    excretion and plasma glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) levels were measured during the next 3 h. Both habitual and post-test symptoms were assessed. RESULTS: Malabsorption of fructose and sorbitol was present in 61% of the patients and 73% of the controls. Nevertheless, the patients......OBJECTIVE: Carbohydrate malabsorption causes more symptoms in patients with functional gastrointestinal disorders than in healthy individuals. The purpose of this study was to investigate whether this could be explained by differences in ileal brake hormone secretion. MATERIAL AND METHODS: Eighteen...... consecutive patients with functional abdominal complaints, referred to our clinic for investigation of self-reported food hypersensitivity, were included in the study and compared with 15 healthy volunteers. All subjects ingested a mixture of 25 g fructose and 5 g sorbitol. Pulmonary hydrogen and methane...

  7. A novel, long-acting glucagon-like peptide receptor-agonist: dulaglutide

    Gurung T

    2015-08-01

    Full Text Available Tara Gurung,1 Deepson S Shyangdan,1 Joseph Paul O’Hare,2 Norman Waugh1 1Warwick Evidence, 2Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK Background: Dulaglutide is a new, long-acting glucagon-like peptide analogue in the treatment of type 2 diabetes. It is available in two doses, 0.75 and 1.5 mg, given by injection once weekly. This systematic review reports the effectiveness and safety of dulaglutide in type 2 diabetes in dual and triple therapy.Methods: MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, and conference abstracts were searched from 2005 to August 2014, and updated in January 2015. Company websites and references of included studies were checked for potentially relevant studies. European Medicines Agency and US Food and Drug Administration websites were searched.Results: Four trials were included. All were manufacturer-funded randomized controlled trials from the Assessment of Weekly Administration of Dulaglutide in Diabetes (AWARD program. AWARD-1 compared dulaglutide 1.5 mg against exenatide 10 µg twice daily and placebo, AWARD-2 compared dulaglutide 0.75 and 1.5 mg against insulin glargine, AWARD-5 compared dulaglutide 0.75 and 1.5 mg against sitagliptin 100 mg and placebo, and AWARD-6 compared dulaglutide 1.5 mg against liraglutide 1.8 mg. The duration of follow-up in the trials ranged from 26 to 104 weeks. The primary outcome of all the included trials was change in HbA1c. At 26 weeks, greater HbA1c reductions were seen with dulaglutide than with twice daily exenatide (dulaglutide 1.5/0.75 mg: −1.5%/−1.3%; exe: 0.99% and sitagliptin (1.5/0.75 mg −1.22%/−1.01%; sitagliptin: −0.6%. HbA1c change was greater with dulaglutide 1.5 mg (−1.08% than with glargine (−0.63%, but not with dulaglutide 0.75 mg (−0.76%. Dulaglutide 1.5 mg was found to be noninferior to liraglutide 1.8 mg. More patients treated with dulaglutide achieved HbA1c

  8. Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells.

    Leech, Colin A; Dzhura, Igor; Chepurny, Oleg G; Kang, Guoxin; Schwede, Frank; Genieser, Hans-G; Holz, George G

    2011-11-01

    Insulin secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the β cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM). An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV (DPP-IV) inhibitors (e.g., Januvia, Galvus). These compounds slow metabolic degradation of intestinally released GLP-1, thereby raising post-prandial levels of circulating GLP-1 substantially. Investigational compounds that stimulate GLP-1 secretion also exist, and in this regard a noteworthy advance is the demonstration that small molecule GPR119 agonists (e.g., AR231453) stimulate L cell GLP-1 secretion while also directly stimulating β cell insulin release. In this review, we summarize what is currently known concerning the signal transduction properties of the β cell GLP-1R as they relate to insulin secretion. Emphasized are the cyclic AMP, protein kinase A, and Epac2-mediated actions of GLP-1 to regulate ATP-sensitive K⁺ channels, voltage-dependent K⁺ channels, TRPM2 cation channels, intracellular Ca⁺ release channels, and Ca⁺-dependent exocytosis. We also discuss new evidence that provides a conceptual framework with which to understand why GLP-1R agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM. PMID:21782840

  9. Glucagon-like peptide-1 activates endothelial nitric oxide synthase in human umbilical vein endothelial cells

    Li DING; Jin ZHANG

    2012-01-01

    To investigate the effects of glucagon-like peptide-1 (GLP-1) on endothelial NO synthase (eNOS) in human umbilical vein endothelial cells (HUVECs),and elucidate whether GLP-1 receptor (GLP-1R) and GLP-1(9-36) are involved in these effects.Methods:HUVECs were used.The activity of eNOS was measured with NOS assay kit.Phosphorylated and total eNOS proteins were detected using Western blot analysis.The level of eNOS mRNA was quantified with real-time RT-PCR.Results:Incubation of HUVECs with GLP-1 (50-5000 pmol/L) for 30 min significantly increased the activity of eNOS.Incubation of HUVECs with GLP-1 (500-5000 pmol/L) for 5 or 10 min increased eNOS phosphorylated at ser-1177.Incubation with GLP-1 (5000 pmol/L) for 48 h elevated the level of eNOS protein,did not affect the level of eNOS mRNA.GLP-1R agonists exenatide and GLP-1(9-36) at the concentration of 5000 pmol/L increased the activity,phosphorylation and protein level of eNOS.GLP-1R antagonist exendin(9-39) or DPP-4 inhibitor sitagliptin,which abolished GLP-1(9-36) formation,at the concentration of 5000 pmol/L partially blocked the effects of GLP-1 on eNOS.Conclusion:GLP-1 upregulated the activity and protein expression of eNOS in HUVECs through the GLP-1R-dependent and GLP-1(9-36)-related pathways.GLP-1 may prevent or delay the formation of atherosclerosis in diabetes mellitus by improving the function of eNOS.

  10. Glucagon-like-peptide-1 secretion from canine L-cells is increased by glucose-dependent-insulinotropic peptide but unaffected by glucose

    Damholt, A B; Buchan, A M; Kofod, Hans

    1998-01-01

    Glucagon-like peptide-1(7-36)amide (GLP-1) is a potent insulinotropic peptide released from the small intestine. To investigate the regulation of GLP-1 secretion, we established a GLP-1 release assay based on primary canine intestinal L-cells. The ileal mucosa was digested with collagenase/EDTA t...

  11. Cholecystokinin, glucose dependent insulinotropic peptide and glucagon-like peptide 1 secretion in children with anorexia nervosa and simple obesity.

    Tomasik, Przemyslaw J; Sztefko, Krystyna; Starzyk, Jerzy

    2004-12-01

    Cholecystokinin (CCK), glucose dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1) regulate satiety as enterogastrons and incretins. They also directly affect the satiety centers. Therefore, these peptides may participate in the pathogenesis of eating disorders. CCK, GIP, and GLP-1 secretion were studied in 13 adolescent girls suffering from simple obesity, 13 girls with anorexia nervosa, and 10 healthy girls. Each girl was subjected to an oral glucose tolerance test (OGTT) and standard meal test. Blood was collected before stimulation and at 15, 30, 60, and 120 min. The concentrations of all peptides were determined by RIA commercial kits. Fasting and postprandial levels of these peptides as well as integrated outputs were measured. High postprandial levels of CCK observed in the girls with anorexia may aggravate the course of this disease by intensifying nausea and vomiting. Low postprandial level of GLP-1 in girls with simple obesity may be responsible for excessive ingestion of food and weaker inhibition of gastric emptying, which also leads to obesity. PMID:15645696

  12. Glucagon like peptide-2 induces intestinal restitution through VEGF release from subepithelial myofibroblasts.

    Bulut, Kerem; Pennartz, Christian; Felderbauer, Peter; Meier, Juris J; Banasch, Matthias; Bulut, Daniel; Schmitz, Frank; Schmidt, Wolfgang E; Hoffmann, Peter

    2008-01-14

    Glucagon like peptide-2 (GLP-2) exerts intestinotrophic actions, but the underlying mechanisms are still a matter of debate. Recent studies demonstrated the expression of the GLP-2 receptor on fibroblasts located in the subepithelial tissue, where it might induce the release of growth factors such as keratinocyte growth factor (KGF) or vascular endothelial growth factor (VEGF). Therefore, in the present studies we sought to elucidate the downstream mechanisms involved in improved intestinal adaptation by GLP-2. Human colonic fibroblasts (CCD-18Co), human colonic cancer cells (Caco-2 cells) and rat ileum IEC-18 cells were used. GLP-2 receptor mRNA expression was determined using real time RT-PCR. Conditioned media from CCD-18Co cells were obtained following incubation with GLP-2 (50-250 nM) for 24 h. Cell viability was assessed by a 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT)-assay, and wound healing was determined with an established migration-assay. Transforming Growth Factor beta (TGF-beta), VEGF and KGF mRNA levels were determined by RT-PCR. Protein levels of VEGF and TGF-beta in CCD-18Co cells following GLP-2 stimulation were determined using ELISA. Neutralizing TGF-beta and VEGF-A antibodies were utilized to assess the role of TGF-beta and VEGF-A in the process of wound healing. GLP-2 receptor expression was detected in CCD-18Co cells. Conditioned media from CCD-18Co cells dose-dependently induced proliferation in Caco-2 cells, but not in IEC-18 cells. Conditioned media also enhanced cell migration in IEC-18 cells (PCCD-18Co. The migratory effects of GLP-2 were completely abolished in the presence of TGF-beta and VEGF-A antibodies. GLP-2 exerts differential effects on the epithelium of the small intestine and the colon. Thus, in small intestinal cells GLP-2 stimulates wound repair, whereas no such effects were observed in colonic cells. The mechanisms underlying GLP-2 induced intestinal wound repair seem to involve the secretion of

  13. The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion.

    Wang, Fei; Yang, Qing; Huesman, Sarah; Xu, Min; Li, Xiaoming; Lou, Danwen; Woods, Stephen C; Marziano, Corina; Tso, Patrick

    2015-10-15

    Both glucagon-like peptide-1 (GLP-1) and apolipoprotein A-IV (apoA-IV) are produced from the gut and enhance postprandial insulin secretion. This study investigated whether apoA-IV regulates nutrient-induced GLP-1 secretion and whether apoA-IV knockout causes compensatory GLP-1 release. Using lymph-fistula-mice, we first determined lymphatic GLP-1 secretion by administering apoA-IV before an intraduodenal Ensure infusion. apoA-IV changed neither basal nor Ensure-induced GLP-1 secretion relative to saline administration. We then assessed GLP-1 in apoA-IV-/- and wild-type (WT) mice administered intraduodenal Ensure. apoA-IV-/- mice had comparable lymph flow, lymphatic triglyceride, glucose, and protein outputs as WT mice. Intriguingly, apoA-IV-/- mice had higher lymphatic GLP-1 concentration and output than WT mice 30 min after Ensure administration. Increased GLP-1 was also observed in plasma of apoA-IV-/- mice at 30 min. apoA-IV-/- mice had comparable total gut GLP-1 content relative to WT mice under fasting, but a lower GLP-1 content 30 min after Ensure administration, suggesting that more GLP-1 was secreted. Moreover, an injection of apoA-IV protein did not reverse the increased GLP-1 secretion in apoA-IV-/- mice. Finally, we assessed gene expression of GLUT-2 and the lipid receptors, including G protein-coupled receptor (GPR) 40, GPR119, and GPR120 in intestinal segments. GLUT-2, GPR40 and GPR120 mRNAs were unaltered by apoA-IV knockout. However, ileal GPR119 mRNA was significantly increased in apoA-IV-/- mice. GPR119 colocalizes with GLP-1 in ileum and stimulates GLP-1 secretion by sensing OEA, lysophosphatidylcholine, and 2-monoacylglycerols. We suggest that increased ileal GPR119 is a potential mechanism by which GLP-1 secretion is enhanced in apoA-IV-/- mice. PMID:26294669

  14. Retinal Pigment Epithelial Cells Express a Functional Receptor for Glucagon-Like Peptide-1 (GLP-1

    Alessandra Puddu

    2013-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a gut-derived incretin hormone that has been shown to improve glucose homeostasis in type 2 diabetes. The biological effects of GLP-1 are mediated by its specific receptor GLP-1R that is expressed in a wide range of tissues, where it is responsible of the extra-pancreatic effects of GLP-1. Since the retinal pigment epithelium (RPE, that forms the outer retinal barrier, has a key role in protecting from diabetic retinopathy (DR, we investigated the potential expression and function of GLP-1R in a RPE cell line. ARPE-19 cells were cultured in DMEM/F12 supplemented with 10% FBS. The expression of GLP-1R was evaluated at both mRNA and protein levels. Then, the activation postreceptor intracellular signal transduction pathways (extracellular signal-regulated kinases 1 and 2 [ERK1/2] and protein kinase B [PKB] were assessed by western blot in normal cells or silenced for GLP-1R in the presence or absence of 10 nmol/L GLP-1. The potential connections between intracellular signalling pathways triggered by GLP-1 stimulation were performed before incubating cells with kinase pharmacological inhibitors of mitogen-activated protein kinase (MEK1/2, phosphatydilinositol-3kinase (PI3K, or epidermal growth factor receptor (EGFR. The results showed that GLP1R is expressed at both mRNA and protein level in ARPE-19 cells. Stimulation with GLP-1 strongly activated PKB and ERK1/2 phosphorylation till 40 min of exposure. GLP-1-mediated activation of both kinases was dependent on the upstream activation of PI3K and EGFR. Finally, treatment with GLP-1 did not affect the spontaneous release of VEGF-A from ARPE-19 cells. In conclusion, this paper showed that the presence of functional GLP-1R is expressed in RPE cells. These data might represent the rationale to further investigate the potential direct beneficial effects of GLP-1 treatment against DR.

  15. Glucagon-Like Peptide-1 Receptor Agonist Treatment Patterns Among Type 2 Diabetes Patients in Six European Countries

    Divino, Victoria; DeKoven, Mitch; Hallinan, Shawn; Varol, Nebibe; Wirta, Sara Bruce; Lee, Won Chan; Reaney, Matthew

    2014-01-01

    Introduction The objective of this study was to evaluate real-world treatment patterns of type 2 diabetes (T2D) patients initiating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in Germany (GE), the United Kingdom (UK), France (FR), the Netherlands (NE), Belgium (BE), and Sweden (SE). Methods Adult T2D patients initiating exenatide twice daily (exBID), liraglutide once daily (LIRA) or exenatide once weekly (exQW) were identified using the IMS LifeLink™ (IMS Health, Danbury, CT, USA): ...

  16. Minireview: Finding the Sweet Spot: Peripheral Versus Central Glucagon-Like Peptide 1 Action in Feeding and Glucose Homeostasis

    Williams, Diana L.

    2009-01-01

    Glucagon-like peptide 1 (GLP-1) is both a gut-derived hormone and a neurotransmitter synthesized in the brain. Early reports suggested that GLP-1 acts in the periphery to promote insulin secretion and affect glucose homeostasis, whereas central GLP-1 reduces food intake and body weight. However, current research indicates that in fact, GLP-1 in each location plays a role in these functions. This review summarizes the evidence for involvement of peripheral and brain GLP-1 in food intake regula...

  17. Glucagon-like peptide-2 (GLP-2) increases small intestinal blood flow and mucosal growth in ruminating calves

    Taylor-Edwards, C C; Burrin, D G; Holst, Jens Juul; McLeod, K R; Harmon, D L

    2011-01-01

    Glucagon-like peptide-2 (GLP-2) increases small intestinal mass and blood flow in nonruminants but its effect in ruminants is unknown. Eight Holstein calves with an ultrasonic flow probe around the superior mesenteric artery and catheters in the carotid artery and mesenteric vein were paired by age......, GLP-2 increased villus height, crypt depth, and BrdU-labeling in small intestinal segments. These results demonstrate that GLP-2 induces similar increases in small intestinal blood flow and growth in ruminants to those observed in nonruminants. Furthermore, GLP-2 increases small intestinal blood flow...

  18. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice

    Sorensen, Gunnar; Reddy, India A.; Weikop, Pia;

    2015-01-01

    Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral...... tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food...

  19. Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans

    Orskov, C; Rabenhøj, L; Wettergren, A; Kofod, Hans; Holst, J J

    1994-01-01

    Using specific radioimmunoassays, we studied the occurrence of amidated and glycine-extended glucagon-like peptide I (GLP-I) molecules in the human small intestine and pancreas and in the circulation system in response to a breakfast meal. Through gel permeation chromatography of extracts of the...... plasma were 7 +/- 1 and 6 +/- 1 pM, respectively (n = 6). In response to a breakfast meal, the concentration of amidated GLP-I rose significantly amounting to 41 +/- 5 pM 90 min after the meal ingestion, whereas the concentration of glycine-extended GLP-I only rose slightly to a maximum of 10 +/- 1 p...

  20. Glucagon-like peptide 1 receptor playsa critical role in geniposide-regulated insulin secretion in INS-1 cells

    Li-xia GUO; Zhi-ning XIA; Xue GAO; Fei YIN; Jian-hui LIU

    2012-01-01

    Aim:To explore the role of the glucagon-like peptide 1 receptor (GLP-1R) in geniposide regulated insulin secretion in rat INS-1 insulinoma cells.Methods:Rat INS-1 insulinoma cells were cultured.The content of insulin in the culture medium was measured with ELISA assay.GLP-1R gene in INS-1 cells was knocked down with shRNA interference.The level of GLP-1R protein in INS-1 cells was measured with Western blotting.Results:Geniposide (0.01-100 μmol/L) increased insulin secretion from INS-1 cells in a concentration-dependent manner.Geniposide (10 μmol/L) enhanced acute insulin secretion in response to both the low (5.5 mmol/L) and moderately high levels (11 mmol/L) of glucose.Blockade of GLP-1R with the GLP-1R antagonist exendin (9-39) (200 nmol/L) or knock-down of GLP-1R with shRNA interference in INS-1 cells decreased the effect of geniposide (10 μmol/L) on insulin secretion stimulated by glucose (5.5 mmol/L).Conclusion:Geniposide increases insulin secretion through glucagon-like peptide 1 receptors in rat INS-1 insulinoma cells.

  1. Exogenous glucagon-like peptide-2 (GLP-2) prevents chemotherapy-induced mucositis in rat small intestine

    Kissow, Hannelouise; Viby, Niels-Erik; Hartmann, Bolette;

    2012-01-01

    PURPOSE: Gastrointestinal mucositis is an unwanted and often dose-limiting side effect to most cancer treatments. Glucagon-like peptide-2 (GLP-2) is a peptide secreted from intestinal L-cells in response to nutrient intake. The peptide is involved in the regulation of apoptosis and proliferation in...... the intestine. We aimed to investigate the role of GLP-2 in experimental chemotherapy-induced mucositis. METHODS STUDY 1: Rats were given a single injection with 5-fluorouracil (5-FU) and killed in groups of five each day for 5 days. Blood samples were analysed for GLP-2 concentrations. The intestine...... was analysed for weight loss, morphometric estimates and proliferation. Study 2 Rats were treated with GLP-2 or control vehicle 2 days before a single injection of 5-FU or saline. The treatments continued until kill 2 days after. The intestine was investigated for influx of myeloperoxidase (MPO...

  2. Glucagon-like peptide-1 receptor ligand interactions: structural cross talk between ligands and the extracellular domain.

    Graham M West

    Full Text Available Activation of the glucagon-like peptide-1 receptor (GLP-1R in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM. Like other class B G protein-coupled receptors (GPCRs, the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R. In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands.

  3. Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes

    Meier, Juris J; Weyhe, Dirk; Michaely, Mark;

    2004-01-01

    GLP-1 (1.2 pmol x kg x min) and placebo over 8 hrs, each administered in randomized order in the fasting state. C-reactive protein concentrations of 4.9+/-4.2 mg/dL indicated a systemic inflammation. Blood was drawn in 30-min intervals for glucose (glucose oxidase), insulin, C-peptide, glucagon, and......OBJECTIVE: Hyperglycemia is a major risk factor for a poor outcome after major surgery in patients with type 2 diabetes. Intensive insulin treatment aiming at normoglycemia can markedly improve the survival of critically ill patients, but the broad clinical application is limited by its...... practicability and the risk of hypoglycemia. Therefore, the glucose-lowering effect of the incretin hormone glucagon-like peptide 1 (GLP-1) was investigated in patients with type 2 diabetes after major surgery. DESIGN: Randomised clinical study. SETTING: A surgical unit of a university hospital. PATIENTS AND...

  4. CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice

    Parlevliet, E.T.; Schröder-van der Elst, J.P.; Corssmit, E.P.M.; Picha, K.; O'Neil, K.; Stojanovic-Susulic, V.; Ort, T.; Havekes, L.M.; Romijn, J.A.; Pijl, H.

    2009-01-01

    CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimeti-body platform. We evaluate the potential of acute and chronic CNTO736 treatment on insulin sensitivity and very low-density lipoprotein (VLDL) metabolism. For acute studies, diet

  5. Glucagon-like peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients

    Høyerup, P; Hellström, P M; Schmidt, P T;

    2013-01-01

    In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunost......In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end...

  6. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

    Jensen, Michael Gejl; Lerche, Susanne; Egefjord, Lærke; Brock, Birgitte; Møller, Niels; Vang, Kim; Rodell, Anders B; Bibby, Bo M; Holst, Jens Juul; Rungby, Jørgen; Gjedde, Albert

    2013-01-01

    phosphorylation velocity (V max) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (T max) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain......In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion...... potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute...

  7. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients

    Toft-Nielsen, M B; Madsbad, Sten; Holst, J J

    1999-01-01

    energy intake and on plasma glucose, insulin, glucagon, postprandial lipidemia, blood pressure, heart rate, and basal metabolic rate. RESULTS: The infusion resulted in elevations of the plasma concentrations of intact GLP-1 similar to those observed after intravenous infusion of 1.2 pmol.kg-1.min-1...... fullness was unaffected. No side effects during GLP-1 infusion were recorded except for a brief cutaneous reaction. Basal metabolic rate and heart rate did not change significantly during GLP-1 administration. Both systolic and diastolic blood pressure tended to be lower during the GLP-1 infusion......OBJECTIVE: The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore...

  8. Encapsulated glucagon-like peptide-1-producing mesenchymal stem cells have a beneficial effect on failing pig hearts

    Wright, Elizabeth J; Farrell, Kelly A; Malik, Nadim;

    2012-01-01

    function and reduced epicardial infarct size. This was associated with increased angiogenesis and an altered remodeling response. Combined benefits of paracrine stem cell factors and GLP-1 were superior to those of stem cells alone. These results suggest that encapsulated genetically modified MSCs would......Stem cell therapy is an exciting and emerging treatment option to promote post-myocardial infarction (post-MI) healing; however, cell retention and efficacy in the heart remain problematic. Glucagon-like peptide-1 (GLP-1) is an incretin hormone with cardioprotective properties but a short half......-life in vivo. The effects of prolonged GLP-1 delivery from stromal cells post-MI were evaluated in a porcine model. Human mesenchymal stem cells immortalized and engineered to produce a GLP-1 fusion protein were encapsulated in alginate (bead-GLP-1 MSC) and delivered to coronary artery branches. Control groups...

  9. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects

    Vilsbøll, Tina; Agersø, H; Krarup, T; Holst, Jens Møller

    2003-01-01

    We have previously shown that type 2 diabetic patients have decreased plasma concentrations of glucagon-like peptide 1 (GLP-1) compared with healthy subjects after ingestion of a standard mixed meal. This decrease could be caused by differences in the metabolism of GLP-1. The objective of this...... subjects. The volume of distribution ranged from 9-26 liters per subject. No significant differences were found between healthy subjects and type 2 diabetic subjects. We conclude that elimination of GLP-1 is the same in obese type 2 diabetic patients and matched healthy subjects. The impaired incretin...... response seen after ingestion of a standard breakfast meal must therefore be caused by a decreased secretion of GLP-1 in type 2 diabetic patients....

  10. Intestinal growth adaptation and glucagon-like peptide 2 in rats with ileal--jejunal transposition or small bowel resection

    Thulesen, J; Hartmann, B; Kissow, Hannelouise; Jeppesen, P B; Orskov, C; Holst, J J; Poulsen, S S

    2001-01-01

    twofold in the distally resected group. Tissue GLP-2 levels were unchanged in resected rats. The data indicate that transposition of a distal part of the small intestine, and thereby exposure of L cells to a more nutrient-rich chyme, leads to intestinal growth. The adaptive intestinal growth is associated......Glucagon-like peptide 2 (GLP-2), produced by enteroendocrine L-cells, regulates intestinal growth. This study investigates circulating and intestinal GLP-2 levels in conditions with altered L-cell exposure to nutrients. Rats were allocated to the following experimental groups: ileal......-jejunal transposition, resection of the proximal or distal half of the small intestine, and appropriate sham-operated controls. After two weeks, ileal-jejunal transposition led to pronounced growth of the transposed segment and also of the remaining intestinal segments. Plasma GLP-2 levels increased twofold, whereas...

  11. Involvement of endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion

    Witte, Anne-Barbara; Grybäck, Per; Jacobsson, Hans;

    2011-01-01

    Objective. To study the role of endogenous glucagon-like peptide-1 (GLP-1) on gastric emptying rates of a solid meal as well as postprandial hormone secretion and glucose disposal. Material and methods. In nine healthy subjects, gastric emptying of a 310-kcal radio-labelled solid meal and plasma...... was 15.1 ± 0.7 pmol·L-1 compared to 5.4 ± 1.4 during saline) and after the meal, and postprandial GLP-1 levels increased. Basal insulin and glucose levels were not affected by Ex(9-39), but the postprandial rise of insulin and glucose enhanced during Ex(9-39). Conclusions. Endogenous GLP-1 is involved...

  12. Endogenous Glucagon-like peptide-1 suppresses high-fat food intake by reducing synaptic drive onto mesolimbic dopamine neurons

    Wang, Xue-Feng; Liu, Jing-Jing; Xia, Julia; Liu, Ji; Mirabella, Vincent; Pang, Zhiping P.

    2016-01-01

    SUMMARY Glucagon-like peptide-1 (GLP-1) and its analogs act as appetite suppressants and have been proven to be clinically efficacious in reducing body weight in obese individuals. Central GLP-1 is expressed in a small population of brainstem cells located in the nucleus tractus solitarius (NTS), which project to a wide range of brain areas. However, it remains unclear how endogenous GLP-1 released in the brain contributes to appetite regulation. By using chemogenetic tools, we discovered that central GLP-1 acts on the midbrain ventral tegmental area (VTA) and suppresses high-fat food intake. We used integrated pathway tracing and synaptic physiology to further demonstrate that activation of GLP-1 receptors specifically reduces the excitatory synaptic strength of dopamine (DA) neurons within the VTA that project to the nucleus accumbens (NAc) medial shell. These data suggest that GLP-1 released from NTS neurons can reduce highly palatable food intake by suppressing mesolimbic DA signaling. PMID:26212334

  13. Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R).

    Yang, Dehua; de Graaf, Chris; Yang, Linlin; Song, Gaojie; Dai, Antao; Cai, Xiaoqing; Feng, Yang; Reedtz-Runge, Steffen; Hanson, Michael A; Yang, Huaiyu; Jiang, Hualiang; Stevens, Raymond C; Wang, Ming-Wei

    2016-06-17

    The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members of the class B family are distinguished by their large extracellular domain, which works cooperatively with the canonical seven-transmembrane (7TM) helical domain to signal in response to binding of various peptide hormones. We have combined structure-based site-specific mutational studies with molecular dynamics simulations of a full-length model of GLP-1R bound to multiple peptide ligand variants. Despite the high sequence similarity between GLP-1R and its closest structural homologue, the glucagon receptor (GCGR), nearly half of the 62 stably expressed mutants affected GLP-1R in a different manner than the corresponding mutants in GCGR. The molecular dynamics simulations of wild-type and mutant GLP-1R·ligand complexes provided molecular insights into GLP-1R-specific recognition mechanisms for the N terminus of GLP-1 by residues in the 7TM pocket and explained how glucagon-mimicking GLP-1 mutants restored binding affinity for (GCGR-mimicking) GLP-1R mutants. Structural analysis of the simulations suggested that peptide ligand binding mode variations in the 7TM binding pocket are facilitated by movement of the extracellular domain relative to the 7TM bundle. These differences in binding modes may account for the pharmacological differences between GLP-1 peptide variants. PMID:27059958

  14. Simultaneous quantification of intracellular and secreted active and inactive glucagon-like peptide-1 from cultured cells.

    Amao, Michiko; Kitahara, Yoshiro; Tokunaga, Ayaka; Shimbo, Kazutaka; Eto, Yuzuru; Yamada, Naoyuki

    2015-03-01

    Glucagon-like peptide-1 (GLP-1) is an incretin peptide that regulates islet hormone secretion. During recent years, incretin-based therapies have been widely used for patients with type 2 diabetes. GLP-1 peptides undergo N- and C-terminal processing for gain or loss of functions. We developed a method to quantify picomolar quantities of intact GLP-1 peptides using liquid chromatography-tandem mass spectrometry (LC-MS/MS). By employing this label-free selected reaction monitoring (SRM) method, we were able to analyze secreted GLP-1(1-37), GLP-1(7-37), and GLP-1(7-36 amid from human enteroendocrine NCI-H716 cells after stimulation with nateglinide, glucose, and sucralose. The absolute total concentrations of secreted GLP-1 peptides at baseline and after stimulation with nateglinide, glucose, and sucralose were 167.3, 498.9, 238.3, and 143.1 pM, respectively. Meanwhile, the ratios of GLP-1(1-37), GLP-1(7-37), and GLP-1(7-36 amide) to total GLP-1 peptides were similar (6 ± 3, 26 ± 3, and 78 ± 5%, respectively). The SRM assay can analyze the concentrations of individual GLP-1 peptides and, therefore, is a tool to investigate the physiological roles of GLP-1 peptides. Furthermore, the molecular species secreted from NCI-H716 cells were unknown. Therefore, we performed a secretopeptidome analysis of supernatants collected from cultured NCI-H716 cells. Together with GLP-1 peptides, we detected neuroendocrine convertase 1, which regulates peptide hormones released from intestinal endocrine L-cells. PMID:25461479

  15. Synergistic effect of supplemental enteral nutrients and exogenous glucagon-like peptide 2 on intestinal adaptation in a rat model of short bowel syndrome

    Liu, Xiaowen; Nelson, David W; Holst, Jens Juul;

    2006-01-01

    BACKGROUND: Short bowel syndrome (SBS) can lead to intestinal failure and require total or supplemental parenteral nutrition (TPN or PN, respectively). Glucagon-like peptide 2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that stimulates intestinal adaptation. OBJECTIVE: Our ob...

  16. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients

    Jeppesen, P B; Sanguinetti, E L; Buchman, A; Howard, L.; Scolapio, J S; Ziegler, T R; Gregory, J; Tappenden, K A; Holst, J.; Mortensen, P B

    2005-01-01

    Background and aims: Glucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity.

  17. Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes

    Thomsen, Claus; Storm, Hanne; Holst, Jens Juul;

    2003-01-01

    metabolism and the responses of the duodenal incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide after meals rich in saturated and monounsaturated fatty acids (oleic acid), respectively. OBJECTIVE: The objective was to compare the postprandial responses (8 h) of glucose...

  18. Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy

    Andersen, O; Haugaard, S B; Holst, Jens Juul;

    2005-01-01

    OBJECTIVES: We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV...

  19. Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans

    Meier, Juris J; Holst, Jens Juul; Schmidt, Wolfgang E; Nauck, Michael A

    2007-01-01

    Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP)-1. Given the recent availability of drugs based on incretin hormones, such clearance...

  20. Glucagon-like peptide-1 secretion is influenced by perfusate glucose concentration and by a feedback mechanism involving somatostatin in isolated perfused porcine ileum

    Hansen, Lene; Hartmann, Bolette; Mineo, Hitoshi; Holst, Jens Juul

    Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to ingestion of meals. The mechanisms regulating its secretion are not clear, but local somatostatin (SS) restrains GLP-1 secretion. We investigated feedback and substrate regulation of GLP-1 and SS secretion, using...

  1. Acute effects of the Glucagon-Like Peptide 2 analogue, teduglutide, on intestinal adaptation in newborn pigs with short bowel syndrome

    Thymann, Thomas; Stoll, Barbara; Mecklenburg, Lars;

    2014-01-01

    Neonatal short bowel syndrome following massive gut resection associates with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult short bowel patients, but its effect in pediatric patients remains unknown. Our objective was to test...

  2. The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis.

    Jessica E Potts

    Full Text Available To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus.Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo in adults with type 2 diabetes and a mean body mass index ≥ 25 kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator.In the mixed treatment comparison (27 trials, the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2 mg/week: -1.62 kg (95% CrI: -2.95 kg, -0.30 kg, exenatide 20 μg: -1.37 kg (95% CI: -222 kg, -0.52 kg, liraglutide 1.2 mg: -1.01 kg (95%CrI: -2.41 kg, 0.38 kg and liraglutide 1.8 mg: -1.51 kg (95% CI: -2.67 kg, -0.37 kg compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.

  3. The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis

    Potts, Jessica E.; Gray, Laura J.; Brady, Emer M.; Khunti, Kamlesh; Davies, Melanie J.; Bodicoat, Danielle H.

    2015-01-01

    Aims To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus. Methods Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo) in adults with type 2 diabetes and a mean body mass index ≥ 25kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator. Results In the mixed treatment comparison (27 trials), the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2mg/week: -1.62kg (95% CrI: -2.95kg, -0.30kg), exenatide 20μg: -1.37kg (95% CI: -222kg, -0.52kg), liraglutide 1.2mg: -1.01kg (95%CrI: -2.41kg, 0.38kg) and liraglutide 1.8mg: -1.51 kg (95% CI: -2.67kg, -0.37kg) compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss. Conclusions This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed. PMID:26121478

  4. Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations

    Ellrichmann, Mark; Kapelle, Mario; Ritter, Peter R;

    2008-01-01

    .0001), whereas appetite and prospective food consumption increased (P alters gastric and gallbladder emptying and reduces...... of Orlistat or placebo. Gastric emptying, gallbladder volume and the plasma levels of CCK, PYY, GLP-1, and ghrelin were determined and appetite sensations were measured using visual analogue scales. RESULTS: Gastric emptying was accelerated by Orlistat administration (P emptying...... whether Orlistat alters the secretion of glucagon-like peptide-1-(7-36)-amide (GLP-1), cholecystokinin (CCK), peptide YY (PYY), and ghrelin as well as postprandial appetite sensations. METHODS: Twenty-five healthy human volunteers were examined with a solid-liquid test meal after the oral administration...

  5. The insulinotropic effect of exogenous glucagon-like peptide-1 is not affected by acute vagotomy in anaesthetized pigs.

    Veedfald, Simon; Hansen, Marie; Christensen, Louise Wulff; Larsen, Sara Agnete Hjort; Hjøllund, Karina Rahr; Plamboeck, Astrid; Hartmann, Bolette; Deacon, Carolyn Fiona; Holst, Jens Juul

    2016-07-01

    What is the central question of this study? We investigated whether intestinal vagal afferents are necessary for the insulinotropic effect of glucagon-like peptide-1 (GLP-1) infused into a mesenteric artery or a peripheral vein before and after acute truncal vagotomy. What is the main finding and its importance? We found no effect of truncal vagotomy on the insulinotropic effect of exogenous GLP-1 and speculate that high circulating concentrations of GLP-1 after i.v. and i.a. infusion might have overshadowed any neural signalling component. We propose that further investigations into the possible vagal afferent signalling of GLP-1 would best be pursued using enteral stimuli to provide high subepithelial levels of endogenous GLP-1. Glucagon-like peptide 1 (GLP-1) is secreted from the gut in response to luminal stimuli and stimulates insulin secretion in a glucose-dependent manner. As a result of rapid enzymatic degradation of GLP-1 by dipeptidyl peptidase-4, a signalling pathway involving activation of intestinal vagal afferents has been proposed. We conducted two series of experiments in α-chloralose-anaesthetized pigs. In protocol I, pigs (n = 14) were allocated for either i.v. or i.a. (mesenteric) GLP-1 infusions (1 and 2 pmol kg(-1)  min(-1) , 30 min) while maintaining permissive glucose concentrations at 6 mmol l(-1) by i.v. glucose infusion. The GLP-1 infusions were repeated after acute truncal vagotomy. In protocol II, pigs (n = 27) were allocated into six groups. Glucagon-like peptide 1 was infused i.v. or i.a. (mesenteric) for 1 h at 3 or 30 pmol kg(-1)  min(-1) . During the steady state (21 min into the GLP-1 infusion), glucose (0.2 g kg(-1) , i.v.) was administered over 9 min to stimulate β-cell secretion. Thirty minutes after the glucose infusion, GLP-1 infusions were discontinued. Following a washout period, the vagal trunks were severed in four of six groups (vagal trunks were left intact in two of six groups), whereupon all

  6. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients

    Toft-Nielsen, M B; Madsbad, Sten; Holst, J J

    1999-01-01

    OBJECTIVE: The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore......, previously shown to lower blood glucose effectively in type 2 diabetic patients. Fasting plasma glucose (day 2) decreased from 14.1 +/- 0.9 (saline) to 12.2 +/- 0.7 mmol/l (GLP-1), P = 0.009, and 24-h mean plasma glucose decreased from 15.4 +/- 1.0 to 13.0 +/- 1.0 mmol/l, P = 0.0009. Fasting and total area...... under the curve for insulin and C-peptide levels were significantly higher during the GLP-1 administration, whereas glucagon levels were unchanged. Neither triglycerides nor free fatty acids were affected. GLP-1 administration decreased hunger and prospective food intake and increased satiety, whereas...

  7. [Liraglutide (Victoza): human glucagon-like peptide-1 used in once daily injection for the treatment of type 2 diabetes].

    Scheen, A J; Van Gaal, L F

    2010-01-01

    Liraglutide (Victoza) is a peptide produced by DNA recombinant technology, which presents 97% homology with human glucagon-like peptide-1 (GLP-1) but is resistant to dipeptidylpeptidase-4, the enzyme that degrades the natural hormone. It actives the GLP-1 receptor and exerts an incretin mimetic effect during at least 24 hours after a single subcutaneous injection. Besides a glucose-dependent stimulatory effect of insulin secretion, liraglutide inhibits glucagon secretion and retards gastric emptying. In patients with type 2 diabetes, it reduces glycated haemoglobin by at least 1%, without inducing hypoglycaemia. It also induces a moderate weight loss and a mild reduction in blood pressure. Gastrointestinal adverse events (nausea, vomiting) may occur during the initial phase of treatment, but rarely impose the interruption of the medication and usually diminish with time.Although indicated in combination with other glucose-lowering agents, liraglutide is currently reimbursed in Belgium only if administered in patients with type 2 diabetes not sufficiently controlled with a combination of metformin plus sulfonylurea or metformin plus a thiazolidinedione. Victoza is presented in prefilled pens and is injected subcutaneously once a day. Treatment will be initiated with 0.6 mg to improve digestive tolerance and the daily dose will be increased to 1.2 mg (usual dose) after at least one week, and up to 1.8 mg (maximal dose) if necessary. PMID:20857706

  8. Glutamine reduces postprandial glycemia and augments the glucagon-like peptide-1 response in type 2 diabetes patients

    Samocha-Bonet, Dorit; Wong, Olivia; Synnott, Emma-Leigh;

    2011-01-01

    Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally essential amino acid glutamine stimulates GLP-1 secretion in vitro and in vivo. In a randomized, crossover study, we evaluated the effect of oral...... glutamine, with or without sitagliptin (SIT), on postprandial glycemia and GLP-1 concentration in 15 type 2 diabetes patients (glycated hemoglobin 6.5 ± 0.6%). Participants ingested a low-fat meal (5% fat) after receiving either water (control), 30 g l-glutamine (Gln-30), 15 g L-glutamine (Gln-15), 100 mg...... SIT, or 100 mg SIT and 15 g L-glutamine (SIT+Gln-15). Studies were conducted 1-2 wk apart. Blood was collected at baseline and postprandially for 180 min for measurement of circulating glucose, insulin, C-peptide, glucagon, and total and active GLP-1. Gln-30 and SIT+Gln-15 reduced the early (t = 0...

  9. Glucagon-like peptide-1 receptor is present in pancreatic acinar cells and regulates amylase secretion through cAMP.

    Hou, Yanan; Ernst, Stephen A; Heidenreich, Kaeli; Williams, John A

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is a glucoincretin hormone that can act through its receptor (GLP-1R) on pancreatic β-cells and increase insulin secretion and production. GLP-1R agonists are used clinically to treat type 2 diabetes. GLP-1 may also regulate the exocrine pancreas at multiple levels, including inhibition through the central nervous system, stimulation indirectly through insulin, and stimulation directly on acinar cells. However, it has been unclear whether GLP-1R is present in pancreatic acini and what physiological functions these receptors regulate. In the current study we utilized GLP-1R knockout (KO) mice to study the role of GLP-1R in acinar cells. RNA expression of GLP-1R was detected in acutely isolated pancreatic acini. Acinar cell morphology and expression of digestive enzymes were not affected by loss of GLP-1R. GLP-1 induced amylase secretion in wild-type (WT) acini. In GLP-1R KO mice, this effect was abolished, whereas vasoactive intestinal peptide-induced amylase release in KO acini showed a pattern similar to that in WT acini. GLP-1 stimulated cAMP production and increased protein kinase A-mediated protein phosphorylation in WT acini, and these effects were absent in KO acini. These data show that GLP-1R is present in pancreatic acinar cells and that GLP-1 can regulate secretion through its receptor and cAMP signaling pathway. PMID:26542397

  10. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    Kielgast, Urd; Holst, Jens Juul; Madsbad, Sten

    2009-01-01

    GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces...... appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence for a...... beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes, as...

  11. Effects of prepartum fat supplementation on plasma concentrations of glucagon-like peptide-1, peptide YY, adropin, insulin, and leptin in periparturient dairy cows.

    Zapata, Rizaldy C; Salehi, Reza; Ambrose, Divakar J; Chelikani, Prasanth K

    2015-10-01

    Dietary fat supplementation during the periparturient period is one strategy to increase energy intake and attenuate the degree of negative energy balance during early lactation; however, little is known of the underlying hormonal and metabolic adaptations. We evaluated the effects of prepartum fat supplementation on energy-balance parameters and plasma concentrations of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), adropin, insulin, leptin, glucose, nonesterified fatty acid, and β-hydroxybutyric acid in dairy cows. Twenty-four pregnant dairy cows were randomized to diets containing either rolled canola or sunflower seed at 8% of dry matter, or no oilseed supplementation, during the last 5 wk of gestation and then assigned to a common lactation diet postpartum. Blood samples were collected at -2, +2, and +14 h relative to feeding, at 2 wk after the initiation of the diets, and at 2 wk postpartum. Dietary canola and sunflower supplementation alone did not affect energy balance, body weight, and plasma concentrations of glucagon-like peptide-1, PYY, adropin, insulin, leptin, nonesterified fatty acid, and β-hydroxybutyric acid; however, canola decreased and sunflower tended to decrease dry matter intake. We also observed that the physiological stage had a significant, but divergent, effect on circulating hormones and metabolite concentrations. Plasma glucagon-like peptide-1, PYY, adropin, nonesterified fatty acid, and β-hydroxybutyric acid concentrations were greater postpartum than prepartum, whereas glucose, insulin, leptin, body weight, and energy balance were greater prepartum than postpartum. Furthermore, the interaction of treatment and stage was significant for leptin and adropin, and tended toward significance for PYY and insulin; only insulin exhibited an apparent postprandial increase. Postpartum PYY concentrations exhibited a strong negative correlation with body weight, suggesting that PYY may be associated with body weight regulation during

  12. Glucagon-like peptide-2 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro.

    Baldassano, Sara; Liu, Sumei; Qu, Mei-Hu; Mulè, Flavia; Wood, Jackie D

    2009-10-01

    Glucagon-like peptide-2 (GLP-2) is an important neuroendocrine peptide in intestinal physiology. It influences digestion, absorption, epithelial growth, motility, and blood flow. We studied involvement of GLP-2 in intestinal mucosal secretory behavior. Submucosal-mucosal preparations from guinea pig ileum were mounted in Ussing chambers for measurement of short-circuit current (I(sc)) as a surrogate for chloride secretion. GLP-2 action on neuronal release of acetylcholine was determined with ELISA. Enteric neuronal expression of the GLP-2 receptor (GLP-2R) was studied with immunohistochemical methods. Application of GLP-2 (0.1-100 nM) to the serosal or mucosal side of the preparations evoked no change in baseline I(sc) and did not alter transepithelial ionic conductance. Transmural electrical field stimulation (EFS) evoked characteristic biphasic increases in I(sc), with an initially rapid rising phase followed by a sustained phase. Application of GLP-2 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-2R antagonist GLP-2-(3-33) significantly reversed suppression of the EFS-evoked responses by GLP-2. Tetrodotoxin, scopolamine, and hexamethonium, but not vasoactive intestinal peptide type 1 receptor (VPAC1) antagonist abolished or reduced to near zero the EFS-evoked responses. GLP-2 suppressed EFS-evoked acetylcholine release as measured by ELISA. Pretreatment with GLP-2-(3-33) offset this action of GLP-2. In the submucosal plexus, GLP-2R immunoreactivity (-IR) was expressed in choline acetyltransferase-IR neurons, somatostatin-IR neurons, neuropeptide Y-IR neurons, and vasoactive intestinal peptide-IR neurons. We conclude that submucosal neurons in the guinea pig ileum express GLP-2R. Activation of GLP-2R decreases neuronally evoked epithelial chloride secretion by suppressing acetylcholine release from secretomotor neurons. PMID:19628655

  13. Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals.

    Connor, E E; Evock-Clover, C M; Wall, E H; Baldwin, R L; Santin-Duran, M; Elsasser, T H; Bravo, D M

    2016-07-01

    Numerous endocrine cell subtypes exist within the intestinal mucosa and produce peptides contributing to the regulation of critical physiological processes including appetite, energy metabolism, gut function, and gut health. The mechanisms of action and the extent of the physiological effects of these enteric peptides are only beginning to be uncovered. One peptide in particular, glucagon-like peptide 2 (GLP-2) produced by enteroendocrine L cells, has been fairly well characterized in rodent and swine models in terms of its ability to improve nutrient absorption and healing of the gut after injury. In fact, a long-acting form of GLP-2 recently has been approved for the management and treatment of human conditions like inflammatory bowel disease and short bowel syndrome. However, novel functions of GLP-2 within the gut continue to be demonstrated, including its beneficial effects on intestinal barrier function and reducing intestinal inflammation. As knowledge continues to grow about GLP-2's effects on the gut and its mechanisms of release, the potential to use GLP-2 to improve gut function and health of food animals becomes increasingly more apparent. Thus, the purpose of this review is to summarize: (1) the current understanding of GLP-2's functions and mechanisms of action within the gut; (2) novel applications of GLP-2 (or stimulators of its release) to improve general health and production performance of food animals; and (3) recent findings, using dairy calves as a model, that suggest the therapeutic potential of GLP-2 to reduce the pathogenesis of intestinal protozoan infections. PMID:27345324

  14. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion

    Hagemann, Dirk; Holst, Jens Juul; Gethmann, Arnica;

    2007-01-01

    INTRODUCTION: Ghrelin is an orexigenic peptide predominantly secreted by the stomach. Ghrelin plasma levels rise before meal ingestion and sharply decline afterwards, but the mechanisms controlling ghrelin secretion are largely unknown. Since meal ingestion also elicits the secretion of the...... ghrelin levels 150 and 360 min after meal ingestion (p<0.05). The patterns of ghrelin concentrations in the experiments with GLP-1 and placebo administration were inversely related to the respective plasma levels of insulin and C-peptide. CONCLUSIONS: GLP-1 reduces the rise in ghrelin levels in the late...... meal was served. Venous blood was drawn frequently for the determination of glucose, insulin, C-peptide, GLP-1 and ghrelin. RESULTS: During the infusion of exogenous GLP-1 and placebo, GLP-1 plasma concentrations reached steady-state levels of 139+/-15 pmol/l and 12+/-2 pmol/l, respectively (p<0...

  15. Unprecedented high insulin secretion in a healthy human subject after intravenous glucagon-like peptide-1

    Knop, Filip K; Lund, Asger; Madsbad, Sten; Holst, Jens Juul; Krarup, Thure; Vilsbøll, Tina

    2014-01-01

    to as one of the most insulinotropic substances known. CASE PRESENTATION: Plasma insulin and C-peptide concentrations were measured in a healthy Caucasian male (age: 53 years; body mass index: 28.6 kg/m2; fasting plasma glucose: 5.7 mM; 2 h plasma glucose value following 75 g-oral glucose tolerance...

  16. The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents.

    Vallöf, Daniel; Maccioni, Paola; Colombo, Giancarlo; Mandrapa, Minja; Jörnulf, Julia Winsa; Egecioglu, Emil; Engel, Jörgen A; Jerlhag, Elisabet

    2016-03-01

    The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release, and GLP-1 analogs are therefore approved for treatment of type II diabetes. GLP-1 receptors are expressed in reward-related areas such as the ventral tegmental area and nucleus accumbens, and GLP-1 was recently shown to regulate several alcohol-mediated behaviors as well as amphetamine-induced, cocaine-induced and nicotine-induced reward. The present series of experiments were undertaken to investigate the effect of the GLP-1 receptor agonist, liraglutide, on several alcohol-related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well-documented effects of alcohol on the mesolimbic dopamine system, namely alcohol-induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self-administration of alcohol in selectively bred Sardinian alcohol-preferring rats. Collectively, these data suggest that GLP-1 receptor agonists could be tested for treatment of alcohol dependence in humans. PMID:26303264

  17. Teduglutide, a glucagon-like peptide-2 analog for the treatment of gastrointestinal diseases, including short bowel syndrome.

    Yazbeck, Roger

    2010-12-01

    Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential for the prevention or treatment of an expanding number of gastrointestinal diseases, including short bowel syndrome (SBS). Teduglutide, being developed by NPS Allelix and licensee Nycomed, is a protease-resistant analog of GLP-2 for the potential treatment of gastrointestinal disease. Teduglutide has prolonged biological activity compared with native GLP-2, and preclinical studies demonstrated significant intestinotrophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. Patients with SBS rely on parenteral nutrition (PN) following bowel resection, and in a phase III clinical trial with teduglutide, > 20% reduction in PN was observed in patients with SBS receiving teduglutide. A phase II clinical trial for teduglutide in Crohn's disease observed remission rates of 55.6% in patients. At the time of publication, phase III clinical trials for SBS were ongoing, as were preclinical studies for chemotherapy-induced mucositis and pediatric indications. Teduglutide represents a novel, efficacious drug capable of increasing intestinal growth and improving intestinal function, and may change clinical management of intestinal disease and damage. PMID:21154171

  18. Glucagon-like peptide-1 receptor agonist therapeutics for total diabetes management: assessment of composite end-points.

    Yabe, Daisuke; Kuwata, Hitoshi; Usui, Ryota; Kurose, Takeshi; Seino, Yutaka

    2015-01-01

    Assessment of the benefits of anti-diabetic drugs for type 2 diabetes requires analysis of composite end-points, taking HbA1c, bodyweight, hypoglycemia and other metabolic parameters into consideration; continuous, optimal glycemic control as well as bodyweight, blood pressure and lipid levels are critical to prevent micro- and macro-vascular complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now established as an important total treatment strategy for type 2 diabetes, exerting glucose-lowering effects with little hypoglycemia risk and also ameliorating bodyweight, blood pressure and lipid levels, which are therapeutic targets for prevention of complications of the disease. The available data strongly suggest only beneficial effects of GLP-1RAs; however, long-term evaluation of the relevant composite end-points including health-related quality of life and cost-effectiveness remain to be investigated in adequately powered, prospective, controlled clinical trials. In the meantime, healthcare professionals need to be scrupulously attentive for potential, rare adverse events in patients using GLP-1RAs. PMID:25916903

  19. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

    Simonsen, L; Holst, Jens Juul; Deacon, C F

    2006-01-01

    AIMS/HYPOTHESIS: The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as...... anaesthetised pigs (n=9). RESULTS: Metabolism of GLP-1 (C-terminal RIA; t (1/2) 2.0+/-0.2 min, metabolic clearance rate [MCR] 23.2+/-2.8 ml min(-1) kg(-1); N-terminal RIA; t (1/2) 1.5+/-0.2 min, MCR 88.1+/-10.6 ml min(-1) kg(-1)) was significantly faster than the metabolism of exendin-4 (t (1/2) 22.0+/-2.1 min......, p<0.0001; MCR 1.7+/-0.3 ml min(-1) kg(-1), p<0.01). Differences in arteriovenous concentrations revealed organ extraction of GLP-1 by the kidneys (C-terminal 56.6+/-2.6%; N-terminal 48.3+/-5.9%), liver (N-terminal 41.4+/-3.8%), and peripheral tissues (C-terminal 42.3+/-6.0%; N-terminal 33...

  20. The glucagon-like peptide 1 receptor agonist enhances intrinsic peroxisome proliferator-activated receptor γ activity in endothelial cells

    Onuma, Hirohisa; Inukai, Kouichi, E-mail: kinukai@ks.kyorin-u.ac.jp; Kitahara, Atsuko; Moriya, Rie; Nishida, Susumu; Tanaka, Toshiaki; Katsuta, Hidenori; Takahashi, Kazuto; Sumitani, Yoshikazu; Hosaka, Toshio; Ishida, Hitoshi

    2014-08-22

    Highlights: • PPARγ activation was involved in the GLP-1-mediated anti-inflammatory action. • Exendin-4 enhanced endogenous PPARγ transcriptional activity in HUVECs. • H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement. • The anti-inflammatory effects of GLP-1 may be explained by PPARγ activation. - Abstract: Recent studies have suggested glucagon-like peptide-1 (GLP-1) signaling to exert anti-inflammatory effects on endothelial cells, although the precise underlying mechanism remains to be elucidated. In the present study, we investigated whether PPARγ activation is involved in the GLP-1-mediated anti-inflammatory action on endothelial cells. When we treated HUVEC cells with 0.2 ng/ml exendin-4, a GLP-1 receptor agonist, endogenous PPARγ transcriptional activity was significantly elevated, by approximately 20%, as compared with control cells. The maximum PPARγ activity enhancing effect of exendin-4 was observed 12 h after the initiation of incubation with exendin-4. As H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement, the signaling downstream from GLP-1 cross-talk must have been involved in PPARγ activation. In conclusion, our results suggest that GLP-1 has the potential to induce PPARγ activity, partially explaining the anti-inflammatory effects of GLP-1 on endothelial cells. Cross-talk between GLP-1 signaling and PPARγ activation would have major impacts on treatments for patients at high risk for cardiovascular disease.

  1. Glucagon-Like Peptide-1 Triggers Protective Pathways in Pancreatic Beta-Cells Exposed to Glycated Serum

    Alessandra Puddu

    2013-01-01

    Full Text Available Advanced glycation end products (AGEs might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1, an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs, in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2, glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS.

  2. Glucagon-Like Peptide-1 as Predictor of Body Mass Index and Dentate Gyrus Neurogenesis: Neuroplasticity and the Metabolic Milieu

    Jeremy D. Coplan

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1, and body mass index (BMI in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

  3. The glucagon-like peptide 1 analogue, exendin-4, attenuates the rewarding properties of psychostimulant drugs in mice.

    Emil Egecioglu

    Full Text Available Glucagon-like peptide 1 (GLP-1 is an incretine hormone that controls consummatory behavior and glucose homeostasis. It is released in response to nutrient ingestion from the intestine and production in the brain has also been identified. Given that GLP-1 receptors are expressed in reward areas, such as the nucleus accumbens and ventral tegmental area, and that common mechanisms regulate food and drug-induced reward we hypothesize that GLP-1 receptors are involved in reward regulation. Herein the effect of the GLP-1 receptor agonist Exendin-4 (Ex4, on amphetamine- and cocaine-induced activation of the mesolimbic dopamine system was investigated in mice. In a series of experiments we show that treatment with Ex4, at a dose with no effect per se, reduce amphetamine- as well as cocaine-induced locomotor stimulation, accumbal dopamine release as well as conditioned place preference in mice. Collectively these data propose a role for GLP-1 receptors in regulating drug reward. Moreover, the GLP-1 signaling system may be involved in the development of drug dependence since the rewarding effects of addictive drugs involves interferences with the mesolimbic dopamine system. Given that GLP-1 analogues, such as exenatide and liraglutide, are clinically available for treatment of type II diabetes, we propose that these should be elucidated as treatments of drug dependence.

  4. Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

    Minglin Pan

    2011-01-01

    Full Text Available The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1 receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX- sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

  5. Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man

    Hvidberg, A; Nielsen, M T; Hilsted, J;

    1994-01-01

    /L during the infusion, changes that were within physiologic limits. In a control experiment only saline was infused. During GLP-1 infusion, plasma glucose level decreased significantly (from 5.3 +/- 0.1 to 4.7 +/- 0.1 and 4.3 +/- 0.1 pmol/L at the end of the two infusion periods). Despite this, plasma......The newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1) (proglucagon 78-107amide), stimulates insulin secretion and inhibits glucagon secretion in man and may therefore be anticipated to influence hepatic glucose production. To study this, we infused synthetic GLP-1 sequentially at...... rates of 25 and 75 pmol.kg-1.h-1 into eight healthy volunteers after an overnight fast and measured plasma concentrations of glucose, insulin, and glucagon and glucose turnover by a technique involving infusion of 3-3H-glucose. Plasma levels of GLP-1 increased by 21.3 +/- 3.1 and 75.4 +/- 3.2 pmol...

  6. An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes

    Alessandra Puddu

    2013-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia. Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications, the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreatic β-cell dysfunction. This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.

  7. Umami Receptor Activation Increases Duodenal Bicarbonate Secretion via Glucagon-Like Peptide-2 Release in Rats

    Wang, Joon-Ho; Inoue, Takuya; Higashiyama, Masaaki; Guth, Paul H.; Engel, Eli; Kaunitz, Jonathan D.; Akiba, Yasutada

    2011-01-01

    Luminal nutrient chemosensing during meal ingestion is mediated by intestinal endocrine cells, which regulate secretion and motility via the release of gut hormones. We have reported that luminal coperfusion of l-Glu and IMP, common condiments providing the umami or proteinaceous taste, synergistically increases duodenal bicarbonate secretion (DBS) possibly via taste receptor heterodimers, taste receptor type 1, member 1 (T1R1)/R3. We hypothesized that glucose-dependent insulinotropic peptide...

  8. Glucagon-like peptide-1 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro.

    Baldassano, Sara; Wang, Guo-Du; Mulè, Flavia; Wood, Jackie D

    2012-02-01

    Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA was used to study GLP-1R effects on neural release of acetylcholine (ACh). Intramural localization of GLP-1R was assessed with immunohistochemistry. Application of GLP-1 to serosal or mucosal sides of flat-sheet preparations in Ussing chambers did not change baseline short-circuit current (I(sc)), which served as a marker for chloride secretion. Transmural EFS evoked neurally mediated biphasic increases in I(sc) that had an initial spike-like rising phase followed by a sustained plateau-like phase. Blockade of the EFS-evoked responses by tetrodotoxin indicated that the responses were neurally mediated. Application of GLP-1 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-1 receptor antagonist exendin-(9-39) suppressed this action of GLP-1. The GLP-1 inhibitory action on EFS-evoked responses persisted in the presence of nicotinic or vasoactive intestinal peptide receptor antagonists but not in the presence of a muscarinic receptor antagonist. GLP-1 significantly reduced EFS-evoked ACh release. In the submucosal plexus, GLP-1R immunoreactivity (IR) was expressed by choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons, and vasoactive intestinal peptide-IR neurons. Our results suggest that GLP-1R is expressed in guinea pig submucosal neurons and that its activation leads to a decrease in neurally evoked chloride secretion by suppressing release of ACh at neuroepithelial junctions in the enteric neural networks

  9. Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

    Riz, Michela; Pedersen, Morten Gram

    2015-12-01

    Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1), peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT) and ATP-sensitive K+-channels (K(ATP)-channels) to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP) current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP)-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release. PMID:26630068

  10. Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

    Michela Riz

    2015-12-01

    Full Text Available Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1, peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT and ATP-sensitive K+-channels (K(ATP-channels to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release.

  11. Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs

    The glucagon-like peptide-1 receptor (GLP-1R) has been proposed as a target for molecular imaging of beta cells. The feasibility of non-invasive imaging and quantification of GLP-1R in pancreas using the positron emission tomography (PET) tracer [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in non-diabetic and streptozotocin (STZ)-induced diabetic pigs treated with insulin was investigated. Non-diabetic (n = 4) and STZ-induced diabetic pigs (n = 3) from the same litter were examined. Development of diabetes was confirmed by blood glucose values, clinical examinations and insulin staining of pancreatic sections post mortem. Tissue perfusion in the pancreas and kidneys was evaluated by [15O]water PET/computed tomography (CT) scans. The in vivo receptor specificity of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 was assessed by administration of either tracer alone or by competition with 3-6.5 μg/kg of Exendin-4. Volume of distribution and occupancy in the pancreas were quantified with a single tissue compartment model. [15O]water PET/CT examinations showed reduced perfusion in the pancreas and kidneys in diabetic pigs. [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 uptake in the pancreas of both non-diabetic and diabetic pigs was almost completely abolished by co-injection of unlabeled Exendin-4 peptide. [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 uptake did not differ between non-diabetic and diabetic pigs. In all animals, administration of the tracer resulted in an immediate increase in the heart rate (HR). Pancreatic uptake of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 was not reduced by destruction of beta cells in STZ-induced diabetic pigs. (orig.)

  12. Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome.

    Thymann, Thomas; Stoll, Barbara; Mecklenburg, Lars; Burrin, Douglas G; Vegge, Andreas; Qvist, Niels; Eriksen, Thomas; Jeppesen, Palle B; Sangild, Per T

    2014-06-01

    Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P < 0.05). There was a dose-dependent increase in weight per length of the remnant intestine (P < 0.01) and fractional protein synthesis rate in the intestine was increased in the 0.2 mg · kg · day group versus placebo (P < 0.001); however, functional and structural endpoints including activity of digestive enzymes, absorption of enteral nutrients, and immunohistochemistry (Ki67, villin, FABP2, ChgA, and GLP-2R) were not affected by the treatment. Teduglutide induces trophicity on the remnant intestine but has limited acute effects on functional endpoints. Significant effects of teduglutide on gut function may require a longer adaptation period and/or a more frequent administration of the peptide. In perspective, GLP-2 or its analogues may be relevant to improve intestinal adaptation in pediatric patients with short bowel syndrome. PMID:24399211

  13. Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance.

    Wiśniewski, Kazimierz; Sueiras-Diaz, Javier; Jiang, Guangcheng; Galyean, Robert; Lu, Mark; Thompson, Dorain; Wang, Yung-Chih; Croston, Glenn; Posch, Alexander; Hargrove, Diane M; Wiśniewska, Halina; Laporte, Régent; Dwyer, John J; Qi, Steve; Srinivasan, Karthik; Hartwig, Jennifer; Ferdyan, Nicky; Mares, Monica; Kraus, John; Alagarsamy, Sudarkodi; Rivière, Pierre J M; Schteingart, Claudio D

    2016-04-14

    Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly(2),Nle(10),d-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),d-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),d-Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),d-Phe(11),Leu(16)]hGLP-2-(1-33)-NHEt), and 85 ([Gly(2),Nle(10),d-Phe(11),Leu(16)]hGLP-2-(1-33)-NH-((CH2)2O)4-(CH2)2-CONH2) displayed the desired profiles (EC50 (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound 73 (FE 203799) was selected as a candidate for clinical development. PMID:26986178

  14. Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease.

    Christine Bernsmeier

    Full Text Available BACKGROUND & AIMS: The incretins glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD. However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients. METHODS: N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH patients and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration. RESULTS: Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001. In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH. CONCLUSIONS: Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

  15. Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed.

    King, Klim; Lin, Nai-Pin; Cheng, Yu-Hong; Chen, Gao-Hui; Chein, Rong-Jie

    2015-10-23

    The glucagon-like peptide-1 receptor (GLP-1R) is expressed in many tissues and has been implicated in diverse physiological functions, such as energy homeostasis and cognition. GLP-1 analogs are approved for treatment of type 2 diabetes and are undergoing clinical trials for other disorders, including neurodegenerative diseases. GLP-1 analog therapies maintain chronically high plasma levels of the analog and can lead to loss of spatiotemporal control of GLP-1R activation. To avoid adverse effects associated with current therapies, we characterized positive modulators of GLP-1R signaling. We screened extracts from edible plants using an intracellular cAMP biosensor and GLP-1R endocytosis assays. Ethanol extracts from fenugreek seeds enhanced GLP-1 signaling. These seeds have previously been found to reduce glucose and glycated hemoglobin levels in humans. An active compound (N55) with a new N-linoleoyl-2-amino-γ-butyrolactone structure was purified from fenugreek seeds. N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner. N55 specifically enhanced GLP-1 potency more than 40-fold, but not that of exendin 4, to stimulate cAMP production. In contrast to the current allosteric modulators that bind to GLP-1R, N55 binds to GLP-1 peptide and facilitates trypsin-mediated GLP-1 inactivation. These findings identify a new class of modulators of GLP-1R signaling and suggest that GLP-1 might be a viable target for drug discovery. Our results also highlight a feasible approach for screening bioactive activity of plant extracts. PMID:26336108

  16. Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon

    Haderslev, K V; Jeppesen, P B; Hartmann, B;

    2002-01-01

    Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition ...... that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients.......Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition...

  17. Effect of Teduglutide, a Glucagon-like Peptide 2 Analog, on Citrulline Levels in Patients With Short Bowel Syndrome in Two Phase III Randomized Trials

    Seidner, Douglas L; Joly, Francisca; Youssef, Nader N

    2015-01-01

    Objectives: In clinical trials, treatment with the glucagon-like peptide 2 analog teduglutide was associated with improved fluid and nutrient absorption and increased intestinal villus height and crypt depth in patients with short bowel syndrome (SBS). Plasma citrulline, an amino acid produced by enterocytes, is considered a measure of enterocyte mass. This analysis assessed changes in plasma citrulline levels in patients with SBS in 2 phase III clinical studies of teduglutide. Methods: Both ...

  18. Incretins and the specific mechanism of action of liraglutide, the first applicable human glucagon-like peptide 1 analog in the treatment of type 2 diabetes

    Mannucci, Edoardo

    2010-01-01

    Edoardo Mannucci, Caterina LamannaDiabetes Agency, Careggi Teaching Hospital, Florence, ItalyAbstract: Liraglutide is a once-daily glucagon-like peptide 1 (GLP-1) receptor agonist, approved for use as a treatment of type 2 diabetes. Like other drugs of the same class, liraglutide stimulates insulin secretion in a glucose-dependent fashion, has the potential of preventing β-cell mass decline, and inhibits food intake. In addition, experimental studies suggest that the GLP-1 receptor a...

  19. Metabolically-inactive glucagon-like peptide-1(9-36)amide confers selective protective actions against post-myocardial infarction remodelling

    Robinson, Emma; Tate, Mitchel; Lockhart, Samuel; McPeake, Claire; O'Neill, Karla M; Edgar, Kevin S; Calderwood, Danielle; Green, Brian D; McDermott, Barbara J.; Grieve, David J

    2016-01-01

    BACKGROUND: Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9-36)amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-1(9-36)amide on chronic post-myocardial in...

  20. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2

    Tolhurst, Gwen; Heffron, Helen; Lam, Yu Shan; Parker, Helen E; Habib, Abdella M; Diakogiannaki, Eleftheria; Cameron, Jennifer; Grosse, Johannes; Reimann, Frank; Gribble, Fiona M.

    2012-01-01

    Interest in how the gut microbiome can influence the metabolic state of the host has recently heightened. One postulated link is bacterial fermentation of “indigestible” prebiotics to short-chain fatty acids (SCFAs), which in turn modulate the release of gut hormones controlling insulin release and appetite. We show here that SCFAs trigger secretion of the incretin hormone glucagon-like peptide (GLP)-1 from mixed colonic cultures in vitro. Quantitative PCR revealed enriched expression of the ...

  1. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

    Feng Sun; Sanbao Chai; Lishi Li; Kai Yu; Zhirong Yang; Shanshan Wu; Yuan Zhang; Linong Ji; Siyan Zhan

    2015-01-01

    To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean du...

  2. Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies

    Li, Ling; Li, Sheyu; Liu, Jiali; Deng, Ke; Busse, Jason W; Vandvik, Per Olav; Wong, Evelyn; Sohani, Zahra N.; Bala, Malgorzata M; Rios, Lorena P; Malaga, German; Ebrahim, Shanil; Shen, Jiantong; Zhang, Longhao; Zhao, Pujing

    2016-01-01

    Background The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. We therefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure or hospitalization for heart failure in patients with type 2 diabetes. Methods We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addresse...

  3. Unique roles od glucagon and glucagon-like peptides: Parallels in understanding the functions of adipokinetic hormones in stress responses in insects

    Bednářová, Andrea; Kodrík, Dalibor; Krishnan, N.

    2013-01-01

    Roč. 164, č. 1 (2013), s. 91-100. ISSN 1095-6433 R&D Projects: GA ČR GAP501/10/1215 Grant ostatní: National Science Foundation, EPSCOR(US) MSU 012156-014 Institutional support: RVO:60077344 Keywords : adipokinetic hormone * glucagon * glucagon-like peptide Subject RIV: ED - Physiology Impact factor: 2.371, year: 2013 http://www.sciencedirect.com/science/article/pii/S1095643312004904

  4. Uncoupling protein 2 regulates glucagon-like peptide-1secretion in L-cells

    Yan Chen; Zheng-Yang Li; Yan Yang; Hong-Jie Zhang

    2012-01-01

    AIM:To investigate whether uncoupling protein 2(UCP2) affects oleic acid-induced secretion of glucagonlike peptide-1 (GLP-1) in L-cells.METHODS:mRNA and protein expression of UCP2were analyzed in human NCI-H716 cells,which serve as a model for enteroendocrine L-cells,by quantitative reverse transcription-polymerase chain reaction and Western blotting before and after treatment with oleic acid.Localization of UCP2 and GLP-1 in NCI-H716 cells was assessed by immunofluorescence labeling.NCI-H716cells were transiently transfected with a small interfering RNA (siRNA) that targets UCP2 (siUCP2) or with a nonspecific siRNA using Lipofectamine 2000.The concentrations of bioactive GLP-1 in the medium were measured by enzyme linked immunosorbent assay.RESULTS:Both GLP-1 and UCP2 granules were expressed mainly in the cytoplasm of NCI-H716 cells.NCI-H716 cells that secreted GLP-1 also expressed UCP2.Time-course experiments revealed that release of GLP-1 from NCI-H716 cells into the medium reached a maximum at 120 min and remained stable until at least 180 min after treatment with oleic acid (the level of GLP-1 increased about 2.3-fold as compared with the level of GLP-1 in the control cells,P < 0.05).In an experiment to determine dose dependence,stimulation of NCI-H716 cells with ≤ 8 mmol oleic acid led to a concentration-dependent release of GLP-1 into the medium; 10 mmol oleic acid diminished the release of GLP-1.Furthermore,GLP-1 secretion induced by oleic acid from NCI-H716 cells that were transfected with siUCP2 decreased to 41.8%,as compared with NCI-H716 cells that were transfected with a non-specific siRNA (P < 0.01).CONCLUSION:UCP2 affected GLP-1 secretion induced by oleic acid.UCP2 plays an important role in L-cell secretion that is induced by free fatty acids.

  5. Glucagon-like peptide-1(GLP-1) receptor agonists: potential to reduce fracture risk in diabetic patients?

    Luo, Guojing; Liu, Hong; Lu, Hongyun

    2016-01-01

    This review summarizes current knowledge about glucagon-like peptide 1 receptor agonists (GLP-1 RA) and their effects on bone metabolism and fracture risk. Recent in vivo and in vitro experiments indicated that GLP-1 RA could improve bone metabolism. GLP-1 could affect the fat-bone axis by promoting osteogenic differentiation and inhibiting adipogenic differentiation of bone mesenchymal precursor cells (BMSCs), which express the GLP-1 receptor. GLP-1 RA may also influence the balance between osteoclasts and osteoblasts, thus leading to more bone formation and less bone resorption. Wnt/β-catenin signalling is involved in this process. Mature osteocytes, which also express the GLP-1 receptor, produce sclerostin which inhibits Wnt/β-catenin signalling by binding to low density lipoprotein receptor-related protein (LRP) 5 and preventing the binding of Wnt. GLP-1 RA also decreases the expression of sclerostin (SOST) and circulating levels of SOST. In addition, GLP-1 receptors are expressed in thyroid C cells, where GLP-1 induces calcitonin release and thus indirectly inhibits bone resorption. Furthermore, GLP-1 RA influences the osteoprotegerin(OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) system by increasing OPG gene expression, and thus reverses the decreased bone mass in rats models. However, a recent meta-analysis and a cohort study did not show a significant relationship between GLP-RA use and fracture risk. Future clinical trials will be necessary to investigate thoroughly the relationship between GLP-1 RA use and fracture risk in diabetic patients. PMID:27099876

  6. Effects and mechanism of glucagon-like peptide-1 on injury of rats cardiomyocytes induced by hypoxia-reoxygenation

    XIE Yun; WANG Shao-xin; SHA Wei-wei; ZHOU Xue; WANG Wei-lin; HAN Li-pin; LI Dai-qing; YU De-min

    2008-01-01

    Background Although the insulinotropic role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes mellitus has been substantiated,its role in cardioprotection remains largely unknown.This study aimed to determine the effects of GLP-1 on injury of rats cardiac myocytes induced by hypoxia-reoxygenation (H/R) and the possible mechanisms.Methods The cultured neonatal rats cardiac myocytes were randomly divided into seven groups:the normal control group,the H/R group,the GLP-1+H/R group,the GLP-1+H/R+UO126 (the p42/44 mitogen-activated protein kinase (MAPK) inhibitor) group,the GLP-1+H/R+LY294002 (phosphatidylinositol 3-kinase (P13K) inhibitor) group,the H/R+UO126 group,and the H/R+LY294002 group.The lactate dehydrogenase (LDH) activity,apoptosis rate of cardiac myocytes,and caspase-3 activity were detected after the injury of H/R.Results Compared with the normal control group,the activity of LDH,cardiac myocyte apoptosis rate,and caspase-3 activity all increased significantly in the H/R group (P<0.01).Compared with the H/R group,these three indices all decreased in the H/R+GLP-1 group (P<0.01).However,the changes of LDH activity,apoptosis rate,and caspase-3 activity were inhibited by LY294002 and UO126 respectively.Conclusions GLP-1 can directly act on cardiac myocytes and protect them from H/R injury mainly by inhibiting their apoptosis.Its mechanism may be through the P13K-Akt pathway and the MAPK signaling pathway.

  7. Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents.

    Oguma, Takahiro; Nakayama, Keiko; Kuriyama, Chiaki; Matsushita, Yasuaki; Yoshida, Kumiko; Hikida, Kumiko; Obokata, Naoyuki; Tsuda-Tsukimoto, Minoru; Saito, Akira; Arakawa, Kenji; Ueta, Kiichiro; Shiotani, Masaharu

    2015-09-01

    The sodium glucose cotransporter (SGLT) 1 plays a major role in glucose absorption and incretin hormone release in the gastrointestinal tract; however, the impact of SGLT1 inhibition on plasma glucagon-like peptide-1 (GLP-1) levels in vivo is controversial. We analyzed the effects of SGLT1 inhibitors on GLP-1 secretion in normoglycemic and hyperglycemic rodents using phloridzin, CGMI [3-(4-cyclopropylphenylmethyl)-1-(β-d-glucopyranosyl)-4-methylindole], and canagliflozin. These compounds are SGLT2 inhibitors with moderate SGLT1 inhibitory activity, and their IC50 values against rat SGLT1 and mouse SGLT1 were 609 and 760 nM for phloridzin, 39.4 and 41.5 nM for CGMI, and 555 and 613 nM for canagliflozin, respectively. Oral administration of these inhibitors markedly enhanced and prolonged the glucose-induced plasma active GLP-1 (aGLP-1) increase in combination treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in normoglycemic mice and rats. CGMI, the most potent SGLT1 inhibitor among them, enhanced glucose-induced, but not fat-induced, plasma aGLP-1 increase at a lower dose compared with canagliflozin. Both CGMI and canagliflozin delayed intestinal glucose absorption after oral administration in normoglycemic rats. The combined treatment of canagliflozin and a DPP4 inhibitor increased plasma aGLP-1 levels and improved glucose tolerance compared with single treatment in both 8- and 13-week-old Zucker diabetic fatty rats. These results suggest that transient inhibition of intestinal SGLT1 promotes GLP-1 secretion by delaying glucose absorption and that concomitant inhibition of intestinal SGLT1 and DPP4 is a novel therapeutic option for glycemic control in type 2 diabetes mellitus. PMID:26105952

  8. A grape seed extract increases active glucagon-like peptide-1 levels after an oral glucose load in rats.

    González-Abuín, Noemi; Martínez-Micaelo, Neus; Margalef, Maria; Blay, Mayte; Arola-Arnal, Anna; Muguerza, Begoña; Ardévol, Anna; Pinent, Montserrat

    2014-09-01

    We have previously reported that procyanidins, a class of flavonoids, improve glycemia and exert an incretin-like effect, which was linked to their proven inhibitory effect on the dipeptidyl-peptidase 4 (DPP4) activity. However, their actual effect on incretin levels has not been reported yet. Therefore, in the present study we have evaluated whether a grape seed extract enriched in procyanidins (GSPE) modulates plasma incretin levels and attempted to determine the mechanisms involved. An acute GSPE treatment in healthy Wistar female rats prior to an oral glucose load induced an increase in plasma active glucagon-like peptide-1 (GLP-1), which was accompanied by an increase in the plasma insulin/glucose ratio and a simultaneous decrease in glucose levels. In agreement with our previous studies, the intestinal DPP4 activity was inhibited by the GSPE treatment. We have also assayed in vitro whether this inhibition occurs in inner intestinal tissues close to GLP-1-producing cells, such as the endothelium of the capillaries. We have found that the main compounds absorbed by intestinal CaCo-2 cells after an acute treatment with GSPE are catechin, epicatechin, B2 dimer and gallic acid, and that they inhibit the DPP4 activity in endothelial HUVEC cells in an additive way. Moreover, an increase in plasma total GLP-1 levels was found, suggesting an increase in GLP-1 secretion. In conclusion, our results show that GSPE improves glycemia through its action on GLP-1 secretion and on the inhibition of the inner intestinal DPP4 activity, leading to an increase in active GLP-1 levels, which, in turn, may affect the insulin release. PMID:25088664

  9. Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine.

    Schmidt, Heath D; Mietlicki-Baase, Elizabeth G; Ige, Kelsey Y; Maurer, John J; Reiner, David J; Zimmer, Derek J; Van Nest, Duncan S; Guercio, Leonardo A; Wimmer, Mathieu E; Olivos, Diana R; De Jonghe, Bart C; Hayes, Matthew R

    2016-06-01

    Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved treatments. Thus, there is a clear need to identify and develop novel pharmacotherapies for cocaine addiction. Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors in the ventral tegmental area (VTA) reduces intake of highly palatable food. As the neural circuits and neurobiological mechanisms underlying drug taking overlap to some degree with those regulating food intake, these findings suggest that activation of central GLP-1 receptors may also attenuate cocaine taking. Here, we show that intra-VTA administration of the GLP-1 receptor agonist exendin-4 (0.05 μg) significantly reduced cocaine, but not sucrose, self-administration in rats. We also demonstrate that cocaine taking is associated with elevated plasma corticosterone levels and that systemic infusion of cocaine activates GLP-1-expressing neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus that projects monosynaptically to the VTA. To determine the potential mechanisms by which cocaine activates NTS GLP-1-expressing neurons, we microinjected corticosterone (0.5 μg) directly into the hindbrain fourth ventricle. Intraventricular corticosterone attenuated cocaine self-administration and this effect was blocked in animals pretreated with the GLP-1 receptor antagonist exendin-(9-39) (10 μg) in the VTA. Finally, AAV-shRNA-mediated knockdown of VTA GLP-1 receptors was sufficient to augment cocaine self-administration. Taken together, these findings indicate that increased activation of NTS GLP-1-expressing neurons by corticosterone may represent a homeostatic response to cocaine taking, thereby reducing the reinforcing efficacy of cocaine. Therefore, central GLP-1 receptors may represent a novel target for cocaine addiction pharmacotherapies. PMID:26675243

  10. Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist.

    Katsurada, Kenichi; Yada, Toshihiko

    2016-04-01

    Glucagon-like peptide-1 (GLP-1) is derived from both the enteroendocrine L cells and preproglucagon-expressing neurons in the nucleus tractus solitarius (NTS) of the brain stem. As GLP-1 is cleaved by dipeptidyl peptidase-4 yielding a half-life of less than 2 min, it is plausible that the gut-derived GLP-1, released postprandially, exerts its effects on the brain mainly by interacting with vagal afferent neurons located at the intestinal or hepatic portal area. GLP-1 neurons in the NTS widely project in the central nervous system and act as a neurotransmitter. One of the physiological roles of brain-derived GLP-1 is restriction of feeding. GLP-1 receptor agonists have recently been used to treat type 2 diabetic patients, and have been shown to exhibit pleiotropic effects beyond incretin action, which involve brain functions. GLP-1 receptor agonist administered in the periphery is stable because of its resistance to dipeptidyl peptidase-4, and is highly likely to act on the brain by passing through the blood-brain barrier (BBB), as well as interacting with vagal afferent nerves. Central actions of GLP-1 have various roles including regulation of feeding, weight, glucose and lipid metabolism, cardiovascular functions, cognitive functions, and stress and emotional responses. In the present review, we focus on the source of GLP-1 and the pathway by which peripheral GLP-1 informs the brain, and then discuss recent findings on the central effects of GLP-1 and GLP-1 receptor agonists. PMID:27186358

  11. Electrical stimulation of the isolated rat intestine in the presence of nutrient stimulus enhances glucagon-like peptide-1 release

    The release of small intestinal hormones by constituents of ingested food, such as fatty acids, is integral to post-prandial responses that reduce food intake. Recent evidence suggests that small intestinal electrical stimulation reduces food intake, although the mechanism of action is debated. To test the hypothesis that intestinal stimulation directly alters hormone release locally we used isolated rat distal ileum and measured glucagon-like peptide-1 (GLP-1) released in the presence or absence of linoleic acid (LA) and electrical field stimulation (EFS). Intact segments were oriented longitudinally between bipolar stimulating electrodes in organ bath chambers containing modified Krebs–Ringers bicarbonate (KRB) buffer including protease inhibitors. Incubation in LA (3 mg ml−1) for 45 min increased GLP-1 concentration (21.9 ± 2.6 pM versus KRB buffer alone 3.6 ± 0.1 pM). Eleven electrical stimulation conditions were tested. In the presence of LA none of the stimulation conditions inhibited LA-evoked GLP-1 release, whereas two high frequency short pulse widths (14 V, 20 Hz, 5 ms and 14 V, 40 Hz, 5 ms) and one low frequency long pulse width (14 V, 0.4 Hz, 300 ms) EFS conditions enhanced LA-evoked GLP-1 release by >250%. These results are consistent with a local effect of intestinal electrical stimulation to enhance GLP-1 release in response to luminal nutrients in the intestines. Enhancing hormone release could improve the efficacy of intestinal electrical stimulation and provide a potential treatment for obesity and metabolic conditions

  12. Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism.

    Sassoon, Daniel J; Goodwill, Adam G; Noblet, Jillian N; Conteh, Abass M; Herring, B Paul; McClintick, Jeanette N; Tune, Johnathan D; Mather, Kieren J

    2016-07-01

    This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miRNA) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-minutes coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect the blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca(2+) binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion. PMID:27234258

  13. Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results

    Gotthardt, Martin; Fischer, Marc; Naeher, Inga; Holz, Josefin B.; Jungclas, Hartmut; Fritsch, Hans-Walter; Behe, Martin; Joseph, Klaus; Behr, Thomas M. [Department of Nuclear Medicine, Philipps-University of Marburg (Germany); Goeke, Burkhard [Department of Internal Medicine II, Ludwig-Maximilians-University of Munich (Germany)

    2002-05-01

    The non-invasive detection of insulinomas remains a diagnostic problem that is not solved by means of somatostatin receptor scintigraphy. We investigated the biokinetics and specificity of uptake and degradation of the incretin hormone glucagon-like peptide-1 (GLP-1) in a rat insulinoma cell line (RINm5F) in order to ascertain whether radiolabelled GLP-1 may be suitable for specific visualisation of insulinomas in vivo. GLP-1 (7-36)amide was radioiodinated according to the iodogen method. The specificity of the uptake of [{sup 125}I]GLP-1(7-36)amide by RINm5F cells was investigated. Degradation products of GLP-1 (7-36)amide in the cell medium were purified by HPLC. Their masses and amino acid sequences were determined by {sup 252}Cf-plasma desorption mass spectrometry. Lysosomal degradation was inhibited and after differential centrifugation the amount of radiotracer incorporated into lysosomes was determined. Biodistribution studies were performed in a rat insulinoma model (NEDH rats and RINm5F cells) with [{sup 123}I]GLP-1(7-36)amide and its more stable agonist [{sup 123}I]exendin 3. The uptake of radiotracer into insulinoma cells reached a maximum within 5 min. It was inhibited by an excess of unlabelled peptide. [{sup 125}I]GLP-1(7-36)amide accumulated in the cells if lysosomal degradation was inhibited. Degradation products of the peptide were found in the cell medium. We determined their mass and derived their amino acid sequence. Radiolabelling of exendin 3 was more difficult than that of GLP-1 because of the lack of tyrosine in its primary structure. Biodistribution studies showed rapid blood clearance and uptake of the radiotracer into the tumour and the pancreas. It was also possible to detect insulinomas in an animal model by external scintigraphy using radioiodinated GLP-1 (7-36)amide and exendin 3. GLP-1 (7-36)amide is specifically internalised into insulinoma cells by a receptor-mediated mechanism. Our results demonstrate that GLP-1 receptor

  14. Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results

    The non-invasive detection of insulinomas remains a diagnostic problem that is not solved by means of somatostatin receptor scintigraphy. We investigated the biokinetics and specificity of uptake and degradation of the incretin hormone glucagon-like peptide-1 (GLP-1) in a rat insulinoma cell line (RINm5F) in order to ascertain whether radiolabelled GLP-1 may be suitable for specific visualisation of insulinomas in vivo. GLP-1 (7-36)amide was radioiodinated according to the iodogen method. The specificity of the uptake of [125I]GLP-1(7-36)amide by RINm5F cells was investigated. Degradation products of GLP-1 (7-36)amide in the cell medium were purified by HPLC. Their masses and amino acid sequences were determined by 252Cf-plasma desorption mass spectrometry. Lysosomal degradation was inhibited and after differential centrifugation the amount of radiotracer incorporated into lysosomes was determined. Biodistribution studies were performed in a rat insulinoma model (NEDH rats and RINm5F cells) with [123I]GLP-1(7-36)amide and its more stable agonist [123I]exendin 3. The uptake of radiotracer into insulinoma cells reached a maximum within 5 min. It was inhibited by an excess of unlabelled peptide. [125I]GLP-1(7-36)amide accumulated in the cells if lysosomal degradation was inhibited. Degradation products of the peptide were found in the cell medium. We determined their mass and derived their amino acid sequence. Radiolabelling of exendin 3 was more difficult than that of GLP-1 because of the lack of tyrosine in its primary structure. Biodistribution studies showed rapid blood clearance and uptake of the radiotracer into the tumour and the pancreas. It was also possible to detect insulinomas in an animal model by external scintigraphy using radioiodinated GLP-1 (7-36)amide and exendin 3. GLP-1 (7-36)amide is specifically internalised into insulinoma cells by a receptor-mediated mechanism. Our results demonstrate that GLP-1 receptor-directed scintigraphy may be a new

  15. The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo

    Panaro, Brandon L; Tough, Iain R; Engelstoft, Maja S;

    2014-01-01

    The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furtherm......The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon....... Furthermore, MC4R is the second most highly enriched GPCR in peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of α-MSH induces a MC4R-specific PYY-dependent antisecretory...

  16. Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs

    Nalin, Lovisa; Andreasson, Susanne; Wikstrand, Anna; Ryden, Anneli; Nyman, Goerel; Jensen-Waern, Marianne [Swedish University of Agricultural Sciences, Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Uppsala (Sweden); Selvaraju, Ram K.; Eriksson, Olof [Uppsala University, Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala (Sweden); Velikyan, Irina [Uppsala University, Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala (Sweden); Uppsala University, Department of Radiology, Oncology and Radiation Sciences, Uppsala (Sweden); Uppsala University Hospital, PET Centre, Centre for Medical Imaging, Uppsala (Sweden); Berglund, Marie [Uppsala University, Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala (Sweden); Uppsala University, Department of Radiology, Oncology and Radiation Sciences, Uppsala (Sweden); Lubberink, Mark [Uppsala University, Department of Radiology, Oncology and Radiation Sciences, Uppsala (Sweden); Kandeel, Fouad [Beckman Research Institute of the City of Hope, Duarte, CA (United States); Korsgren, Olle [Uppsala University, Department of Immunology, Genetics and Pathology, Uppsala (Sweden)

    2014-09-15

    The glucagon-like peptide-1 receptor (GLP-1R) has been proposed as a target for molecular imaging of beta cells. The feasibility of non-invasive imaging and quantification of GLP-1R in pancreas using the positron emission tomography (PET) tracer [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 in non-diabetic and streptozotocin (STZ)-induced diabetic pigs treated with insulin was investigated. Non-diabetic (n = 4) and STZ-induced diabetic pigs (n = 3) from the same litter were examined. Development of diabetes was confirmed by blood glucose values, clinical examinations and insulin staining of pancreatic sections post mortem. Tissue perfusion in the pancreas and kidneys was evaluated by [{sup 15}O]water PET/computed tomography (CT) scans. The in vivo receptor specificity of [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 was assessed by administration of either tracer alone or by competition with 3-6.5 μg/kg of Exendin-4. Volume of distribution and occupancy in the pancreas were quantified with a single tissue compartment model. [{sup 15}O]water PET/CT examinations showed reduced perfusion in the pancreas and kidneys in diabetic pigs. [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 uptake in the pancreas of both non-diabetic and diabetic pigs was almost completely abolished by co-injection of unlabeled Exendin-4 peptide. [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 uptake did not differ between non-diabetic and diabetic pigs. In all animals, administration of the tracer resulted in an immediate increase in the heart rate (HR). Pancreatic uptake of [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 was not reduced by destruction of beta cells in STZ-induced diabetic pigs. (orig.)

  17. Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease

    Schmidt, Peter T; Ljung, Tryggve; Hartmann, Bolette; Hare, Kristine J; Holst, Jens Juul; Hellström, Per M

    2005-01-01

    BACKGROUND AND AIM: Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in...... the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients. CONCLUSION: The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may...

  18. Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome.

    Jeppesen, Palle Bekker

    2012-05-01

    Short bowel syndrome results from surgical resection, congenital defect or disease-associated loss of absorption. Parenteral support (PS) is lifesaving in patients with short bowel syndrome and intestinal failure who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Together, the symptoms of short bowel syndrome and the inconvenience and complications in relation to PS (e.g. catheter-related blood steam infections, central thrombosis and intestinal failure associated liver disease) may impair the quality of life of patients. The aim of treatment is to maximize intestinal absorption, minimize the inconvenience of diarrhea, and avoid, reduce or eliminate the need for PS to achieve the best possible quality of life for the patient. Conventional treatments include dietary manipulations, oral rehydration solutions, and antidiarrheal and antisecretory treatments. However, the evidence base for these interventions is limited and treatments that improve the structural and functional integrity of the remaining intestine are needed. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth and possibly by restoring gastric emptying and secretion, thereby reducing intestinal losses and promoting intestinal absorption. In a 3-week, phase II balance study, teduglutide reduced diarrhea by around 700 g/day and fecal energy losses by around 0.8 MJ/day. In two randomized, placebo-controlled, 24-week, phase III studies, similar findings were obtained when evaluating the fluid composite effect, which is the sum of the beneficial effects of teduglutide - reduction in the need for PS, increase in urine production and reduction in oral fluid intake. The fluid composite effect reflects the increase in intestinal fluid absorption (and the concomitant reduction in diarrhea) and may be used in studies in which metabolic balance assessments are not performed. In studies of up to 24 weeks

  19. Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia.

    Charlotte J Green

    Full Text Available BACKGROUND: Glucagon like peptide-1 (GLP-1 stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined. METHODS: Skeletal muscle satellite cells isolated from young (22.5 ± 0.97 yr, lean (BMI 22.5 ± 0.6 kg/m(2, healthy males were differentiated in media containing either 22.5 mM (high or 5 mM (normal glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis. RESULTS: We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes. Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia. CONCLUSIONS: GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation

  20. GLP-1(28-36amide, the Glucagon-like peptide-1 metabolite: friend, foe, or pharmacological folly?

    Taing MW

    2014-06-01

    Full Text Available Meng-Wong Taing,1,2 Felicity J Rose,1,3 Jonathan P Whitehead11Metabolic Medicine, Mater Research Institute, University of Queensland, 2School of Pharmacy, University of Queensland, Brisbane, QLD, Australia; 3University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, AustraliaAbstract: The glucagon-like peptide-1 (GLP-1 axis has emerged as a major therapeutic target for the treatment of type 2 diabetes. GLP-1 mediates its key insulinotropic effects via a G-protein coupled receptor expressed on β-cells and other pancreatic cell types. The insulinotropic activity of GLP-1 is terminated via enzymatic cleavage by dipeptidyl peptidase-4. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive; however, accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. Recent reports describing the putative effects of one such metabolite, the GLP-1-derived nonapeptide GLP-1(28-36amide, are the focus of this review. Administration of the nonapeptide elevates cyclic adenosine monophosphate (cAMP and activates protein kinase A, β-catenin, and cAMP response-element binding protein in pancreatic β-cells and hepatocytes. In stressed cells, the nonapeptide targets the mitochondria and, via poorly defined mechanisms, helps to maintain mitochondrial membrane potential and cellular adenosine triphosphate levels and to reduce cytotoxicity and apoptosis. In mouse models of diet-induced obesity, treatment with the nonapeptide reduces weight gain and ameliorates associated pathophysiology, including hyperglycemia, hyperinsulinemia, and hepatic steatosis. Nonapeptide administration in a streptozotocin-induced model of type 1 diabetes also improves glucose disposal concomitant with elevated insulin levels and increased β-cell mass and proliferation. Collectively, these results suggest some of the beneficial

  1. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  2. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L., E-mail: rodney.rouse@fda.hhs.gov

    2012-10-15

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  3. GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon-like peptide-1 analogues: past, present and future

    Glucagon-like peptide 1 (GLP-1) receptors expression has been found on many types of cancer cells. In case of benign insulinoma the density of those receptors is even higher than the density of somatostatin receptors. This article presents the results of clinical trials proving the utility of GLP-1 receptors imaging. Scintigraphy or positron emission tomography with the use of GLP-1 analogues labelled with appropriate radioisotopes (111In, 99mTc, 68Ga, 18F or 64Cu) seem to be superior compared with other available techniques in diagnosis of hardly detectable benign insulinoma. While surgery is the only effective therapy for insulinoma patients, therefore proper preoperative localization of the tumor allows sparing operation. Glucagon-like peptide 1 receptors might become also a target for imaging of other tumors such as gastrinoma, pheochromocytoma and medullary thyroid cancer (MTC), which also were shown to over express this type of receptors. However, studies with larger groups of patients are required to prove the clinical usefulness of this indication. Moreover GLP-1 receptor imaging seems to be a potential tool to evaluate pancreatic beta cell mass (BCM). It may be useful in the early diagnosis of beta cell loss in preclinical phases of diabetes. The panceratic beta cells imaging may influence the prophylaxis of diabetes and management of diabetic patients. Presented results of clinical trials prove that glucagon-like peptide 1 receptor imaging might become helpful diagnostic strategy particularly in case of patients with benign insulinoma tumors, but also patients with gastrinoma, pheochromocytoma, medullary thyroid cancer and diabetes.

  4. Glucagon-like Peptide-1 Increases β-Cell Glucose Competence and Proliferation by Translational Induction of Insulin-like Growth Factor-1 Receptor Expression*

    Cornu, Marion; Modi, Honey; Kawamori, Dan; Kulkarni, Rohit N.; Joffraud, Magali; Thorens, Bernard

    2010-01-01

    Glucagon-like peptide-1 (GLP-1) protects β-cells against apoptosis, increases their glucose competence, and induces their proliferation. We previously demonstrated that the anti-apoptotic effect was mediated by an increase in insulin-like growth factor-1 receptor (IGF-1R) expression and signaling, which was dependent on autocrine secretion of insulin-like growth factor 2 (IGF-2). Here, we further investigated how GLP-1 induces IGF-1R expression and whether the IGF-2/IGF-1R autocrine loop is a...

  5. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans

    Meier, J J; Gethmann, A; Götze, O;

    2006-01-01

    AIMS/HYPOTHESIS: Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels...... administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33+/-0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely...

  6. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis.

    Hogan, A E

    2011-11-01

    The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells.

  7. The effect of a glucagon-like peptide-1 receptor agonist on glucose tolerance in women with previous gestational diabetes mellitus

    Foghsgaard, Signe; Vedtofte, Louise; Mathiesen, Elisabeth R;

    2013-01-01

    INTRODUCTION: Pregnancy is associated with decreased insulin sensitivity, which is usually overcome by a compensatory increase in insulin secretion. Some pregnant women are not able to increase their insulin secretion sufficiently, and consequently develop gestational diabetes mellitus (GDM). The...... disease normally disappears after delivery. Nevertheless, women with previous GDM have a high risk of developing type 2 diabetes (T2D) later in life. We aim to investigate the early development of T2D in women with previous GDM and to evaluate whether treatment with the glucagon-like peptide-1 receptor...

  8. Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

    Brinkman, Adam S; Murali, Sangita G; Hitt, Stacy;

    2012-01-01

    Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that shows promise for the treatment of short bowel syndrome (SBS). Our objective was to investigate how combination GLP-2 + enteral nutrients (EN) affects intestinal adaption in a rat model that mimics severe...... human SBS and requires parenteral nutrition (PN). Male Sprague-Dawley rats were assigned to one of five groups and maintained with PN for 18 days: total parenteral nutrition (TPN) alone, TPN + GLP-2 (100 μg·kg(-1)·day(-1)), PN + EN + GLP-2(7 days), PN + EN + GLP-2(18 days), and a nonsurgical oral...

  9. Differential effects of glucagon-like peptide-1 on microvascular recruitment and glucose metabolism in short- and long-term Insulin resistance

    Sjøberg, Kim Anker; Rattigan, Stephen; Jeppesen, Jacob Fuglsbjerg;

    2015-01-01

    Acute infusion of glucagon-like-peptide-1 (GLP-1) has potent effects on blood flow distribution through the microcirculation in healthy humans and rats. High fat diet induces impairments in insulin-mediated microvascular recruitment (MVR) and muscle glucose uptake, and here we examined whether this......-mediated glucose uptake in skeletal muscle by 90% (P<0.05) after 5 days HF diet but not after 8 weeks. The present study demonstrates that GLP-1 increases MVR in rat skeletal muscle and can reverse early stages of HF diet induced insulin resistance in vivo. This article is protected by copyright. All rights...

  10. GPR119 Is Essential for Oleoylethanolamide-Induced Glucagon-Like Peptide-1 Secretion From the Intestinal Enteroendocrine L-Cell

    Lauffer, Lina M.; Iakoubov, Roman; Brubaker, Patricia L.

    2009-01-01

    OBJECTIVE Intestinal L-cells secrete the incretin glucagon-like peptide-1 (GLP-1) in response to ingestion of nutrients, especially long-chain fatty acids. The Gαs-coupled receptor GPR119 binds the long-chain fatty acid derivate oleoylethanolamide (OEA), and GPR119 agonists enhance GLP-1 secretion. We therefore hypothesized that OEA stimulates GLP-1 release through a GPR119-dependent mechanism. RESEARCH DESIGN AND METHODS Murine (m) GLUTag, human (h) NCI-H716, and primary fetal rat intestinal...

  11. Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas

    Holst, J J; Poulsen, Steen Seier

    1986-01-01

    We developed specific antibodies and RIAs for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), two predicted products of the glucagon gene, and studied the occurrence, nature, and secretion of immunoreactive GLP-1 and GLP-2 in pig pancreas and small intestine. Immunoreactive GLP-1 and GLP-2 were...... identified in glucagon-producing cells of the pancreatic islets, and in glicentin-producing cells of the small intestine. Immunoreactive GLP-1 and 2 in intestinal extracts corresponded in molecular size to peptides synthesized according to the predicted structure. By reverse phase HPLC, intestinal and...... synthetic GLP-1 behaved similarly, whereas synthetic and intestinal GLP-2 differed. Pancreatic extracts contained a large peptide with both GLP-1 and GLP-2 immunoreactivity. Secretion was studied using isolated perfused pig pancreas during arginine stimulation, and isolated perfused pig ileum during either...

  12. The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans

    Meier, Juris J; Gethmann, Arnica; Nauck, Michael A;

    2006-01-01

    Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP-1-(7-36) amide is degraded to the metabolite GLP-1-(9-36) amide. The effects of GLP-1-(9-36) amide in humans are less well characterized. Fourteen...... healthy volunteers were studied with intravenous infusion of GLP-1-(7-36) amide, GLP-1-(9-36) amide, or placebo over 390 min. After 30 min, a solid test meal was served, and gastric emptying was assessed. Blood was drawn for GLP-1 (total and intact), glucose, insulin, C-peptide, and glucagon measurements......-(7-36) amide administration]. GLP-1-(7-36) amide reduced fasting and postprandial glucose concentrations (P gastric emptying (P

  13. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects

    Meier, Juris J; Kemmeries, Guido; Holst, Jens Juul;

    2005-01-01

    Glucagon-like peptide 1 (GLP-1) has been proposed to act as an incretin hormone due to its ability to enhance glucose-stimulated insulin secretion. Because GLP-1 also decelerates gastric emptying, it physiologically reduces rather than augments postprandial insulin secretory responses. Therefore......, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 +/- 4 years, BMI 25.0 +/- 4.9 kg/m2) were studied with an infusion of GLP-1 (0.8 pmol.kg(-1).min(-1) from -30 to 240 min) or placebo......) was administered at 0 min. Capillary and venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1, glucagon, gastric inhibitory polypeptide (GIP), and pancreatic polypeptide (specific immunoassays). Gastric emptying was assessed by the phenol red dilution...

  14. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes

    Meier, Juris J; Gallwitz, Baptist; Salmen, Stefan;

    2003-01-01

    The effects of different i.v. doses of glucagon-like peptide 1 (GLP-1) on glucose homeostasis and gastric emptying were compared in patients with type 2 diabetes. Twelve patients with type 2 diabetes received three different infusion rates of GLP-1 (0.4, 0.8, and 1.2 pmol/kg x min) or placebo...... in the fasting state and after a solid test meal (containing [(13)C]octanoic acid). Blood was drawn for glucose, insulin, C-peptide, glucagon, and GLP-1 determinations. The gastric emptying rate was calculated from the (13)CO(2) excretion rates in breath samples. Statistics were determined using repeated...... ingestion (P = 0.0031 and 0.0074, respectively). Glucagon secretion was suppressed with GLP-1. Gastric emptying was decelerated by GLP-1 in a dose-dependent fashion (P

  15. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects

    Meier, Juris J; Nauck, Michael A; Kranz, Daniel; Holst, Jens J; Deacon, Carolyn F; Gaeckler, Dirk; Schmidt, Wolfgang E; Gallwitz, Baptist

    2004-01-01

    Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important factors in the pathogenesis of type 2 diabetes and have a promising therapeutic potential. Alterations of their secretion, in vivo degradation, and elimination in patients with chronic renal insufficiency (CRI......, C-peptide, GLP-1 (total and intact), and GIP (total and intact; specific immunoassays). Plasma levels of GIP (3-42) and GLP-1 (9-36 amide) were calculated. Statistics were performed using repeated-measures and one-way ANOVA. After the oral glucose load, plasma concentrations of intact GLP-1 and...... elimination of GIP and GLP-1. The initial dipeptidyl peptidase IV-mediated degradation of both hormones is almost unaffected by impairments in renal function. Delayed elimination of GLP-1 and GIP in renal insufficiency may influence the pharmacokinetics and pharmacodynamics of dipeptidyl peptidase IV...

  16. Short reaction of C-peptide, glucagon-like peptide-1, ghrelin and endomorphin-1 for different style diet in type 2 diabetic patients

    CHEN Yi; WANG Xin; ZHANG Mei-fang; LI Yan-xiang; LI Ying; GU Ting; XIA Fang-zhen; YU Jiao; LU Ying-li

    2011-01-01

    Background Food composition and style is changing dramatically now,which causes inappropriate secretion of hormones from brain,gastrointestinal and endo-pancreas,may be related to unbalance of glucose in blood.The aim of this study was to explore the fast response of C-peptide,glucagon-like peptide-1 (GLP-1),ghrelin and endomorphin-1 (EM-1) to the eastern and western style meals in patients with type 2 diabetes mellitus.Methods The study enrolled 57 patients with type 2 diabetes (20 men and 37 women,mean age (67.05±8.26) years).Eastern style meal (meal A) and western style meal (meal B) were designed to produce the fullness effect.C-peptide,GLP-1,ghrelin and EM-1 were assessed before (0 hour) and after (2 hours) each diet.Results The delta (2h-0h) of C- peptide in meal A was significantly lower than that in meal B (P=0.0004).C-peptide,GLP-1,ghrelin and EM-1 were obviously higher before meal B than those before meal A (P <0.0001,<0.0001,=0.001,=0.0004 respectively).Blood glucose 2 hours and 3 hours after meal B were higher than those after meal A (P=-0.0005,0.0079 respectively).Correlations between GLP-1 and ghrelin were strongly positive before both meals and 2 hours after both meals and also in relation to the delta of meal A and meal B (rA0h=0.7836,rB0h=0.9368,rAsh=0.7615,rB2h=0.9409,rA(2h_0h)=0.7531,rB(2h-0h)=0.9980,respectively,P <0.0001).Conclusion Western style meal (high fat and protein food) could make more response of C-peptide than eastern style meal,and could stimulate more gut hormones (GLP-1,ghrelin) and brain peptide (EM-1) at the first phase of digestion.

  17. Gut hormones, and short bowel syndrome: The enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation

    GR Martin; PL Beck; DL Sigalet

    2006-01-01

    Short bowel syndrome (SBS) refers to the malabsorption of nutrients, water, and essential vitamins as a result of disease or surgical removal of parts of the small intestine. The most common reasons for removing part of the small intestine are due to surgical intervention for the treatment of either Crohn's disease or necrotizing enterocolitis. Intestinal adaptation following resection may take weeks to months to be achieved, thus nutritional support requires a variety of therapeutic measures, which include parenteral nutrition. Improper nutrition management can leave the SBS patient malnourished and/or dehydrated, which can be life threatening. The development of therapeutic strategies that reduce both the complications and medical costs associated with SBS/long-term parenteral nutrition while enhancing the intestinal adaptive response would be valuable.Currently, therapeutic options available for the treatment of SBS are limited. There are many potential stimulators of intestinal adaptation including peptide hormones, growth factors, and neuronally-derived components. Glucagon-like peptide-2 (GLP-2) is one potential treatment for gastrointestinal disorders associated with insufficient mucosal function. A significant body of evidence demonstrates that GLP-2is atrophic hormone that plays an important role in controlling intestinal adaptation. Recent data from clinical trials demonstrate that GLP-2 is safe, well-tolerated, and promotes intestinal growth in SBS patients. However,the mechanism of action and the localization of the glucagon-like peptide-2 receptor (GLP-2R) remains an enigma. This review summarizes the role of a number of mucosal-derived factors that might be involved with intestinal adaptation processes; however, this discussion primarily examines the physiology, mechanism of action,and utility of GLP-2 in the regulation of intestinal mucosal growth.

  18. Satiation and stress-induced hypophagia: examining the role of hindbrain neurons expressing prolactin-releasing peptide (PrRP or glucagon-like peptide 1 (GLP-1

    LindaRinaman

    2013-01-01

    Full Text Available Neural circuits distributed within the brainstem, hypothalamus, and limbic forebrain interact to control food intake and energy balance under normal day-to-day conditions, and in response to stressful conditions under which homeostasis is threatened. Experimental studies using rats and mice have generated a voluminous literature regarding the functional organization of circuits that inhibit food intake in response to satiety signals, and in response to stress. Although the central neural bases of satiation and stress-induced hypophagia often are studied and discussed as if they were distinct, we propose that both behavioral states are generated, at least in part, by recruitment of two separate but intermingled groups of caudal hindbrain neurons. One group comprises a subpopulation of noradrenergic (NA neurons within the caudal nucleus of the solitary tract (cNST; A2 cell group that is immunopositive for prolactin-releasing peptide (PrRP. The second group comprises non-adrenergic neurons within the cNST and nearby reticular formation that synthesize glucagon-like peptide 1 (GLP-1. Axonal projections from PrRP and GLP-1 neurons target distributed brainstem and forebrain regions that shape behavioral, autonomic, and endocrine responses to actual or anticipated homeostatic challenge, including the challenge of food intake. Evidence reviewed in this article supports the view that hindbrain PrRP and GLP-1 neurons contribute importantly to satiation and stress-induced hypophagia by modulating the activity of caudal brainstem circuits that control food intake. Hindbrain PrRP and GLP-1 neurons also engage hypothalamic and limbic forebrain networks that drive parallel behavioral and endocrine functions related to food intake and homeostatic challenge, and modulate conditioned and motivational aspects of food intake.

  19. Imaging exocytosis of single glucagon-like peptide-1 containing granules in a murine enteroendocrine cell line with total internal reflection fluorescent microscopy

    To analyze the exocytosis of glucagon-like peptide-1 (GLP-1) granules, we imaged the motion of GLP-1 granules labeled with enhanced yellow fluorescent protein (Venus) fused to human growth hormone (hGH-Venus) in an enteroendocrine cell line, STC-1 cells, by total internal reflection fluorescent (TIRF) microscopy. We found glucose stimulation caused biphasic GLP-1 granule exocytosis: during the first phase, fusion events occurred from two types of granules (previously docked granules and newcomers), and thereafter continuous fusion was observed mostly from newcomers during the second phase. Closely similar to the insulin granule fusion from pancreatic β cells, the regulated biphasic exocytosis from two types of granules may be a common mechanism in glucose-evoked hormone release from endocrine cells.

  20. Short bowel patients treated for two years with glucagon-like peptide 2 (GLP-2): compliance, safety, and effects on quality of life

    Jeppesen, P B; Lund, P; Gottschalck, I B;

    2009-01-01

    BACKGROUND AND AIMS: Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients in a short-term study. This study describes safety, compliance, and changes in quality of life in 11 SBS patients at baseline, week 13, 26, and 52 during two......-ascendo-anastomosis. The investigator excluded a patient due to unreliable feedback. Stoma nipple enlargement was seen in all 9 jejunostomy patients. Reported GLP-2 compliance was excellent (>93%). GLP-2 improved the overall quality of life VAS-score (4.1 +/- 2.8 cm versus 6.0 +/- 2.4 cm, P < .01), the overall SIP score...

  1. Clinical trial simulations in pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 analog in neonates and infants with short-bowel syndrome.

    Mouksassi, M S; Marier, J F; Cyran, J; Vinks, A A

    2009-12-01

    Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect. PMID:19847163

  2. Lack of effect of the glucagon-like peptide-1 receptor agonist liraglutide on psoriasis in glucose-tolerant patients – a randomized placebo-controlled trial

    Faurschou, A; Gyldenløve, M; Rohde, U; Thyssen, Jacob Pontoppidan; Zachariae, Claus; Skov, Lone; Knop, Filip Krag; Vilsbøll, T

    2015-01-01

    BACKGROUND: It has been proposed that glucagon-like peptide-1 receptor (GLP-1R) agonists used for the treatment of patients with type 2 diabetes might also improve their psoriasis. OBJECTIVE: To assess the efficacy and safety of the GLP-1R agonist liraglutide in glucose-tolerant patients with...... end points were improvement in PASI and dermatology life quality index (DLQI). Secondary end points included changes in weight and high sensitive C-reactive protein (hsCRP) levels, as well as adverse events. RESULTS: After 8 weeks of treatment, no significant change in PASI was found in the...... plaque psoriasis. METHODS: A total of 20 obese (body mass index > 25 kg/m(2)), glucose-tolerant patients with plaque psoriasis (psoriasis area and severity index (PASI) of at least 8) were randomized 1:1 to once-daily subcutaneous injections with liraglutide or placebo for an 8-week period. The primary...

  3. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

    Schäfer, S A; Tschritter, O; Machicao, F; Thamer, C; Stefan, N; Gallwitz, B; Holst, Jens Juul; Dekker, J M; 't Hart, L M; t'Hart, L M; Nijpels, G; van Haeften, T W; Häring, H U; Fritsche, A

    2007-01-01

    AIMS/HYPOTHESIS: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether a...... defect in the enteroinsular axis contributes to impaired insulin secretion in carriers of TCF7L2 polymorphisms. METHODS: We genotyped 1,110 non-diabetic German participants for five single nucleotide polymorphisms in TCF7L2. All participants underwent an OGTT; GLP-1 secretion was measured in 155...... arginine bolus. RESULTS: The OGTT data confirmed that variants in TCF7L2 are associated with reduced insulin secretion. In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 concentrations during the OGTT...

  4. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels

    Reddy, I A; Pino, J A; Weikop, P;

    2016-01-01

    Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine...... actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the...... ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the...

  5. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects

    Greenfield, Jerry R; Farooqi, I Sadaf; Keogh, Julia M;

    2008-01-01

    BACKGROUND: Incretin hormones, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in meal-related insulin secretion. We previously demonstrated that glutamine is a potent stimulus of GLP-1 secretion in vitro. OBJECTIVE: Our...... objective was to determine whether glutamine increases circulating GLP-1 and GIP concentrations in vivo and, if so, whether this is associated with an increase in plasma insulin. DESIGN: We recruited 8 healthy normal-weight volunteers (LEAN), 8 obese individuals with type 2 diabetes or impaired glucose...... tolerance (OB-DIAB) and 8 obese nondiabetic control subjects (OB-CON). Oral glucose (75 g), glutamine (30 g), and water were administered on 3 separate days in random order, and plasma concentrations of GLP-1, GIP, insulin, glucagon, and glucose were measured over 120 min. RESULTS: Oral glucose led to...

  6. An overview of once-weekly glucagon-like peptide-1 receptor agonists--available efficacy and safety data and perspectives for the future

    Madsbad, S; Kielgast, U; Asmar, M; Deacon, C F; Torekov, Signe Sørensen; Holst, J J

    2011-01-01

    daily. Several once-weekly GLP-1 receptor agonists are in phase 3 development. This review examines the efficacy, safety and perspective for the future of the once-weekly GLP-1 receptor agonists: exenatide once weekly, taspoglutide, albiglutide, LY2189265 and CJC-1134-PC, and compared them to the......-weekly GLP-1 receptor analogues are promising candidates for the treatment of type 2 diabetes, although their efficacy may not be superior to once-daily analogue liraglutide.......Incretin-based therapies, such as the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and orally administered dipeptidyl peptidase-4 (DPP-4) inhibitors, have recently been introduced into clinical practice. At present, the GLP-1 receptor agonists need to be administered once or twice...

  7. A pilot study examining the relationship among Crohn disease activity, glucagon-like peptide-2 signalling and intestinal function in pediatric patients

    Sigalet, David L; Kravarusic, Dragan; Butzner, Decker;

    2013-01-01

      BACKGROUND⁄/OBJECTIVES: The relationship between the enteroendocrine hormone glucagon-like peptide 2 (GLP-2) and intestinal inflammation is unclear. GLP-2 promotes mucosal growth, decreases permeability and reduces inflammation in the intestine; physiological stimulation of GLP-2 release...... of the small intestine) with a disease activity index >150. Fasting and postprandial GLP-2 levels and quantitative urinary recovery of orally administered 3-O-methyl-glucose (active transport) and lactulose⁄mannitol (passive) were quantified during the acute and remission phases. RESULTS: Seven patients (mean...... [± SD] age 15.3 ± 1.3 years) and 10 controls (10.3 ± 1.6 years) were studied. In patients with active disease, fasting levels of GLP-2 remained stable but postprandial levels were reduced. Patients with active disease exhibited reduced glucose absorption and increased lactulose⁄mannitol recovery; all...

  8. Exogenous glucagon-like peptide-2 (GLP-2) augments GLP-2 receptor mRNA and maintains proglucagon mRNA levels in resected rats

    Koopmann, Matthew C; Nelson, David W; Murali, Sangita G;

    2008-01-01

    BACKGROUND: Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent proglucagon-derived hormone that stimulates intestinal adaptive growth. Our aim was to determine whether exogenous GLP-2 increases resection-induced adaptation without diminishing endogenous proglucagon and GLP-2 receptor...... expression. METHODS: Rats underwent transection or 70% jejunoileal resection +/- GLP-2 infusion (100 microg/kg body weight/d) and were fed a semipurified diet with continuous infusion of GLP-2 or saline by means of jugular catheter. After 7 days, body weight, mucosal cellularity (dry mass, protein and DNA......), crypt-villus height, and crypt cell proliferation (by bromodeoxyuridine staining) were determined. Plasma bioactive GLP-2 (by radioimmunoassay), proglucagon and GLP-2 receptor mRNA expression (by Northern blot and real-time reverse transcriptase quantitative polymerase chain reaction) were measured. GLP...

  9. Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.

    Min He

    Full Text Available BACKGROUND: Glucagon-like peptide-1 (GLP-1 is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg for 12 weeks. Body weight, body mass index (BMI, food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various

  10. Deficiency of the intestinal growth factor, glucagon-like peptide 2, in the colon of SCID mice with inflammatory bowel disease induced by transplantation of CD4+ T cells

    Schmidt, P T; Hartmann, B; Bregenholt, S;

    2000-01-01

    Glucagon-like peptide 2 (GLP-2) is produced in endocrine L-cells of the intestinal mucosa. Recently, GLP-2 was found to stimulate intestinal mucosal growth. Our objective was to study the content of GLP-2 in the large intestine in a murine model of T-cell-induced inflammatory bowel disease....

  11. Role of glucagon-like peptide-1 analogue liraglutide played in the proliferation of CD4~+ CD25~- T cells in normal people and type 1 diabetic patients in vitro

    胡瑛

    2013-01-01

    Objective To study the role of glucagon-like peptide-1 (GLP-1) analogue liraglutide played in the proliferation of CD4+CD25-T cells in normal people and newly-onset type 1 diabetic patients,and to evaluate the possible immune regulatory role of liraglutide in the

  12. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure

    Halbirk, Mads; Nørrelund, Helene; Møller, Niels;

    2010-01-01

    )) and placebo infusion. At 0 and 48 h, LVEF, diastolic function, tissue Doppler regional myocardial function, exercise testing, noninvasive cardiac output, and brain natriuretic peptide (BNP) were measured. Blood pressure, heart rate, and metabolic parameters were recorded. Fifteen patients completed...

  13. The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes

    Zander, M; Madsbad, S; Deacon, C F;

    2006-01-01

    AIM/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) is metabolised by the enzyme dipeptidyl-peptidase 4 (DPP-4), generating a metabolite with potential antagonistic properties. This study was conducted to evaluate the effect of that metabolite on plasma glucose levels in patients with type 2 diabetes...... the metabolite increased from 1+/-3 (SAL) and 2+/-6 (IB) pmol/l to 42+/-4 (LSC), 64+/-8 (IV) and 327+/-16 (HSC) pmol/l, p<0.0001. Mean plasma glucose levels at 6 h decreased from 12.4+/-1.1 (SAL) mmol/l to 10.4+/-1.1 (LSC), 8.6+/-0.6 (IB), 8.8+/-0.8 (IV) and 9.1+/-0.9 (HSC) mmol/l, p<0....... MATERIALS AND METHODS: The randomised crossover study consisted of five regimens: (1) i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1); IV); (2 and 3) s.c. infusion of GLP-1 (2.4 and 9.6 pmol kg(-1) min(-1); LSC, HSC); (4) s.c. infusion of GLP-1 (2.4 pmol kg(-1) min(-1)) in combination with a DPP-4 inhibitor...

  14. Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway

    Jaye Deborah A

    2011-01-01

    Full Text Available Abstract Background Glucagon-like peptide-1 (GLP-1 is a hormone predominately synthesized and secreted by intestinal L-cells. GLP-1 modulates multiple cellular functions and its receptor agonists are now used clinically for diabetic treatment. Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors. As the effects of GLP-1 on myocyte electrophysiology are largely unknown, this study was to assess if GLP-1 could affect the cardiac voltage-gated L-type Ca2+ current (ICa. Methods The whole-cell patch clamp method was used to record ICa and action potentials in enzymatically isolated cardiomyocytes from adult canine left ventricles. Results Extracellular perfusion of GLP-1 (7-36 amide at 5 nM increased ICa by 23 ± 8% (p Ca; however, the increase in ICa was abolished if Exendin (9-39 was pre-applied 5 min prior to GLP-1 administration. Intracellular dialysis with a protein kinase A inhibitor also blocked the GLP-1-enhanced ICa. In addition, GLP-1 at 5 nM prolonged the durations of the action potentials by 128 ± 36 ms (p p Conclusions Our data demonstrate that GLP-1 enhances ICa in canine cardiomyocytes. The enhancement of ICa is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration.

  15. Chronic elevation of systemic glucagon-like peptide-1 following surgical weight loss: association with nausea and vomiting and effects on adipokines.

    Al-Rasheid, Noora; Gray, Rosaire; Sufi, Pratik; Marina-Gonzalez, Nephtali; Al-Sayrafi, Mohammed; Atherton, Elizabeth; Mohamed-Ali, Vidya

    2015-02-01

    We determined whether persistent nausea and vomiting (N/V) symptoms following Roux-en-Y gastric bypass surgery is due to elevated systemic glucagon-like peptide-1 (GLP-1) and leptin in female non-diabetic subjects. Subjects with N/V post-Roux-en-Y gastric bypass (RYGB) surgery had significantly elevated fasting GLP-1 levels compared to that with post-operative asymptomatic subjects and to morbidly obese, obese and lean subjects not undergoing surgery. Weight loss, glycaemia, insulin and post-prandial GLP-1 levels were similar in all post-operative subjects. Despite comparable BMI, leptin was significantly lower in symptomatic subjects. Furthermore, leptin secretion from subcutaneous adipose tissue was inhibited by GLP-1 (0.1-1.0 nM; n = 6). Persistent N/V following RYGB surgery is associated with elevated fasting GLP-1, but lower leptin levels. The latter may be a consequence of the direct GLP-1 inhibition of leptin secretion from adipose tissue. PMID:25411121

  16. L-glutamine and whole protein restore first-phase insulin response and increase glucagon-like Peptide-1 in type 2 diabetes patients

    Samocha-Bonet, Dorit; Chisholm, Don J; Holst, Jens Juul;

    2015-01-01

    l-glutamine triggers glucagon-like peptide-1 (GLP-1) release from L cells in vitro and when ingested pre-meal, decreases postprandial glycaemia and increases circulating insulin and GLP-1 in type 2 diabetes (T2D) patients. We aimed to evaluate the effect of oral l-glutamine, compared with whole...... protein low in glutamine, on insulin response in well-controlled T2D patients. In a randomized study with a crossover design, T2D patients (n = 10, 6 men) aged 65.1 ± 5.8, with glycosylated hemoglobin (HbA1c) 6.6% ± 0.7% (48 ± 8 mmol/mol), received oral l-glutamine (25 g), protein (25 g) or water...... tested 1–2 weeks apart. Both l-glutamine and protein increased first-phase insulin response (p ≤ 0.02). Protein (p = 0.05), but not l-glutamine (p = 0.2), increased second-phase insulin response. Total GLP-1 was increased by both l-glutamine and protein (p ≤ 0.02). We conclude that oral l-glutamine and...

  17. Efficacy and Acceptability of Glycemic Control of Glucagon-Like Peptide-1 Receptor Agonists among Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

    Li, Zhixia; Zhang, Yuan; Quan, Xiaochi; Yang, Zhirong; Zeng, Xiantao; Ji, Linong

    2016-01-01

    Objective To synthesize current evidence of the impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on hypoglycemia, treatment discontinuation and glycemic level in patients with type 2 diabetes. Design Systematic review and network meta-analysis. Data Sources Literature search (Medline, Embase, the Cochrane library), website of clinical trial, bibliographies of published systematic reviews. Eligibility Criteria Randomized controlled trials with available data comparing GLP-1 RAs with placebo or traditional anti-diabetic drugs in patients with type 2 diabetes. Data Synthesis Traditional pairwise meta-analyses within DerSimonian-Laird random effects model and network meta-analysis within a Bayesian framework were performed to calculate odds ratios for the incidence of hypoglycemia, treatment discontinuation, HbA1ceffect when compared with sitagliptin (HbA1ceffect on hypoglycemia; sulphanylureas, sitagliptin and insulin decrease the incidence of treatment discontinuation most; exe_lar and dulaglutide had the highest impact on glycemic level among 13 treatments. Conclusions Among 13 treatments, GLP-1 RAs had a significant reduction with glycemic level but a slight increase effect on hypoglycemia and treatment discontinuation. While albiglutide had the best decrease effect on hypoglycemia and treatment discontinuation among all GLP-1 RAs. However, further evidence is necessary for more conclusive inferences on mechanisms underlying the rise in hypoglycemia. PMID:27158818

  18. Progress in the biology of glucagon-like peptide 2%GLP-2的生物学作用的研究进展

    吴云红; 朱亮; 邹原

    2009-01-01

    胰高血糖素样肽-2(glucagon-like peptide-2,GLP-2)是胰高血糖素原基因转录、翻译后处理加工的33个氨基酸的多肽.GLP-2是新近发现的肠上皮特异性生长因子,对胃肠道有多方面的作用,包括促进正常小肠的生长和发育,保护和修复各种肠道疾病中损伤的肠粘膜,抑制胃酸的分泌和胃肠的运动,增加肠道的血液供应等.GLP-2通过作用于特异性G蛋白偶联受体(GLP-2受体)来保护肠道细胞.该文全面概括了GLP-2的生理、药理、治疗作用和GLP-2受体信号转导机制,重点讨论了GLP-2最新的研究进展.

  19. Therapeutic Effect of Exendin-4, a Long-Acting Analogue of Glucagon-Like Peptide-1 Receptor Agonist, on Nerve Regeneration after the Crush Nerve Injury

    Koji Yamamoto

    2013-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is glucose-dependent insulinotropic hormone secreted from enteroendocrine L cells. Its long-acting analogue, exendin-4, is equipotent to GLP-1 and is used to treat type 2 diabetes mellitus. In addition, exendin-4 has effects on the central and peripheral nervous system. In this study, we administered repeated intraperitoneal (i.p. injections of exendin-4 to examine whether exendin-4 is able to facilitate the recovery after the crush nerve injury. Exendin-4 injection was started immediately after crush injury and was repeated every day for subsequent 14 days. Rats subjected to sciatic nerve crush exhibited marked functional loss, electrophysiological dysfunction, and atrophy of the tibialis anterior muscle (TA. All these changes, except for the atrophy of TA, were improved significantly by the administration of exendin-4. Functional, electrophysiological, and morphological parameters indicated significant enhancement of nerve regeneration 4 weeks after nerve crush. These results suggest that exendin-4 is feasible for clinical application to treat peripheral nerve injury.

  20. Glucagon-Like Peptide-1 Secreting Cell Function as well as Production of Inflammatory Reactive Oxygen Species Is Differently Regulated by Glycated Serum and High Levels of Glucose

    Alessandra Puddu

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1, an intestinal hormone contributing to glucose homeostasis, is synthesized by proglucagon and secreted from intestinal neuroendocrine cells in response to nutrients. GLP-1 secretion is impaired in type 2 diabetes patients. Here, we aimed at investigating whether diabetic toxic products (glycated serum (GS or high levels of glucose (HG may affect viability, function, and insulin sensitivity of the GLP-1 secreting cell line GLUTag. Cells were cultured for 5 days in presence or absence of different dilutions of GS or HG. GS and HG (alone or in combination increased reactive oxygen species (ROS production and upregulated proglucagon mRNA expression as compared to control medium. Only HG increased total production and release of active GLP-1, while GS alone abrogated secretion of active GLP-1. HG-mediated effects were associated with the increased cell content of the prohormone convertase 1/3 (PC 1/3, while GS alone downregulated this enzyme. HG upregulated Glucokinase (GK and downregulated SYNTHAXIN-1. GS abrogated SYNTHAXIN-1 and SNAP-25. Finally, high doses of GS alone or in combination with HG reduced insulin-mediated IRS-1 phosphorylation. In conclusion, we showed that GS and HG might regulate different pathways of GLP-1 production in diabetes, directly altering the function of neuroendocrine cells secreting this hormone.

  1. 胰高血糖素样肽-2研究的新进展%Present status of research on glucagon-like peptide 2

    吴云红; 朱亮; 邹原; 宫德正

    2010-01-01

    胰高血糖素样肽-2(glucagon-like peptide-2,GLP-2)是胰高血糖素原基因转录、翻译后处理加工的33氨基酸的多肽,GLP-2经二酰肽酶Ⅳ水解后,则失去生物学活性.GLP-2作为一种肠上皮特异性生长因子,能促进正常肠黏膜的生长及损伤肠上皮的修复.GLP-2通过作用于GLP-2受体(GLP-2R)来发挥生物学作用.GLP-2R在肠道的广泛分布(肠上皮细胞、肠内在神经元、肠内分泌细胞、肠黏膜下的肌纤维母细胞),提示GLP-2可能通过直接、间接等多条途径发挥生物学作用.本文概括介绍GLP-2的特性、生理作用及机制等方面的研究进展.

  2. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients

    Vilsbøll, Tina; Krarup, T; Deacon, Carolyn F.; Madsbad, S; Holst, Jens Møller

    2001-01-01

    -like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), we measured plasma concentrations after a mixed breakfast meal (566 kcal) in 12 type 2 diabetic patients (age 57 years [range 49-67], BMI 31 kg/m2 [27-38], and HbA1c 9.2% [7.0-12.5]) and 12 matched healthy subjects. The patients had...

  3. Different domains of the glucagon and glucagon-like peptide-1 receptors provide the critical determinants of ligand selectivity

    Runge, S; Wulff, B S; Madsen, K;

    2003-01-01

    domain with the GLP-1 receptor core domain (chimera A) completely rescued the affinity and potency of GLP-1(7-20)/glucagon(15-29) without compromising the affinity and potency of glucagon. Substituting transmembrane segment 1 (TM1), TM6, TM7, the third extracellular loop and the intracellular carboxy......-terminus of chimera A with the corresponding glucagon receptor segments re-established the ability to distinguish GLP-1(7-20)/glucagon(15-29) from glucagon. Corroborant results were obtained with the opposite chimeric peptide glucagon(1-14)/GLP-1(21-37). (3) The results suggest that the glucagon and GLP-1...

  4. Modulation of Glucagon-like Peptide-1 (GLP-1) Potency by Endocannabinoid-like Lipids Represents a Novel Mode of Regulating GLP-1 Receptor Signaling.

    Cheng, Yu-Hong; Ho, Mei-Shang; Huang, Wei-Ting; Chou, Ying-Ting; King, Klim

    2015-06-01

    Glucagon-like peptide-1 (GLP-1) analogs are approved for treatment of type 2 diabetes and are in clinical trials for disorders including neurodegenerative diseases. GLP-1 receptor (GLP-1R) is expressed in many peripheral and neuronal tissues and is activated by circulating GLP-1. Other than food intake, little is known about factors regulating GLP-1 secretion. Given a normally basal circulating level of GLP-1, knowledge of mechanisms regulating GLP-1R signaling, which has diverse functions in extrapancreatic tissues, remains elusive. In this study, we found that the potency of GLP-1, not exendin 4, is specifically enhanced by the endocannabinoid-like lipids oleoylethanolamide (OEA) and 2-oleoylglycerol but not by stearoylethanolamide (SEA) or palmitoylethanolamide. 9.2 μM OEA enhances the potency of GLP-1 in stimulating cAMP production by 10-fold but does not affect its receptor binding affinity. OEA and 2-oleoylglycerol, but not SEA, bind to GLP-1 in a dose-dependent and saturable manner. OEA but not SEA promoted GLP-1(7-36) amide to trypsin inactivation in a dose-dependent and saturable manner. Susceptibility of GLP-1(7-36) amide to trypsin inactivation is increased 40-fold upon binding to OEA but not to SEA. Our findings indicate that OEA binds to GLP-1(7-36) amide and enhances the potency that may result from a conformational change of the peptide. In conclusion, modulating potency of GLP-1 by physiologically regulated endocannabinoid-like lipids allows GLP-1R signaling to be regulated spatiotemporally at a constant basal GLP-1 level. PMID:25903129

  5. Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study

    Madsen, K B; Askov-Hansen, C; Naimi, R M;

    2013-01-01

    The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this s...... study evaluated the acute effects of continuous intravenous administration of glucagon-like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients....

  6. Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro.

    Swedberg, Joakim E; Schroeder, Christina I; Mitchell, Justin M; Fairlie, David P; Edmonds, David J; Griffith, David A; Ruggeri, Roger B; Derksen, David R; Loria, Paula M; Price, David A; Liras, Spiros; Craik, David J

    2016-07-22

    Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide α-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe(22) into a hydrophobic pocket on the GLP-1R. PMID:27226591

  7. Glucagon-Like Peptide-2 Requires a Full Complement of Bmi-1 for Its Proliferative Effects in the Murine Small Intestine.

    Smither, Bradley R; Pang, Hilary Y M; Brubaker, Patricia L

    2016-07-01

    The intestinal hormone, glucagon-like peptide-2 (GLP-2), stimulates growth, survival, and function of the intestinal epithelium through increased crypt cell proliferation, and a long-acting analog has recently been approved to enhance intestinal capacity in patients with short bowel syndrome. The goal of the present study was to determine whether GLP-2-induced crypt cell proliferation requires a full complement of B-cell lymphoma Moloney murine leukemia virus insertion region-1 homolog (Bmi-1), using the Bmi-1(eGFP/+) mouse model in comparison with age- and sex-matched Bmi-1(+/+) littermates. Bmi-1 is a member of the polycomb-repressive complex family that promotes stem cell proliferation and self-renewal and is expressed by both stem cells and transit-amplifying (TA) cells in the crypt. The acute (6 h) and chronic (11 d) proliferative responses to long-acting human (Gly(2))GLP-2 in the crypt TA zone, but not in the active or reserve stem cell zones, were both impaired by Bmi-1 haploinsufficiency. Similarly, GLP-2-induced crypt regeneration after 10-Gy irradiation was reduced in the Bmi-1(eGFP/+) animals. Despite these findings, chronic GLP-2 treatment enhanced overall intestinal growth in the Bmi-1(eGFP/+) mice, as demonstrated by increases in small intestinal weight per body weight and in the length of the crypt-villus axis, in association with decreased apoptosis and an adaptive increase in crypt epithelial cell migration rate. The results of these studies therefore demonstrate that a full complement of Bmi-1 is required for the intestinal proliferative effects of GLP-2 in both the physiological and pathological setting, and mediates, at least in part, the proliferation kinetics of cells in the TA zone. PMID:27187177

  8. Teduglutide, a glucagon-like peptide 2 analogue: a novel protective agent with anti-apoptotic and anti-oxidant properties in mice with lung injury.

    Arda-Pirincci, Pelin; Oztay, Fusun; Bayrak, Bertan Boran; Yanardag, Refiye; Bolkent, Sehnaz

    2012-12-01

    Teduglutide is a long-acting synthetic analogue of human glucagon-like peptide-2 (GLP-2). GLP-2 regulates cell proliferation and apoptosis as well as normal physiology in the gastrointestinal tract. In the present study, possible cytoprotective and reparative effects of teduglutide were analyzed on a mouse model with lung injury induced by tumor necrosis factor-alpha (TNF-α) and actinomycin D (Act D). BALB/c mice were divided into six groups: control mice (I), mice injected intraperitoneally with 15 μg/kg TNF-α (II), 800 μg/kg Act D (III), Act D 2 min prior to TNF-α administration with the same doses (IV), mice injected subcutaneously with 200 μg/kg teduglutide every 12h for 10 consecutive days (V), and mice given Act D 2 min prior to TNF-α administration on day 11 after receiving teduglutide for 10 days (VI). The TNF-α/Act D administration made the lung a sensitive organ to damage. Mice lung subjected to TNF-α/Act D were characterized by the disruption of alveolar wall, induced pulmonary endothelial/epithelial cell apoptosis and expression of active caspase-3. These mice exhibited an increase in lipid peroxidation, glutathione levels, and activities of myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase, as well as reduced tissue factor and sodium-potassium/ATPase activities. Teduglutide pretreatment regressed the structural damage, cell apoptosis and oxidative stress by reducing lipid peroxidation in mice received TNF-α/Act D. GLP-2 receptors were present on the cell membrane of type II pneumocytes and interstitial cells. Thus, teduglutide can be suggested as a novel protective agent, which possesses anti-apoptotic and anti-oxidant properties, against lung injury. PMID:23059393

  9. Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administrations in healthy subjects.

    Marier, Jean-Francois; Beliveau, Martin; Mouksassi, Mohamad-Samer; Shaw, Paula; Cyran, Jane; Kesavan, Jothi; Wallens, John; Zahir, Hamim; Wells, David; Caminis, John

    2008-11-01

    Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50-mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies. PMID:18974283

  10. Establishment of a Refined Oral Glucose Tolerance Test in Pigs, and Assessment of Insulin, Glucagon and Glucagon-Like Peptide-1 Responses.

    Elin Manell

    Full Text Available Diabetes mellitus is increasing worldwide and reliable animal models are important for progression of the research field. The pig is a commonly used large animal model in diabetes research and the present study aimed to refine a model for oral glucose tolerance test (OGTT in young growing pigs, as well as describing intravenous glucose tolerance test (IVGTT in the same age group. The refined porcine OGTT will reflect that used in children and adolescents. Eighteen pigs were obtained one week after weaning and trained for two weeks to bottle-feed glucose solution, mimicking the human OGTT. The pigs subsequently underwent OGTT (1.75 g/kg BW and IVGTT (0.5 g/kg BW. Blood samples were collected from indwelling vein catheters for measurements of glucose and the diabetes related hormones insulin, glucagon and active glucagon-like peptide-1. The study confirmed that pigs can be trained to bottle-feed glucose dissolved in water and thereby undergo an OGTT more similar to the human standard OGTT than previously described methods in pigs. With the refined method for OGTT, oral intake only consists of glucose and water, which is an advantage over previously described methods in pigs where glucose is given together with feed which will affect glucose absorption. Patterns of hormonal secretion in response to oral and intravenous glucose were similar to those in humans; however, the pigs were more glucose tolerant with lower insulin levels than humans. In translational medicine, this refined OGTT and IVGTT methods provide important tools in diabetes research when pigs are used as models for children and adolescents in diabetes research.

  11. Establishment of a Refined Oral Glucose Tolerance Test in Pigs, and Assessment of Insulin, Glucagon and Glucagon-Like Peptide-1 Responses.

    Manell, Elin; Hedenqvist, Patricia; Svensson, Anna; Jensen-Waern, Marianne

    2016-01-01

    Diabetes mellitus is increasing worldwide and reliable animal models are important for progression of the research field. The pig is a commonly used large animal model in diabetes research and the present study aimed to refine a model for oral glucose tolerance test (OGTT) in young growing pigs, as well as describing intravenous glucose tolerance test (IVGTT) in the same age group. The refined porcine OGTT will reflect that used in children and adolescents. Eighteen pigs were obtained one week after weaning and trained for two weeks to bottle-feed glucose solution, mimicking the human OGTT. The pigs subsequently underwent OGTT (1.75 g/kg BW) and IVGTT (0.5 g/kg BW). Blood samples were collected from indwelling vein catheters for measurements of glucose and the diabetes related hormones insulin, glucagon and active glucagon-like peptide-1. The study confirmed that pigs can be trained to bottle-feed glucose dissolved in water and thereby undergo an OGTT more similar to the human standard OGTT than previously described methods in pigs. With the refined method for OGTT, oral intake only consists of glucose and water, which is an advantage over previously described methods in pigs where glucose is given together with feed which will affect glucose absorption. Patterns of hormonal secretion in response to oral and intravenous glucose were similar to those in humans; however, the pigs were more glucose tolerant with lower insulin levels than humans. In translational medicine, this refined OGTT and IVGTT methods provide important tools in diabetes research when pigs are used as models for children and adolescents in diabetes research. PMID:26859145

  12. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.

    Reddy, I A; Pino, J A; Weikop, P; Osses, N; Sørensen, G; Bering, T; Valle, C; Bluett, R J; Erreger, K; Wortwein, G; Reyes, J G; Graham, D; Stanwood, G D; Hackett, T A; Patel, S; Fink-Jensen, A; Torres, G E; Galli, A

    2016-01-01

    Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA. PMID:27187231

  13. Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats

    Accumulating evidences have showed that gatifloxacin causes dysglycemia in both diabetic and non-diabetic patients. Our preliminary study demonstrated that gatifloxacin stimulated glucagon-like peptide 1 (GLP-1) secretion from intestinal cells. The aim of the study was to investigate the association between gatifloxacin-stimulated GLP-1 release and dysglycemia in both normal and streptozotocin-induced diabetic rats and explore the possible mechanisms. Oral administration of gatifloxacin (100 mg/kg/day and 200 mg/kg/day) for 3 and 12 days led to marked elevation of GLP-1 levels, accompanied by significant decrease in insulin levels and increase in plasma glucose. Similar results were found in normal rats treated with 3-day gatifloxacin. Gatifloxacin-stimulated GLP-1 release was further confirmed in NCI-H716 cells, which was abolished by diazoxide, a KATP channel opener. QT-PCR analysis showed that gatifloxacin also upregulated expression of proglucagon and prohormone convertase 3 mRNA. To clarify the contradiction on elevated GLP-1 without insulinotropic effect, effects of GLP-1 and gatifloxacin on insulin release were investigated using INS-1 cells. We found that short exposure (2 h) to GLP-1 stimulated insulin secretion and biosynthesis, whereas long exposure (24 h and 48 h) to high level of GLP-1 inhibited insulin secretion and biosynthesis. Moreover, we also confirmed gatifloxacin acutely stimulated insulin secretion while chronically inhibited insulin biosynthesis. All the results gave an inference that gatifloxacin stimulated over-secretion of GLP-1, in turn, high levels of GLP-1 and gatifloxacin synergistically impaired insulin release, worsening hyperglycemia. -- Highlights: ► Gatifloxacin induced hyperglycemia both in diabetic rats and normal rats. ► Gatifloxacin enhanced GLP-1 secretion but inhibited insulin secretion in rats. ► Long-term exposure to high GLP-1 inhibited insulin secretion and biosynthesis. ► GLP-1 over-secretion may be involved in

  14. Neonatal intramuscular injection of plasmid encoding glucagon-like peptide-1 affects anxiety behaviour and expression of the hippocampal glucocorticoid receptor in adolescent rats

    Huitao Fan; Lina Wang; Feng Guo; Shi Wei; Ruqian Zhao

    2010-03-01

    Early-life endocrine intervention may programme hippocampal glucocorticoid receptor (GR) expression and cause psychiatric disorders in later life. Glucagon-like peptide-1 (GLP-1) has been implicated in the regulation of neuroendocrine and behavioural responses, but it is yet to be determined whether and how neonatal GLP-1 overexpression may modify hippocampal GR expression and thus programme adolescent behaviour in rats. Two-dayold pups were injected intramuscularly with vacant plasmid (VP) or plasmid DNA encoding secretory GLP-1 (GP). Anxiety-related behaviour was assessed in the elevated plus maze (EPM) test at 8 weeks of age. Plasma corticosterone levels were measured with enzyme immunoassay (EIA). Protein and mRNA levels were determined by western blot and real-time polymerase chain reaction (PCR), respectively. The DNA methylation status of the GR exon 17 promoter was determined by bisulphate sequencing PCR (BSP). GP rats exhibited anxiolytic behaviour compared with their VP counterparts. Hippocampal GLP-1 receptor (GLP-1R) and GR mRNA expression were significantly elevated in GP rats without a significant difference in plasma corticosterone. Significant reduction in DNA methyltransferase 1 (DNMT1) expression was observed in GP rats disconnected with alterations in DNA methylation of the GR exon 17 promoter. Nevertheless, mRNA expression of nerve growth factor-inducible protein A (NGFI-A) was significantly elevated in GP rats. These results suggest that neonatal intramuscular injection of plasmid DNA encoding GLP-1 affects anxiety behaviour in adolescent rats, probably through NGFI-A-activated upregulation of hippocampal GR expression.

  15. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    Puddu, A., E-mail: alep100@hotmail.com [University of Genova, Department of Internal Medicine and Medical Specialties, Viale Benedetto XV, 16132 Genova (Italy); Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L. [University of Genova, Department of Internal Medicine and Medical Specialties, Viale Benedetto XV, 16132 Genova (Italy)

    2010-07-30

    Research highlights: {yields} GLP-1 prevents AGEs-induced cell death. {yields} GLP-1 prevents AGEs-induced oxidative stress. {yields} GLP-1 ameliorated AGEs-induced cell dysfunction. {yields} GLP-1 attenuates AGEs-induced RAGE increment. {yields} GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  16. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    Research highlights: → GLP-1 prevents AGEs-induced cell death. → GLP-1 prevents AGEs-induced oxidative stress. → GLP-1 ameliorated AGEs-induced cell dysfunction. → GLP-1 attenuates AGEs-induced RAGE increment. → GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  17. Mosapride citrate, a 5-HT₄ receptor agonist, increased the plasma active and total glucagon-like peptide-1 levels in non-diabetic men.

    Aoki, Kazutaka; Kamiyama, Hiroshi; Masuda, Kiyomi; Togashi, Yu; Terauchi, Yasuo

    2013-01-01

    Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion. PMID:23257734

  18. Short Bowel Patients Treated for Two Years with Glucagon-Like Peptide 2 (GLP-2: Compliance, Safety, and Effects on Quality of Life

    P. B. Jeppesen

    2009-01-01

    Full Text Available Background and aims. Glucagon-like peptide 2 (GLP-2 has been shown to improve intestinal absorption in short bowel syndrome (SBS patients in a short-term study. This study describes safety, compliance, and changes in quality of life in 11 SBS patients at baseline, week 13, 26, and 52 during two years of subcutaneous GLP-2 treatment, 400 microgram TID, intermitted by an 8-week washout period. Methods. Safety and compliance was evaluated during the admissions. The Sickness Impact Profile (SIP, Short Form 36 (SF 36, and Inflammatory Bowel Disease Questionnaire (IBDQ evaluated quality of life. Results. The predominant adverse event was transient abdominal discomfort in 5 of 11 patients, but in 2, both suffering from Crohns disease, it progressed to abdominal pain and led to discontinuation of GLP-2 treatment. One had a fibrostenotic lesion electively resected at the jejuno-ascendo-anastomosis. The investigator excluded a patient due to unreliable feedback. Stoma nipple enlargement was seen in all 9 jejunostomy patients. Reported GLP-2 compliance was excellent (>93%. GLP-2 improved the overall quality of life VAS-score (4.1±2.8 cm versus 6.0±2.4 cm, P<.01, the overall SIP score (10.3±8.9% versus 6.2±9.5%, P<.001, the mental component of the SF-36 (45±13% versus 53±11%, P<.05, and the overall IBDQ score (5.1±0.9 versus 5.4±0.9, P<.007 in the 8 patients completing the study. Conclusions. Long-term treatment with GLP-2 is feasible in SBS patients, although caution must be exercised in patients with a history of abdominal pain. Although conclusions cannot be made in a noncontrolled trial, the high reported compliance might reflect a high treatment satisfaction, where the clinical benefits of GLP-2 may outweigh the discomforts of injections.

  19. In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

    Araújo, F.; Shrestha, N.; Gomes, M. J.; Herranz-Blanco, B.; Liu, D.; Hirvonen, J. J.; Granja, P. L.; Santos, H. A.; Sarmento, B.

    2016-05-01

    Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.

  20. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD. PMID:27233809

  1. High-Fat Diet and Palmitate Alter the Rhythmic Secretion of Glucagon-Like Peptide-1 by the Rodent L-cell.

    Gil-Lozano, Manuel; Wu, W Kelly; Martchenko, Alexandre; Brubaker, Patricia L

    2016-02-01

    Secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), by the intestinal L-cell is rhythmically regulated by an independent molecular clock. However, the impact of factors known to affect the activity of similar cell-autonomous clocks, such as circulating glucocorticoids and high-fat feeding, on GLP-1 secretory patterns remains to be elucidated. Herein the role of the endogenous corticosterone rhythm on the pattern of GLP-1 and insulin nutrient-induced responses was examined in corticosterone pellet-implanted rats. Moreover, the impact of nutrient excess on the time-dependent secretion of both hormones was assessed in rats fed a high-fat, high-sucrose diet. Finally, the effects of the saturated fatty acid, palmitate, on the L-cell molecular clock and GLP-1 secretion were investigated in vitro using murine GLUTag L-cells. Diurnal variations in GLP-1 and insulin nutrient-induced responses were maintained in animals lacking an endogenous corticosterone rhythm, suggesting that glucocorticoids are not the predominant entrainment factor for L-cell rhythmic activity. In addition to hyperglycemia, hyperinsulinemia, insulin resistance, and disorganization of feeding behavior, high-fat high-sucrose-fed rats showed a total abrogation of the diurnal variation in GLP-1 and insulin nutrient-induced responses, with comparable levels of both hormones at the normal peak (5:00 pm) and trough (5:00 am) of their daily pattern. Finally, palmitate incubation induced profound derangements in the rhythmic expression of circadian oscillators in GLUTag L-cells and severely impaired the secretory activity of these cells. Collectively our findings demonstrate that obesogenic diets disrupt the rhythmic activity of the L-cell, partially through a direct effect of specific nutritional components. PMID:26646204

  2. Evaluating preferences for profiles of glucagon-like peptide-1 receptor agonists among injection-naive type 2 diabetes patients in Japan

    Gelhorn, Heather L; Bacci, Elizabeth D; Poon, Jiat Ling; Boye, Kristina S; Suzuki, Shuichi; Babineaux, Steven M

    2016-01-01

    Objective The objective of this study was to use a discrete choice experiment (DCE) to estimate patients’ preferences for the treatment features, safety, and efficacy of two specific glucagon-like peptide-1 receptor agonists, dulaglutide and liraglutide, among patients with type 2 diabetes mellitus (T2DM) in Japan. Methods In Japan, patients with self-reported T2DM and naive to treatment with self-injectable medications were administered a DCE through an in-person interview. The DCE examined the following six attributes of T2DM treatment, each described by two levels: “dosing frequency”, “hemoglobin A1c change”, “weight change”, “type of delivery system”, “frequency of nausea”, and “frequency of hypoglycemia”. Part-worth utilities were estimated using logit models and were used to calculate the relative importance (RI) of each attribute. A chi-square test was used to determine the differences in preferences for the dulaglutide versus liraglutide profiles. Results The final evaluable sample consisted of 182 participants (mean age: 58.9 [standard deviation =10.0] years; 64.3% male; mean body mass index: 26.1 [standard deviation =5.0] kg/m2). The RI values for the attributes in rank order were dosing frequency (44.1%), type of delivery system (26.3%), frequency of nausea (15.1%), frequency of hypoglycemia (7.4%), weight change (6.2%), and hemoglobin A1c change (1.0%). Significantly more participants preferred the dulaglutide profile (94.5%) compared to the liraglutide profile (5.5%; P70% of the RI. These findings are similar to those of a previous UK study, providing information about patients’ preferences that may be informative for patient–clinician treatment discussions. PMID:27524889

  3. Intracerebroventricular injection of encapsulated human mesenchymal cells producing glucagon-like peptide 1 prolongs survival in a mouse model of ALS.

    Sarah Knippenberg

    Full Text Available BACKGROUND: As pharmacological therapies have largely failed so far, stem cell therapy has recently come into the focus of ALS research. Neuroprotective potential was shown for several types of stem and progenitor cells, mainly due to release of trophic factors. In the present study, we assessed the effects of intracerebroventricular injection of glucagon-like peptide 1 (GLP-1 releasing mesenchymal stromal cells (MSC in mutant SOD1 (G93A transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: To improve the neuroprotective effects of native MSC, they had been transfected with a plasmid vector encoding a GLP-1 fusion gene prior to the injection, as GLP-1 was shown to exhibit neuroprotective properties before. Cells were encapsulated and therefore protected against rejection. After intracerebroventricular injection of these GLP-1 MSC capsules in presymptomatic SOD1 (G93A mice, we assessed possible protective effects by survival analysis, measurement of body weight, daily monitoring and evaluation of motor performance by rotarod and footprint analyses. Motor neuron numbers in the spinal cord as well as the amount of astrocytosis, microglial activation, heat shock response and neuronal nitric oxide synthase (nNOS expression were analyzed by immunohistological methods. Treatment with GLP-1 producing MSC capsules significantly prolonged survival by 13 days, delayed symptom onset by 15 days and weight loss by 14 days and led to significant improvements in motor performance tests compared to vehicle treated controls. Histological data are mainly in favour of anti-inflammatory effects of GLP-1 producing MSC capsules with reduced detection of inflammatory markers and a significant heat shock protein increase. CONCLUSION/SIGNIFICANCE: Intracerebroventricular injection of GLP-1 MSC capsules shows neuroprotective potential in the SOD1 (G93A mouse model.

  4. Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease

    Masuda Takashi

    2010-05-01

    Full Text Available Abstract Background Glucagon-like peptide-1 (GLP-1 is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility. Metabolic syndrome (MetS is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4 inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP. In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown. Methods To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60 and pre-MetS (n = 37. Results Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P Conclusion Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

  5. Glucagon-like peptide-1

    Holst, Jens Juul

    2006-01-01

    GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA(1)c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight...... loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA(1)c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed...

  6. Effects of Green Tea Extract on Insulin Resistance and Glucagon-Like Peptide 1 in Patients with Type 2 Diabetes and Lipid Abnormalities: A Randomized, Double-Blinded, and Placebo-Controlled Trial

    Liu, Chia-Yu; Huang, Chien-Jung; Huang, Lin-Huang; Chen, I-Ju; Chiu, Jung-Peng; Hsu, Chung-Hua

    2014-01-01

    The aim of this study is to investigate the effect of green tea extract on patients with type 2 diabetes mellitus and lipid abnormalities on glycemic and lipid profiles, and hormone peptides by a double-blinded, randomized and placebo-controlled clinical trial. This trial enrolled 92 subjects with type 2 diabetes mellitus and lipid abnormalities randomized into 2 arms, each arm comprising 46 participants. Of the participants, 39 in therapeutic arm took 500 mg green tea extract, three times a day, while 38 in control arm took cellulose with the same dose and frequency to complete the 16-week study. Anthropometrics measurements, glycemic and lipid profiles, safety parameters, and obesity-related hormone peptides were analyzed at screening and after 16-week course. Within-group comparisons showed that green tea extract caused a significant decrease in triglyceride and homeostasis model assessment of insulin resistance index after 16 weeks. Green tea extract also increased significantly high density lipoprotein cholesterol. The HOMA-IR index decreased from 5.4±3.9 to 3.5±2.0 in therapeutic arm only. Adiponectin, apolipoprotein A1, and apolipoprotein B100 increased significantly in both arms, but only glucagon-like peptide 1 increased in the therapeutic arm. However, only decreasing trend in triglyceride was found in between-group comparison. Our study suggested that green tea extract significantly improved insulin resistance and increased glucagon-like peptide 1 only in within-group comparison. The potential effects of green tea extract on insulin resistance and glucagon-like peptide 1 warrant further investigation. Trial Registration ClinicalTrials.gov NCT01360567 PMID:24614112

  7. Effects of green tea extract on insulin resistance and glucagon-like peptide 1 in patients with type 2 diabetes and lipid abnormalities: a randomized, double-blinded, and placebo-controlled trial.

    Chia-Yu Liu

    Full Text Available The aim of this study is to investigate the effect of green tea extract on patients with type 2 diabetes mellitus and lipid abnormalities on glycemic and lipid profiles, and hormone peptides by a double-blinded, randomized and placebo-controlled clinical trial. This trial enrolled 92 subjects with type 2 diabetes mellitus and lipid abnormalities randomized into 2 arms, each arm comprising 46 participants. Of the participants, 39 in therapeutic arm took 500 mg green tea extract, three times a day, while 38 in control arm took cellulose with the same dose and frequency to complete the 16-week study. Anthropometrics measurements, glycemic and lipid profiles, safety parameters, and obesity-related hormone peptides were analyzed at screening and after 16-week course. Within-group comparisons showed that green tea extract caused a significant decrease in triglyceride and homeostasis model assessment of insulin resistance index after 16 weeks. Green tea extract also increased significantly high density lipoprotein cholesterol. The HOMA-IR index decreased from 5.4±3.9 to 3.5±2.0 in therapeutic arm only. Adiponectin, apolipoprotein A1, and apolipoprotein B100 increased significantly in both arms, but only glucagon-like peptide 1 increased in the therapeutic arm. However, only decreasing trend in triglyceride was found in between-group comparison. Our study suggested that green tea extract significantly improved insulin resistance and increased glucagon-like peptide 1 only in within-group comparison. The potential effects of green tea extract on insulin resistance and glucagon-like peptide 1 warrant further investigation.ClinicalTrials.gov NCT01360567.

  8. Quality of life in patients with short bowel syndrome treated with the new glucagon-like peptide-2 analogue teduglutide--analyses from a randomised, placebo-controlled study

    Jeppesen, P B; Pertkiewicz, M; Forbes, A; Pironi, L; Gabe, S M; Joly, F; Messing, B; Loth, S; Youssef, N N; Heinze, H; Berghöfer, P

    2013-01-01

    Short bowel syndrome (SBS)-intestinal failure (IF) patients have impaired quality of life (QoL) and suffer from the burden of malabsorption and parenteral support (PS). A phase III study demonstrated that treatment with teduglutide, a glucagon-like peptide 2 analogue, reduces PS volumes by 32......% while maintaining oral fluid intake constant; placebo-treated patients had reduced PS by 21%, but oral fluid intake increased accordingly. As effects of teduglutide on QoL are unknown, they were investigated here....

  9. A dose-equivalent comparison of the effects of continuous subcutaneous glucagon-like peptide 2 (GLP-2) infusions versus meal related GLP-2 injections in the treatment of short bowel syndrome (SBS) patients

    Naimi, R M; Madsen, K B; Askov-Hansen, C; Brandt, C F; Hartmann, B; Holst, Jens Juul; Mortensen, P B; Jeppesen, P B

    2013-01-01

    Glucagon-like peptide 2 (GLP-2), secreted endogenously from L-cells in the distal bowel in relation to meals, modulates intestinal absorption by adjusting gastric emptying and secretion and intestinal growth. Short bowel syndrome (SBS) patients with distal intestinal resections have attenuated...... endogenous GLP-2 secretion, which may contribute to their rapid gastric emptying, gastric hypersecretion and poor intestinal adaptation, whereas SBS patients with preserved terminal ileum and colon, who have a constantly elevated GLP-2 secretion, seem to do better in these respects. This study compared...

  10. Relationship between placental glucagon like peptide-1,glucagon like peptide-1 receptor levels and birth weight of neonates%胎盘胰高血糖素样肽-1、胰高血糖素样肽-1受体水平与新生儿出生体重的关系

    刘鑫; 王晶; 尚丽新; 李萍; 张文晶

    2011-01-01

    目的:探讨胎盘胰高血糖素样肽-1(GLP-1)、胰高血糖素样肽-1受体(GLP-1R)水平与新生儿出生体重的关系.方法:采用免疫组织化学SABC法检测30例分娩正常出生体重儿组(AGA组)、28例高出生体重儿组(LGA组)及28例低出生体重儿组(SGA组)胎盘组织中GLP-1、GLP-1R的表达水平.结果:①LGA组胎盘组织中GLP-1、GLP-IR的表达水平低于AGA组,差异有统计学意义(P<0.05).SGA组胎盘组织中GLP-1、GLP-IR的表达水平高于AGA组,差异有统计学意义(P<0.05).②胎盘组织中GLP-1、GLP-1R的表达水平与新生儿出生体重呈负相关(r=0.454,P<0.05;r=-0.512,P<0.05).结论:胎盘组织中GLP-1、GLP-1R表达水平的变化可能在新生儿出生体重的调节中起重要作用.%Objective: To explore the relationship between placental glucagon like peptide - 1 { GLP - 1) , glucagon like peplide - 1 receptor ( GLP - 1R) levels and birth weight of neonates. Methods: Immunohistochemjcal SABC method was used to detect the expression levels of GLP - 1 and GLP - 1R in appropriate for gestational age group ( AGA group, 30 neonates) , large for gestational age group ( LGA group, 28 neonates ) and small for gestational age group ( SGA group, 28 neonates) . Results: The expression levels of GLP - 1 and GLP - 1R in placental tissue in LGA group were significantly lower than those in AGA group ( P < 0. 05 ) . The expression levels of GLPI and GLP - IR in placental tissue in SGA group were significantly higher than those in AGA group ( P < 0. 05 ) . There was negative correlation between the expression levels of GLP - 1 and GLP - 1R in placental tissue and birth weight of neonates (y = - 0. 454, P < 0. 05 ; y = -0. 512, P <0. 05) . Conclusion: The changes of GLP - 1 and GLP- 1R expression levels in placental tissue may play important roles in regulation of neonatal birth weight.

  11. Glucagon-Like Peptide-1 (GLP-1) Response to Oral Glucose is Reduced in Pre-diabetes, Screen-detected Type 2 Diabetes and Obesity, and Influenced by Sex

    Færch, Kristine; Torekov, Signe S; Vistisen, Dorte;

    2015-01-01

    concentrations of glucose, insulin and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT, n=774), pre-diabetes (n=523) or screen-detected type 2 diabetes (n=163) who attended the Danish ADDITION-PRO study (n=1,462). Compared with individuals with......The role of glucose-stimulated release of glucagon-like peptide-1 (GLP-1) in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating...... glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and beta cell function, higher age and lower degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs...

  12. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

    Hoelmkjaer, Kirsten M.; Wewer Albrechtsen, Nicolai J.; Holst, Jens J.; Cronin, Anna M.; Nielsen, Dorte H.; Mandrup-Poulsen, Thomas; Bjornvad, Charlotte R.

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats. PMID:27136422

  13. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

    Højberg, P V; Vilsbøll, T; Rabøl, R;

    2008-01-01

    )). CONCLUSIONS: Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. CLINICALTRIALS.GOV ID NO.: NCT 00612950. FUNDING: This study was supported by The Novo Nordisk......OBJECTIVE: The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks......-peptide curve. RESULTS: Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0-10 min). The late phase C-peptide response (10-120 min) increased during GIP infusion from 33.0 +/- 8.5 to 103.9 +/- 24.2 (nmol/l) x (110 min)(-1...

  14. The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice.

    Emil Egecioglu

    Full Text Available The gastrointestinal peptide glucagon-like peptide 1 (GLP-1 is known to regulate consummatory behavior and is released in response to nutrient ingestion. Analogues of this peptide recently emerged as novel pharmacotherapies for treatment of type II diabetes since they reduce gastric emptying, glucagon secretion as well as enhance glucose-dependent insulin secretion. The findings that GLP-1 targets reward related areas including mesolimbic dopamine areas indicate that the physiological role of GLP-1 extends beyond food intake and glucose homeostasis control to include reward regulation. The present series of experiments was therefore designed to investigate the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4, on established nicotine-induced effects on the mesolimbic dopamine system in mice. Specifically, we show that treatment with Ex4, at a dose with no effect per se, attenuate nicotine-induced locomotor stimulation, accumbal dopamine release as well as the expression of conditioned place preference in mice. In accordance, Ex4 also blocks nicotine-induced expression of locomotor sensitization in mice. Given that development of nicotine addiction largely depends on the effects of nicotine on the mesolimbic dopamine system these findings indicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for nicotine cessations in humans.

  15. Intestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon-like peptide 1 and dipeptidyl peptidase 4.

    Vallon, Volker; Docherty, Neil G

    2014-09-01

    The tubular hypothesis of glomerular filtration and nephropathy in diabetes is a pathophysiological concept that assigns a critical role to the tubular system, including proximal tubular hyper-reabsorption and growth, which is relevant for early glomerular hyperfiltration and later chronic kidney disease. Here we focus on how harnessing the bioactivity of hormones released from the gut may ameliorate the early effects of diabetes on the kidney in part by attenuating proximal tubular hyper-reabsorption and growth. The endogenous tone of the glucagon-like peptide 1 (GLP-1)/GLP-1 receptor (GLP-1R) system and its pharmacological activation are nephroprotective in diabetes independent of changes in blood glucose. This is associated with suppression of increases in kidney weight and glomerular hyperfiltration, which may reflect, at least in part, its inhibitory effects on tubular hyper-reabsorption and growth. Inhibition of dipeptidyl peptidase 4 (DPP-4) is also nephroprotective independent of changes in blood glucose and involves GLP-1/GLP-1R-dependent and -independent mechanisms. The GLP-1R agonist exendin-4 induces natriuresis via activation of the GLP-1R. In contrast, DPP4 inhibition increases circulating GLP-1, but drives a GLP-1R-independent natriuretic response, implying a role for other DPP-4 substrates. The extent to which the intrarenal DPP-4/GLP-1 receptor system contributes to all these changes remains to be established, as does the direct impact of the system on renal inflammation. PMID:25085841

  16. Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling

    Gromada, J; Bokvist, K; Ding, W G; Holst, J J; Nielsen, Jens Høiriis; Rorsman, P

    1998-01-01

    The effect of glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide] on membrane potential, whole-cell ATP-sensitive potassium channel (K[ATP]) and Ca2+ currents, cytoplasmic Ca2+ concentration, and exocytosis was explored in single human beta-cells. GLP-1(7-36) amide induced membrane...... depolarization that was associated with inhibition of whole-cell K(ATP) current. In addition, GLP-1(7-36) amide (and forskolin) produced greater than fourfold potentiation of Ca2+-dependent exocytosis. The latter effect resulted in part (40%) from acceleration of Ca2+ influx through voltage-dependent (L-type) Ca......2+ channels. More importantly, GLP-1(7-36) amide (via generation of cyclic AMP and activation of protein kinase A) potentiated exocytosis at a site distal to a rise in the cytoplasmic Ca2+ concentration. Photorelease of caged cAMP produced a two- to threefold potentiation of exocytosis when the...

  17. Efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide added to insulin therapy in poorly regulated patients with type 1 diabetes-a protocol for a randomised, double-blind, placebo-controlled study

    Dejgaard, Thomas Fremming; Knop, Filip Krag; Tarnow, Lise;

    2015-01-01

    receptor agonist (GLP-1RA) therapy has proven effective in reducing weight gain and insulin dose. The present publication describes a protocol for a study evaluating the efficacy and safety of adding a GLP-1RA to insulin treatment in overweight patients with T1D in a randomised, double-blinded, controlled......INTRODUCTION: Intensive insulin therapy is recommended for the treatment of type 1 diabetes (T1D). Hypoglycaemia and weight gain are the common side effects of insulin treatment and may reduce compliance. In patients with insulin-treated type 2 diabetes, the addition of glucagon-like peptide-1...... design. METHODS AND ANALYSIS: In total, 100 patients with type 1 diabetes, poor glycaemic control (glycated haemoglobin (HbA1c) >8%) and overweight (body mass index >25 kg/m(2)) will be randomised to either liraglutide 1.8 mg once daily or placebo as an add-on to intensive insulin therapy in this...

  18. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers

    Nauck, Michael A; Heimesaat, Markus M; Behle, Kai; Holst, Jens Juul; Nauck, Markus S; Ritzel, Robert; Hüfner, Michael; Schmiegel, Wolff H

    2002-01-01

    neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of C-peptide kinetics). At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P...... other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses...... with normal oral glucose tolerance received infusions of regular insulin (1 mU x kg(-1) x min(-1)) over 360 min on two occasions in the fasting state. Capillary glucose concentrations were clamped at plateaus of 4.3, 3.7, 3.0, and 2.3 mmol/liter for 90 min each (stepwise hypoglycemic clamp); on one...

  19. Sardine protein diet increases plasma glucagon-like peptide-1 levels and prevents tissue oxidative stress in rats fed a high-fructose diet.

    Madani, Zohra; Sener, Abdullah; Malaisse, Willy J; Dalila, Ait Yahia

    2015-11-01

    The current study investigated whether sardine protein mitigates the adverse effects of fructose on plasma glucagon‑like peptide-1 (GLP-1) and oxidative stress in rats. Rats were fed casein (C) or sardine protein (S) with or without high‑fructose (HF) for 2 months. Plasma glucose, insulin, GLP‑1, lipid and protein oxidation and antioxidant enzymes were assayed. HF rats developed obesity, hyperglycemia, hyperinsulinemia, insulin resistance and oxidative stress despite reduced energy and food intakes. High plasma creatinine and uric acid levels, in addition to albuminuria were observed in the HF groups. The S‑HF diet reduced plasma glucose, insulin, creatinine, uric acid and homeostasis model assessment‑insulin resistance index levels, however increased GLP‑1 levels compared with the C‑HF diet. Hydroperoxides were reduced in the liver, kidney, heart and muscle of S‑HF fed rats compared with C‑HF fed rats. A reduction in liver, kidney and heart carbonyls was observed in S‑HF fed rats compared with C‑HF fed rats. Reduced levels of nitric oxide (NO) were detected in the liver, kidney and heart of the S‑HF fed rats compared with C‑HF fed rats. The S diet compared with the C diet reduced levels of liver hydroperoxides, heart carbonyls and kidney NO. The S‑HF diet compared with the C‑HF diet increased the levels of liver and kidney superoxide dismutase, liver and muscle catalase, liver, heart and muscle glutathione peroxidase and liver ascorbic acid. The S diet prevented and reversed insulin resistance and oxidative stress, and may have benefits in patients with metabolic syndrome. PMID:26398482

  20. Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor κB signaling pathways.

    Tang, Song-Tao; Zhang, Qiu; Tang, Hai-Qin; Wang, Chang-Jiang; Su, Huan; Zhou, Qing; Wei, Wei; Zhu, Hua-Qing; Wang, Yuan

    2016-07-01

    Interaction between advanced glycation endproducts (AGEs) and receptor for AGEs (RAGE) as well as downstream pathways leads to vascular endothelial dysfunction in diabetes. Glucagon-like peptide-1 (GLP-1) has been reported to attenuate endothelial dysfunction in the models of atherosclerosis. However, whether GLP-1 exerts protective effects on aortic endothelium in diabetic animal model and the underlying mechanisms are still not well defined. Experimental diabetes was induced through administration with combination of high-fat diet and intraperitoneal injection of streptozotocin. Rats were randomly divided into four groups, including controls, diabetes, diabetes + sitagliptin (30 mg/kg/day), diabetes + exenatide (3 μg/kg/12 h). Eventually, endothelial damage, markers of inflammation and oxidative stress, were measured. After 12 weeks administration, diabetic rats received sitagliptin and exenatide showed significant elevation of serum NO level and reduction of ET-1 as well as inflammatory cytokines levels. Moreover, sitagliptin and exenatide significantly inhibited aortic oxidative stress level and improved aortic endothelial function in diabetic rats. Importantly, these drugs inhibited the protein expression level in AGE/RAGE-induced RhoA/ROCK/NF-κB/IκBα signaling pathways and activated AMPK in diabetic aorta. Finally, the target proteins of p-eNOS, iNOS, and ET-1, which reflect endothelial function, were also changed by these drugs. Our present study indicates that sitagliptin and exenatide administrations can improve endothelial function in diabetic aorta. Of note, RAGE/RhoA/ROCK and AMPK mediated NF-κB signaling pathways may be the intervention targets of these drugs to protect aortic endothelium. PMID:26758998

  1. Deoxynivalenol (Vomitoxin)-Induced Cholecystokinin and Glucagon-Like Peptide-1 Release in the STC-1 Enteroendocrine Cell Model Is Mediated by Calcium-Sensing Receptor and Transient Receptor Potential Ankyrin-1 Channel.

    Zhou, Hui-Ren; Pestka, James J

    2015-06-01

    Food refusal is a hallmark of exposure of experimental animals to the trichothecene mycotoxin deoxynivalenol (DON), a common foodborne contaminant. Although studies in the mouse suggest that DON suppresses food intake by aberrantly inducing the release of satiety hormones from enteroendocrine cells (EECs) found in the gut epithelium, the underlying mechanisms for this effect are not understood. To address this gap, we employed the murine neuroendocrine tumor STC-1 cell line, a widely used EEC model, to test the hypothesis that DON-induced hormone exocytosis is mediated by G protein-coupled receptor (GPCR)-mediated Ca(2+) signaling. The results indicate for the first time that DON elicits Ca(2)-dependent secretion of cholecystokinin (CCK) and glucagon-like peptide-1(7-36) amide (GLP-1), hormones that regulate food intake and energy homeostasis and that are products of 2 critical EEC populations--I cells of the small intestine and L cells of the large intestine, respectively. Furthermore, these effects were mediated by the GPCR Ca(2+)-sensing receptor (CaSR) and involved the following serial events: (1)PLC-mediated activation of the IP3 receptor and mobilization of intracellular Ca(2+) stores, (2) activation of transient receptor potential melastatin-5 ion channel and resultant L-type voltage-sensitive Ca(2+) channel-facilitated extracellular Ca(2+) entry, (3) amplification of extracellular Ca(2+) entry by transient receptor potential ankyrin-1 channel activation, and finally (4) Ca(2+)-driven CCK and GLP-1 excytosis. These in vitro findings provide a foundation for future investigation of mechanisms by which DON and other trichothecenes modulate EEC function in ex vivo and in vivo models. PMID:25787141

  2. Evidence that Ca2+ within the microdomain of the L-type voltage gated Ca2+ channel activates ERK in MIN6 cells in response to glucagon-like peptide-1.

    Joanne Selway

    Full Text Available Glucagon like peptide-1 (GLP-1 is released from intestinal L-cells in response to nutrient ingestion and acts upon pancreatic β-cells potentiating glucose-stimulated insulin secretion and stimulating β-cell proliferation, differentiation, survival and gene transcription. These effects are mediated through the activation of multiple signal transduction pathways including the extracellular regulated kinase (ERK pathway. We have previously reported that GLP-1 activates ERK through a mechanism dependent upon the influx of extracellular Ca(2+ through L-type voltage gated Ca(2+ channels (VGCC. However, the mechanism by which L-type VGCCs couple to the ERK signalling pathway in pancreatic β-cells is poorly understood. In this report, we characterise the relationship between L-type VGCC mediated changes in intracellular Ca(2+ concentration ([Ca(2+](i and the activation of ERK, and demonstrate that the sustained activation of ERK (up to 30 min in response to GLP-1 requires the continual activation of the L-type VGCC yet does not require a sustained increase in global [Ca(2+](i or Ca(2+ efflux from the endoplasmic reticulum. Moreover, sustained elevation of [Ca(2+](i induced by ionomycin is insufficient to stimulate the prolonged activation of ERK. Using the cell permeant Ca(2+ chelators, EGTA-AM and BAPTA-AM, to determine the spatial dynamics of L-type VGCC-dependent Ca(2+ signalling to ERK, we provide evidence that a sustained increase in Ca(2+ within the microdomain of the L-type VGCC is sufficient for signalling to ERK and that this plays an important role in GLP-1- stimulated ERK activation.

  3. 胰高糖素样肽1类似物治疗糖尿病的研究进展%The Progress of Glucagon-like Peptide-1 Analogue in Treatment of Diabetes Mellitus

    蒋飞霞

    2011-01-01

    胰高糖素样肽1(GLP-1)是一种肠肽类激素,GLP-1不仅可促进胰岛素合成和分泌、抑制B细胞凋亡、促进B细胞增殖、抑制胰高糖素分泌;还可降低食欲,延缓胃排空;GLP-1对心血管功能产生有益作用.人GLP-1类似物适用于二甲双胍、磺脲类和(或)胰岛素增敏剂控制血糖仍不满意的2型糖尿病患者.在1型糖尿病中,GLP-1对空腹血糖的作用,取决于患者血糖、胰升糖素水平及残存胰岛B细胞功能.GLP-1能改善餐后血糖的波动,根据患者残存B细胞功能的多少,其作用机制可能有差别.%Glucagon-like peptide-l( GLP-1 ),as a gut hormone,in addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion, delays gastric emptying and inhibits food intake. Their glucose-dependent mechanism limits the risk for hypoglycemia. GLP-1 improved cardiac function in humans. GLP-1 analogue is used in type 2 diabetic patients who are not sufficiently controlled by metformin and sulfonylurea. GLP-1 is able to lower fasting glycemia also in type Ⅰ diabetic patients,mainly by reducing glucagon concentrations and by remnant pancreatic B-cell secretion. The mechanism of lowering postprandial glycemia in type Ⅰ diabetic patients is different according to remnant pancreatic B-cell mass.

  4. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  5. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1 Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Henrik H Hansen

    Full Text Available One of the major histopathological hallmarks of Alzheimer's disease (AD is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1 receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP and presenilin-1 (PS1 are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9 of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c., or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.. In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  6. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

    Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  7. Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4 inhibitors and human glucagon-like peptide-1 (GLP-1 analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review.

    Martin C S Wong

    Full Text Available The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4 inhibitors and the human glucagon-like peptide-1 (GLP-1 analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59-0.90% and 0.77-1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major

  8. 胰高血糖素样肽-1受体激活在脑缺血中的神经保护作用%Neuroprotective effect of glucagon-like peptide-1 receptor activation in cerebral ischemia

    韩玲; 薛国芳; 李东芳

    2015-01-01

    Glucagon-like peptide 1(GLP-1) is an important member of incretin.Takingitoralymay stimulate the terminal ileum and colon L cel s to secrete GLP-1. After GLP-1 biding specific receptor GLP-1 receptor ( GLP-1R), it exerts the roles of promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, and decreasing plasma glucagon level. The molecular mass of GLP-1 is relatively smal er and can directly cross the blood-brain barrier, and both central and peripheral nervous systems have the GLP-1R expression. GLP-1 significantly improves neurological deficits and reduces infarct volume. It may exert neuroprotective effect through the mechanisms of inhibiting the inflammatory response, oxidative stress, and cel apoptosis. This article review s the discovery of GLP-1, its biological characteristics and neuroprotective effect in cerebral ischemia.%胰高血糖素样肽-1(glucagon-likepeptide1,GLP-1)是肠促胰岛素的重要成员。经口进食可刺激末端回肠和结肠L 细胞分泌GLP-1。 GLP-1与特异性受体GLP-1受体( GLP-1 receptor, GLP-1R)结合后发挥促进葡萄糖依赖的胰岛素分泌、抑制胰高血糖素分泌和降低血浆胰高血糖素水平等作用。 GLP-1具有分子质量相对较小,可直接透过血脑屏障,且中枢和外周神经系统均有GLP-1R表达。 GLP-1可显著改善神经功能缺损和缩小梗死体积,其可能通过抑制炎症反应、氧化应激和细胞凋亡等机制发挥神经保护作用。文章就GLP-1的发现、生物学特性和在脑缺血中的神经保护作用进行了综述。

  9. GLP-1对人脐静脉内皮细胞释放NO的影响及机制的研究%Effects and Mechanism of Glucagon like Peptide-1 on Nitric Oxide Release in Human Umbilical Vein Endothelial Cells

    丁丽; 张绍维; 赵文洲; 罗晶; 王巍; 张锦

    2015-01-01

    Objective:To investigate the effects of glucagon-like peptide-1 (GLP-1) on nitric oxide (NO) release in human umbilical vein endothelial cells (HUVECs) and whether GLP-1 receptor (GLP-1R) and GLP-1 (9-36) are involved in mediating the effects.Methods:HUVECs were incubated in the presence or absence of GLP-1,exenatide (a GLP-1R agonist) or GLP-1 (9-36),or incubated in the presence of GLP-1 with or without exendin (9-39) (a GLP-1R antagonist) and/or sitagliptin (inhibitting formation of GLP-1 [9-36]).NO content in the cell culture medium was measured by adopting nitrate reductase method.Results:GLP-1 dose-dependently promoted NO release in HUVECs.Exenatide and GLP-1 (9-36) both increased NO release.Exendin (9-39) and sitagliptin both partly blocked the effects of GLP-1.Conclusion:GLP-1 may have directly protective effect on endothelium by increasing NO release in HUVECs through GLP-1 R-dependent and GLP-1 (9-36)-related pathways.%目的:观察胰高糖素样肽-1(GLP-1)对脐静脉内皮细胞(HUVECs)释放一氧化氮(NO)的影响,并探讨GLP-1受体及GLP-1(9-36)在其中的作用.方法:分别以GLP-1、艾塞那肽、GLP-1 (9-36)、GLP-1+exendin(9-39)、GLP-1+西格列汀、GLP-1+西格列汀+exendin(9-39)孵育HUVECs,取培养上清以硝酸还原酶法检测NO浓度.结果:GLP-1剂量依赖性的增加HUVECs中NO释放,艾塞那肽和GLP-1 (9-36)均可刺激NO释放,exendin(9-39)和西格列汀均可部分阻断GLP-1引起的NO释放.结论:GLP-1可能通过GLP-1受体及GLP-1 (9-36)相关的途径刺激HUVECs NO释放,发挥直接的血管保护作用.

  10. 石斛合剂对糖尿病模型大鼠胰高血糖素样肽-1的影响%The effects of Dendrobium compound on diabtetes model rats about glucagon-like peptide-1

    高长花; 余文珍; 施红; 刘宏波; 郑远燕

    2013-01-01

    目的:观察石斛合剂对糖尿病模型大鼠高糖负荷后胰高血糖素样肽-1(GLP-1)影响。方法:选取雌性Wistar大鼠随机分为正常对照组(n=10)和观察组(n=30),观察组予高脂高糖饲料喂养4周后腹腔注射小剂量链脲佐菌素(30mg/kg)造模,成模后随机分为模型组(n=10)、石斛合剂组(n=10)、二甲双胍组(n=10)。灌胃8周后,禁食10h行口服葡萄糖耐量(OGTT)试验,尾尖采血,用ELISA法检测血清GLP-1水平。结果:治疗8周后,与模型组比较,石斛合剂组的血糖降低(P<0.01),血清基础(0h)GLP-1水平明显升高(P<0.01),高糖负荷1h后,各组大鼠血清GLP-1水平均升高,石斛合剂组高于模型组与二甲双胍组(P<0.05),且与正常对照组无显著差异;高糖负荷2h后,石斛合剂组、正常对照组大鼠血清GLP-1水平均回落(组内比较,P<0.01),模型组与二甲双胍组则继续上升,各组间比较无差异;高糖负荷3h后,各组大鼠血清GLP-1水平均降低,石斛合剂组血清GLP-1水平较模型组高。结论:石斛合剂能有效的降低糖尿病模型大鼠血糖,增加血清GLP-1水平,其降糖机制可能是通过GLP-1及其降解产物信号途径介导。%Objetctive:To observe the effect of Dendrobium compound on serum glucagon-like peptide 1(GLP-1) level in type 2 diabetic rats after high sugar load. Methods:Select female Wistar rats in addition to the normal control group (n=10), give high sugar and high fat diet plus small dose of chain urea with streptozotocin (30mg/kg) to build mold, then randomly divided into model group (n=10), Dendrobium compound group, metformin group (n=10), respectively given saline, Dendrobium compound, metformin for 8 weeks. Fasted for 10h then take oral glucose tolerance test (OGTT), and serum GLP-1 level at each time point were also tested by ELISA. Result:After 8 weeks of treatment, compared

  11. “Persistente secrezione di Exendin-4, un agonista recettoriale del Glucagon-like peptide-1, mediante terapia genica mediata da Adeno-associated Viruses, su ghiandole salivari di roditori in due differenti modelli di obesità/diabete tipo 2”

    Ilaria Dicembrini

    2013-01-01

    Exendin-4 (Ex-4)è un agonista recettoriale del Glucagon-like peptide 1 (GLP-1)attualmente approvato per il trattamento del Diabete Mellito tipo 2 e prevede una somministrazione per via iniettiva sottocutanea due volte al giorno. Nei pazienti affetti da Diabete tipo 2, la somministrazione di GLP-1 riduce significativamente la glicemia ed i livelli di HbA1c con una modesta, ma significativa riduzione del peso corporeo. In questa tesi di dottorato si è valutata la persistenza di espressione d...

  12. Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes

    Nielsen, Lotte B; Ploug, Kenneth B; Swift, Peter;

    2007-01-01

    OBJECTIVE: The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose...... on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes. DESIGN AND METHODS: Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in...... 12 month study period (coefficient = 0.42%, P = 0.03). CONCLUSIONS: Kir6.2 and SUR1 co-localise in the gastrointestinal endocrine L- and K-cells. The hyperactive Glu23Lys variant of the K(ATP) channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control...

  13. Research advance in glucagon-like peptide-1-A new drug in treatment of type Ⅱ diabetes%治疗2型糖尿病新药胰高血糖素样肽-1的研究进展

    刘青; 杨翰仪

    2001-01-01

    @@本文作者回顾了近年来关于胰高血糖素样肽-1(Glucagon-Like Peptide-1,GLP-1)的研究情况,讨论了GLP-1的临床实际应用及今后的开发方向。   1 GLP-1的生物化学   GLP-1是肠胰高血糖素原的主要转化终产物〔1〕,是由在空肠、回肠和结肠发现的L细胞分泌的一种肽类激素,其与胰高血糖素的氨基酸序列有50%同源性,因而得名〔2〕。在人类GLP-1约80%以α羧基酰化形式存在,即GLP-1酰胺〔GLP-1(7~36)〕,其余以GLP-1甘氨酸变异体形式存在,即GLP-1(7~37),两者具有相同的生理活性。

  14. Effects of Green Tea Extract on Insulin Resistance and Glucagon-Like Peptide 1 in Patients with Type 2 Diabetes and Lipid Abnormalities: A Randomized, Double-Blinded, and Placebo-Controlled Trial

    Chia-Yu Liu; Chien-Jung Huang; Lin-Huang Huang; I-Ju Chen; Jung-Peng Chiu; Chung-Hua Hsu

    2014-01-01

    The aim of this study is to investigate the effect of green tea extract on patients with type 2 diabetes mellitus and lipid abnormalities on glycemic and lipid profiles, and hormone peptides by a double-blinded, randomized and placebo-controlled clinical trial. This trial enrolled 92 subjects with type 2 diabetes mellitus and lipid abnormalities randomized into 2 arms, each arm comprising 46 participants. Of the participants, 39 in therapeutic arm took 500 mg green tea extract, three times a ...

  15. alpha-Glucosidase inhibition (acarbose) fails to enhance secretion of glucagon-like peptide 1 (7-36 amide) and to delay gastric emptying in Type 2 diabetic patients

    Hücking, K; Kostic, Z; Pox, C;

    2005-01-01

    AIM: Acarbose is able to enhance GLP-1 release and delay gastric emptying in normal subjects. The effect of alpha-glucosidase inhibition on GLP-1 has been less evident in Type 2 diabetic patients. The aim of this study was to investigate the possible influence of acarbose on GLP-1 release...... and gastric emptying in Type 2 diabetic patients after a mixed test meal. PATIENTS AND METHODS: Ten Type 2 diabetic patients were tested with 100 mg acarbose or placebo served with a mixed meal that was labelled with 100 mg 13C-octanoic acid. Plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP......-1 and GIP were determined over 6 h. Gastric emptying was measured by determining breath 13CO2 using infrared absorptiometry. Statistics repeated-measures anova. RESULTS: Gastric emptying rates (t1/2: 162 +/- 45 vs. 163 +/- 62 min, P = 0.65) and plasma concentrations (increasing from approximately 12...

  16. Effects of glucagon like peptide-1 treatment on the alveolar capillary basal lamina in Otsuka Long-Evans Tokushima Fatty rats%胰高血糖素样多肽-1对OLETF大鼠肺泡毛细血管基板的影响

    汤秀英; 王昱; 郭晓蕙; 王书合; 柴立军; 张烨

    2008-01-01

    目的:电镜观察并定量分析胰高血糖素样多肽-1(glucagon like peptide-1, GLP-1)对自发性2型糖尿病OLETF(Otsuka Long-Evans Tokushima Fatty)大鼠肺泡毛细血管基板的影响.方法:将OLETF大鼠分为未治疗的OLETF组及GLP-1治疗组(OLETF/G组),对照为LETO(Long-Evans Tokushima Otsuka)组大鼠.用透射电镜观察及形态计量学方法测量肺泡毛细血管基板的超微结构及厚度.结果:与LETO组大鼠相比,OLETF大鼠肺泡毛细血管内皮细胞基板与Ⅰ型肺泡上皮细胞基板融合部(F-BL)及肺泡毛细血管内皮细胞基板(Cap-BL)均增厚,分别为 (110.60±14.14) nm vs (57.30±11.08) nm和 (118.40±19.12) nm vs (66.80±8.63) nm (P<0.01).OLETF/G组大鼠肺F-BL及Cap-BL均比OLETF组大鼠明显变薄,分别为 (79.70±5.44) nm vs (110.60±14.14) nm和 (69.80±3.32) nm vs (118.40±19.12) nm (P<0.01).结论:OLETF大鼠肺泡毛细血管基板发生明显的超微结构变化;GLP-1治疗能减轻OLETF大鼠肺泡毛细血管基板损伤.

  17. The physiology of glucagon-like peptide 1

    Holst, Jens Juul

    2007-01-01

    before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine...... actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to...... limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor...

  18. Glucagon-like peptide 2 inhibits ghrelin secretion in humans

    Banasch, Matthias; Bulut, Kerem; Hagemann, Dirk;

    2006-01-01

    INTRODUCTION: The growth hormone secretagogue receptor ligand ghrelin is known to play a pivotal role in the central nervous control of energy homeostasis. Circulating ghrelin levels are high under fasting conditions and decline after meal ingestion, but the mechanisms underlying the postprandial...... fasting ghrelin levels and the ambient concentrations of glucagon or intact GLP-2. CONCLUSIONS: GLP-2 inhibits ghrelin secretion in humans at plasma levels of approximately 200 pmol/l. However, the physiological...... drop in ghrelin levels are poorly understood. In the present study we addressed, whether (1) exogenous GLP-2 administration decreases ghrelin levels and (2) what other endogenous factors are related to ghrelin secretion under fasting conditions. PATIENTS AND METHODS: Fifteen healthy male volunteers...

  19. Make a movie in 48 hours

    Brokk Toggerson

    2011-01-01

    This year, the 48-hour film project (48hfp) returns to Geneva after a one-year hiatus. Organized by Neal Hartman and the CERN film-making club, Open Your Eyes Films, the 48hfp challenges teams of film-makers to write, shoot, soundtrack and edit a 4 to 7 minute film in 48 hours from 4 to 6 November.   At the start of the festival, contestants picked their film genre from a hat. The films will be screened on 8 and 9 November, with the awards presentation on the 9th. The winner will receive a trip to the US to compete in the international version of the competition. “There are so many short films being made now," says Hartman, “I think, however, that the 48hfp allows a critical creative mass to form. The result is that these 20 teams make 20 better films than if each participant were making their own." Each team draws a genre from a hat and is given a character, a prop and a line of dialogue that must appear in their film. The genres run the gamut from &am...

  20. Effect of glucagon-like peptide-1 and its receptor agonists on weight loss and protection of the cardiovascular system for patients with type 2 diabetes%胰高血糖素样肽-1及其受体激动剂对2型糖尿病患者体重减轻和心血管保护的作用

    李意; 祝开思

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family:secreted by the distal gastrointestinal tract (the ileum and colon) L cells (a kind of endocrine cells) and reduces blood glucose through the stimulation of insulin secretion and the inhibition of glucagon release. In recent years, more and more clinical evidences dedicate that GLP-1 possesses more extensive and important functions out of pancreas including slowing gastric emptying, reducing food intake, improving endothelial function, cardiac function, anti-inflammatory response, lowering blood pressure, lipid, reducing weight via inhibiting feeding behavior and delaying gastrointestinal motility, thus it can benefit on cardiovascular function. This paper aimed at reviewing the effects of glucagon-like peptide-1 and its receptor agonists on weight loss and the cardiovascular system.%胰高血糖素样肽-1(GLP-1)属于肠降血糖素激素家族:由远端消化道(回肠和结肠)L细胞(一种内分泌细胞)分泌,以葡萄糖依赖的模式促进胰岛素释放及抑制胰高糖素分泌,从而降低血糖。近年来越来越多的临床证据显示,GLP-1拥有更广泛而重要的胰腺外作用,如通过抑制食欲、延缓胃排空作用使体重减轻,改善内皮细胞功能、心脏功能,抗炎、降脂对心血管起到保护作用。本文就胰高血糖素样肽-1及其受体激动剂对体重减轻和心血管系统影响作一综述。

  1. 胰高血糖素样肽-1对葡萄糖刺激下胰岛β细胞胰岛素原合成的短期作用%SHORT TERM EFFECT OF GLUCAGONS-LIKE PEPTIDE-1 ON PROINSULIN BIOSYNTHESIS UNDER THE STIMULATION OF GLUCOSE

    钟慕贤; 刘红; 荣曦; 岳惠芬; 吴宇娟

    2013-01-01

    Objective:To investigate the short term effect of glucagons-like peptide-1(GLP-1) on proinsulin biosynthesis under conditions of normal or high glucose concentrations.Methods:The NIT-1 cells were cultured and randomly divided into four groups,low glucose control group (LG),low glucose + GLP-1 (LGG),high glucose (HG),high glucose+GLP-1 (HGG).Proinsulin mRNA and protein levels at baseline and 4 hours after stimulation were assessed by semi-quantitative RT-PCR and HE method respectively.Results:At baseline there was no difference between patterns.Four hours after stimulation,the expression of proinsulin in HG and HGG groups increased (P<0.05),however there was no significant changes in LG and LGG groups (P>0.05).The expression level of proinsulin in the HGG group was higher than that in LG,LGG and HG groups (P<0.05).The expression level of proinsulin in the HG group was higher than that in LG and LGG groups (P<0.05).Conclusion:Short term GLP-1 stimulation can promote proinsulin biosynthesis and proinsulin gene expression under high concentration of glucose.The combination of GLP-1 and high concentration of glucose can lead to a synergy effect on proinsulin biosynthesis.%目的:探讨胰高血糖素样肽-1(GLP-1)在高浓度、低浓度葡萄糖作用下对胰岛β细胞胰岛素原合成的短期影响.方法:将NIT-1细胞随机分为低浓度葡萄糖(LG)组、低浓度葡萄糖+GLP-1(LGG)组、高浓度葡萄糖(HG)组和高浓度葡萄糖+GLP-1 (HGG)组4组.检测基线0h及葡萄糖和(或)GLP-1刺激后4h各组细胞胰岛素原基因和蛋白表达.结果:基线时各组胰岛素原表达无显著差异(P>0.05),4h后HG组、HGG组胰岛素原表达均明显增高(P<0.05),而LG和LGG组无明显变化(P>0.05).组间比较,HGG组胰岛素原表达量明显高于LG组、LGG组及HG组(均P<0.05).HG组胰岛素原表达量显著高于LG组、LGG组(均P<0.05).结论:在高浓度葡萄糖条件下,短期GLP-1刺激可显著增加胰岛β

  2. 胰高血糖素样肽-2对幼鼠肠缺血-再灌注损伤的保护作用%Protective effects of glucagon-like peptide 2 on intestinal ischemia-reperfusion injury of young rats

    张敏; 胡毓华; 张伟

    2009-01-01

    目的 研究胰高血糖素样肽2(GLP-2)对肠缺血-再灌注(I-R)幼鼠肠屏障功能的保护作用.方法 采用肠I-R模型,将24只雄性Wistar幼鼠随机均分为假手术(C组)、肠I-R损伤(B组)和肠I-R损伤+GLP-2保护(A组)三组.光镜下观察小肠黏膜形态学改变,检测肠系膜淋巴结的细菌菌落情况、肠黏膜丙二醛(MDA)、血清D-乳酸、内毒素和肿瘤坏死因子α(TNF-α)水平的变化.结果 B组肠黏膜损伤最明显,Chiu's评分、肠系膜淋巴结细菌菌落计数、肠黏膜MDA、血清D-乳酸、内毒素和TNF-α水平均显著高于C组(P<0.01);与B组相比,A组肠黏膜损伤明显减轻,且Chiu's评分、肠系膜淋巴结细菌菌落计数、肠黏膜MDA、血清乳酸、内毒素和TNF-α水平显著降低(P<0.05).结论 GLP-2能够减轻幼鼠肠I-R损伤、保护肠黏膜屏障、减轻细菌/内毒素易位、减少氧自由基和炎性介质的产生和释放.%Objective To explore the protective effects of glucagon-like peptide 2 (GLP-2) on intestinal ischemia-reperfusion(I-R)injury of young rats. Methods Using the rat model of intestinal ischemia-reperfusion, 24 young male Wista rats were randomly assigned to three groups of sham operation( group C), I-R( group B) and I-R+GLP-2 (group A) with 8 rats each. Intestinal pathology was examined under light microscope. Bacterial colony of mesenteric lymph node(MLN), intestinal mucosal malondialdehyde(MDA), serum D-lactate, endotoxin, and tumor necrosis factoe(TNF)-α were studied. Results The intestinal injury was significant in group B, and Chiu's scores, bacterial colony counts of MLN, intestinal mucosal MDA, serum D-lactate, endotoxin, and TNF-α were also significantly higher in group B than those in group C (P<0. 01), which were significantly lower in group A than those in group B (P<0. 05). Conclusion GLP-2 attenuates intestinal I-R injury, protects intestinal mucosal barrier, reduces bacterial/endotoxin translocation, inhibits the release of

  3. The effect of glucagon-like peptide 1 injected into the the dorsal vagal complex on the gastric emptying of diabetic rats%经迷走神经复合体注射胰高血糖素样肽-1对糖尿病大鼠胃排空的影响

    刘玲; 魏良洲; 田字彬; 梁少双; 孔心涓; 武军

    2012-01-01

    [目的]研究经迷走神经复合体(DVC)注射胰高血糖素样肽-1(GLP-1)对糖尿病大鼠胃排空的影响,并探讨相关作用机制.[方法]30只雄性Wistar大鼠随机分为正常对照组、糖尿病组及糖尿病GLP-1注药组.腹腔注射链脲佐菌素(STZ)制备糖尿病大鼠模型,DVC区埋置套管.糖尿病成模2周后,GLP-1注药组经套管注入GLP-1,对照组注入等量生理盐水.检测各组大鼠体质量、血糖、胃排空率、血浆GLP-1浓度及胃黏膜GLP-1受体(GLP-1R)mRNA的表达量.[结果]糖尿病大鼠体质量较正常组显著降低(P<0.05),血糖浓度[(28.0±1.8)mmol/L]较正常组[(5.7±0.5)mmol/L]明显升高(P<0.05),胃排空率[(72±11)%]较对照组[(35±8)%%]明显升高(P<0.05),血浆GLP-1浓度及胃黏膜GLP-1R较对照组无明显变化.GLP-1注药组大鼠的胃排空率[(39±12)%]、血糖浓度[(14.6±1.3)mmol/L]较糖尿病组明显降低(P均<0.05),血浆GLP-1浓度[(15.35±2.21)pmol/L]及胃窦GLP-1R mRNA/β-肌动蛋白(β-actin)(1.33±0.22)较糖尿病组[(10.78±2.06)pmol/L、1.10±0.14,P均<0.05)显著升高,胃排空率与血浆GLP-1浓度及胃窦GLP-1R mRNA表达量呈负相关(r=-0.786、-0.731,P均<0.05),与胃底GLP-1R mRNA表达量无相关性.[结论]DVC区注射GLP-1可减慢糖尿病早期加速的胃排空率,作用机制可能是促进血浆GLP-1的分泌及胃窦GLP-1R的表达.%[Objective]To investigate the effect of the glucagon-like peptide 1 (GLP-1)in the dorsal vagal complex (DVC) on the gastric emptying of streptozotocin-induced diabetic rats,and to study the related mechanisms of these effects.[Methods] Diabetes was induced by intrapritoneal injection of streptozotocin(60 mg/kg) in male Wistar rats.All rats were surgically implanted with indwelling cannulas in the dorsal vagal complex,and saline or GLP-1(1 μg)in 0.5 μl saline was delivered to the DVG.Gastric emptying of phenol red solution and the plasma GLP-1levels measured by enzyme

  4. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

    Madsbad, Sten; Schmitz, Ole; Ranstam, Jonas;

    2004-01-01

    .0003) compared with placebo. Improvement in glycemic control was evident after 1 week. Body weight decreased by 1.2 kg in the 0.45-mg liraglutide group (P = 0.0184) compared with placebo. The proinsulin-to-insulin ratio decreased in the 0.75-mg liraglutide group (-0.18; P = 0.0244) compared with placebo.......45, 0.60, or 0.75 mg), placebo, or open-label sulfonylurea (glimepiride, 1-4 mg). The primary end point was HbA(1c) after 12 weeks; secondary end points were fasting serum glucose, fasting C-peptide, fasting glucagon, fasting insulin, beta-cell function, body weight, adverse events, and hypoglycemic...

  5. Effect of glucagon-like Peptide-1 in the dorsal vagal complex on the expression of GLP-1 receptor in the hypothalamus and the gastric emptying in diabetic rats%迷走神经复合体注射GLP-1对糖尿病大鼠下丘脑GLP-1受体表达及胃排空的影响

    吕丰香; 魏良洲; 田字彬; 王利华; 孔心涓; 尹继萍

    2013-01-01

    Objective To investigate the effect of the glucagons-like Peptide 1 injection in the dorsal vagal complex ( DVC) on the expression of GLP-1 receptor in hypothalamus and the gastric emptying in diabetic rats. Methods 36 male Wistar rats were randomly divided into 3 groups; normal control group ( NC group) , diabetic mellitus group ( DM group) and GLP-1 treated group (GLP-1 group). Diabetes was induced by intraperitoneal injection of streptozotocin (60 mg/kg). All rats were posited cannulas in the dorsal vagal complex (DVC). After 4 weeks of the STZ injection, GLP-1 (0. 5 μg) in 0. 5 μl saline was injected for GLP-1 group while isovolumic normal saline was injected for NC group and DM group through cannulas. Gastric emptying was measured by intragastric administration of methyl cellulose-phenol red solution and the expression levels of GLP-1 RmRNA in the hypothalamus were measured by means of real-time fluorescent quantitative polymerase chain's reaction (RT-PCR). Results After 4 weeks of STZ injection, DM group showed significantly accelerated rates of gastric emptying of the fluid compared with those in the NC group ( P < 0. 05 ) , the gastric emptying decreased significantly in GLP-1 group compared with DM group (P <0.05) , but still accelerated compared with NC group (P<0.05). The expression of GLP-1 RmRNA in hypothalamus of GLP-1 group were increased significantly compared with DM group and NC group (P<0.05) , which showed a negative correlation with decrease of gastric emptying. Conclusion GLP-1 injection in DVC can delay the accelerated gastric emptying during the early stage of diabetic rats. This maybe achieve through promoting the expression of GLP-1 receptor in the hypothalamus.%目的 探讨中枢迷走神经复合体注射GLP-1(胰高血糖素样肽-1)对糖尿病大鼠胃排空的影响和中枢作用机制.方法 36只雄性清洁级Wistar大鼠随机分为正常对照(NC)组、糖尿病(DM)组和糖尿病GLP-1(GLP-1)干预组.DM组和GLP-1组腹腔

  6. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications

    Madsbad, S

    2014-01-01

    obesity. Incretin impairment, probably associated with reduced insulinotropic potency of GLP-1, is also characteristic of type 2 diabetes (T2D). Therefore, it is possible that incretin impairment may contribute to the pathophysiological bridge between obesity and T2D. This review summarises current...

  7. Impact of glucagon-like peptide-1 on myocardial glucose metabolism revisited

    Hansen, Jan; Brock, Birgitte; Bøtker, Hans Erik;

    2014-01-01

    . The potentially beneficial effect of GLP-1 stimulation may rely on, among others, improved myocardial glucose metabolism. This review focuses on the dogma that GLP-1 receptor stimulation may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency, by increasing...... myocardial glucose uptake. The published literature was systematically reviewed and the applied models evaluated since the outcomes of varying studies differ substantially. Reports on the effect of GLP-1R stimulation on myocardial metabolism are conflicting and should be evaluated carefully. There is limited...

  8. Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1)

    Bak, Monika Judyta; Albrechtsen, Nicolai Jacob Wewer; Pedersen, Jens; Knop, Filip Krag; Vilsbøll Lauritsen, Tina; Jørgensen, Nils B; Hartmann, Bolette; Deacon, Carolyn F.; Dragsted, Lars Ove; Holst, Jens Juul

    2014-01-01

    assessed with 3 commercial kits. RESULTS: The USCN LIFE assay detected none of the GLP-1 isoforms. The active GLP-1 ELISAs from Millipore and DRG seemed identical and were specific for intact GLP-1 in buffer and plasma. The Meso Scale Discovery Total GLP-1 kit detected all six GLP-1 isoforms, although...

  9. The effects of glucagon-like peptide-1 on the beta cell

    Vilsbøll, Tina

    2009-01-01

    type 2 diabetes, as assessed by homoeostasis model assessment-B analysis and proinsulin : insulin ratio. Additionally, liraglutide and exenatide are able to enhance first- and second-phase insulin secretion and are able to restore beta-cell sensitivity to glucose. Preclinical studies have shown that...

  10. Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats

    Liu, Xiaowen; Murali, Sangita G; Holst, Jens J;

    2009-01-01

    protein component, casein, soy, or whey protein, potentiates the intestinal growth response to GLP-2 in rats with PN-induced mucosal hypoplasia. Rats received PN and continuous intravenous infusion of GLP-2 (100 microg/kg/day) for 7 days. Six EN groups received PN+GLP-2 for days 1-3 and partial PN+GLP-2...... plus EN for days 4-7. EN was provided by ad libitum intake of a semielemental liquid diet with different protein sources: casein, hydrolyzed soy, whey protein concentrate (WPC), and hydrolyzed WPC+casein. Controls received PN+GLP-2 alone. EN induced significantly greater jejunal sucrase activity and...... whey protein, and not casein or soy, potentiated the ability of GLP-2 to reverse PN-induced mucosal hypoplasia and further increase ileal villus height, crypt depth, and mucosa cellularity compared with PN+GLP-2 alone, P < 0.05. The ability of whey protein to induce greater mucosal surface area was...

  11. Glucagon-like peptide 1-baseret behandling af type 2-diabetes mellitus

    Knop, Filip Krag; Vilsbøll, Tina

    2007-01-01

    GLP-1 is secreted from the small intestine in response to ingestion of nutrients. It has a powerful insulinotropic effect and stimulates beta-cell growth and is therefore being developed for treatment of type 2 diabetes. The GLP-1 analogue, exenatide, is on the market in the USA as an add......-on therapy. Another strategy to increase circulating GLP-1 is to inhibit the enzyme DPP-IV which degrades endogenous GLP-1. GLP-1-based therapy results in HbA1c reductions of approximately 1 percent point, and the lack of serious side effects and the low risk of hypoglycaemic episodes are unique traits....

  12. Functional Consequences of Glucagon-like Peptide-1 Receptor Cross-talk and Trafficking

    Roed, Sarah Noerklit; Nøhr, Anne Cathrine; Wismann, Pernille;

    2015-01-01

    The signaling capacity of seven-transmembrane/G-protein-coupled receptors (7TM/GPCRs) can be regulated through ligand-mediated receptor trafficking. Classically, the recycling of internalized receptors is associated with resensitization, whereas receptor degradation terminates signaling. We have...... glucagon (GCGR) receptors. The interaction and cross-talk between coexpressed receptors is a wide phenomenon of the 7TM/GPCR superfamily. Numerous reports show functional consequences for signaling and trafficking of the involved receptors. On the basis of the high structural similarity and tissue...... coexpression, we here investigated the potential cross-talk between GLP-1R and GIPR or GCGR in both trafficking and signaling pathways. Using a real-time time-resolved FRET-based internalization assay, we show that GLP-1R, GIPR, and GCGR internalize with differential properties. Remarkably, upon coexpression...

  13. Real-time trafficking and signaling of the glucagon-like peptide-1 receptor

    Roed, Sarah Noerklit; Wismann, Pernille; Underwood, Christina Rye;

    2014-01-01

    . A fundamental mechanism controlling the signaling capacity of GPCRs is the post-endocytic trafficking of receptors between recycling and degradative fates. Here, we combined microscopy with novel real-time assays to monitor both receptor trafficking and signaling in living cells. We find that the...... human GLP-1R internalizes rapidly and with similar kinetics in response to equipotent concentrations of GLP-1 and the stable GLP-1 analogues exendin-4 and liraglutide. Receptor internalization was confirmed in mouse pancreatic islets. GLP-1R is shown to be a recycling receptor with faster recycling...

  14. Glucagon-like peptide-2 in umbilical cord blood from mature infants

    Bodé, Susan; Hartmann, Bolette; Holst, Jens Juul; Greisen, Gorm

    2007-01-01

    is comparable to adult fasting levels. No significant correlation to birth weight (p = 0.087) or to cesarean section (p = 0.059) was found. In multiple linear regression analysis (GLP-2 vs. GA + cesarean section), neither vaginal delivery nor GA were statistically significantly related to the level...

  15. Glucagon-like peptide-1 as a treatment for chemotherapy-induced mucositis

    Kissow, Hannelouise; Hartmann, Bolette; Holst, Jens Juul;

    2012-01-01

    . RESULTS: GLP-1 and GLP-2 significantly prevented the loss of mucosal mass and villus height and significantly decreased the mucositis severity score in the duodenum and jejunum 48 h after chemotherapy. The effect was equivalent. Exendin (9-39) reduced the intestinal weight 96 h after chemotherapy. The GLP...

  16. Effect of glucagon-like peptide-2 exposure on bone resorption

    Askov-Hansen, Carsten; Jeppesen, Palle B; Lund, Pernille; Hartmann, Bolette; Holst, Jens Juul; Henriksen, Dennis B

    2013-01-01

    In healthy subjects, subcutaneous injections of GLP-2 have been shown to elicit dose-related decrease in the bone resorption marker, carboxy-terminal telopeptide of type I collagen (CTX), and have been proposed for the treatment of osteoporosis. This study investigated the relation between GLP-2 ...

  17. Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2

    Sigalet, David L; Wallace, Laurie E; Holst, Jens Juul;

    2007-01-01

    colitis was induced in rats by injection of trinitrobenzene sulfonic acid (TNBS), or colitis was induced by administration of dextran sodium sulfate (DSS) in drinking water. Subsets of animals received (1-33)-GLP-2 (50 mug/kg sc bid) either immediately or 2 days after the establishment of inflammation and...

  18. The Relationship between Glucagon-Like Peptide 2 and Feeding Intolerance in Preterm Infants

    Ozer, Esra Arun; Holst, Jens Juul; Duman, Nuray;

    2008-01-01

    in the gastric aspirate. The plasma GLP-2 levels measured prior to enteral feeding (fasting level) and at 60 min after the beginning of the feeding (post-pradial level) were correlated with of clinical parameters. There was no statistical difference between GLP-2 levels of overall preterm babies and...... those of term newborns. However, preterm neonates with feeding intolerance showed significantly lower levels of GLP-2 and increased duration to achieve full enteral feeding and hospitalization. It is suggested that GLP-2 plays a significant role in the regulation of feeding in newborns and that preterm...

  19. Neural regulation of glucagon-like peptide-1 secretion in pigs

    Hansen, Lene; Lampert, Sarah; Mineo, Hitoshi;

    2004-01-01

    (abolished by propranolol). Acetylcholine stimulated GLP-1 secretion, and atropine blocked this effect. Dimethylphenylpiperazine stimulated GLP-1 secretion. In chloralose-anesthetized pigs, however, electrical stimulation of the vagal trunks at the level of the diaphragm had no effect on GLP-1 or GLP-2...

  20. Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs

    Sigalet, David L; de Heuvel, Elaine; Wallace, Laurie; Bulloch, Estrella; Turner, Justine; Wales, Paul W; Nation, Patrick; Wizzard, Pamela R; Hartmann, Bolette; Assad, Meena; Holst, Jens Juul

    2014-01-01

    40 μg/kg/day or control drug vehicle (saline), by subcutaneous injection, given in two doses per day, (n=6/group) for 42 days. Animals were weaned normally, over days 21-25. In the fifth week of life, they underwent neuro-developmental testing, and a pharmacokinetic study. On day 42, they were...... euthanized, and a complete necropsy performed, with histological assessment of tissues from all major organs. RESULTS: GLP-2 treatment was well tolerated, one control animal died from unrelated causes. There were no effects of GLP-2 on weight gain, feed intake, or behavior. In the treated animals, GLP-2...... proliferation (Ki-67 staining) was increased in the GLP-2 treated animals and the rate of apoptosis (Caspase-3) was decreased, the depth of the microvilli was increased and the expression of the mRNA for the GLP-2 receptor was decreased throughout the small and large intestine. CONCLUSIONS: In these growing...

  1. Additive effects of glucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes

    Zander, Mette; Christiansen, Allan; Madsbad, Sten; Holst, Jens Juul

    2004-01-01

    .01). Glucagon levels were reduced in GLP-1 and combination therapy compared with saline and monotherapy with pioglitazone (P < 0.01). FFAs during breakfast (area under the curve, 0-3 h) were reduced in combination therapy compared with saline (P = 0.03). Sensation of appetite was reduced during monotherapy with...

  2. Overnight hypoxic exposure and glucagon-like peptide-1 and leptin levels in humans

    Snyder, Eric M; Carr, Richard D; Deacon, Carolyn F; Johnson, Bruce D

    2008-01-01

    .8 +/- 1.2 pmol.L-1; 40 min postmeal, 19.5 +/- 1.2 vs. 21.0 +/- 1.2 pmol.L-1 for normoxia and hypoxia, respectively; p > 0.05 normoxia vs hypoxia). There was a correlation between SaO2 and leptin after the 17 h exposure (r = 0.45; p < 0.05), but no relation between SaO2 and GLP-1. These data confirm that...

  3. Diabetes and cardiovascular disease: focus on glucagon-like peptide-1 based therapies

    Stranges, Paul; Khanderia, Ujjaini

    2012-01-01

    Type 2 diabetes is a well known risk factor for cardiovascular disease (CVD). While glycemic control has consistently been shown to prevent microvascular complications, large randomized trials have not demonstrated the same consistent beneficial effects of intensive glycemic control in improving cardiovascular (CV) outcomes. Thus, optimal glucose control alone is not sufficient to reduce CV risk. Aggressive management of CV risk factors such as blood pressure, lipids, and body weight is also ...

  4. Porcine glucagon-like peptide-2: structure, signaling, metabolism and effects

    Pedersen, Nis Borbye; Hjøllund, Karina Rahr; Johnsen, Anders H;

    2007-01-01

    MCR of hGLP-2 in pig. The MCR of intact pGLP-2 was reduced by valine-pyrrolidide (p<0.05), but was still greater than that of intact hGLP-2 previously reported. In the isolated perfused porcine pancreas, pGLP-2 stimulated glucagon release (p<0.05), but had no effect on insulin or somatostatin release....... Exocrine secretion was unaffected and there was no apparent vasoactive effect. In mice (n=8), both subcutaneous hGLP-2 and pGLP-2 given twice daily for 10 days, significantly and equally increased small intestinal weight, length and cross-sectional area of proximal ileum. In conclusion, pGLP-2 and hGLP-2...... have similar effects in vivo and in vitro in spite of the structural differences. However, pGLP-2 is cleared more rapidly in pigs than hGLP-2....

  5. Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype

    Anjema, Karen; van Rijn, Margreet; Hofstede, Floris C.; Bosch, Annet M; Hollak, Carla EM; Rubio-Gozalbo, Estela; de Vries, Maaike C; Janssen, Mirian Ch; Boelen, Carolien CA; Burgerhof, Johannes GM; Blau, Nenad; Heiner-Fokkema, M. Rebecca; van Spronsen, Francjan J.

    2013-01-01

    BACKGROUND: How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. METHODS: Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with >=30% phenylalanine reduction at >=1 time points during the 48 hours (potential responders) were invited...

  6. Angioplastic necrolytic migratory erythema. Unique association of necrolytic migratory erythema, extensive angioplasia, and high molecular weight glucagon-like polypeptide

    A diabetic patient developed necrolytic migratory erythema with extensive angioplasia and high molecular weight glucagon-like polypeptide. There was no associated neoplasm such as glucagonoma. Lesions in the skin were studied by standard optical microscopy and by radioautography after incorporation of tritiated thymidine. Alterations in the skin begin as focal necrosis in the epidermis and in epithelial structures of adnexa, followed by marked angioplasia and a superficial and deep perivascular dermatitis

  7. The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake

    Tang-Christensen, M.; Larsen, Philip J.; Thulesen, Jesper; Rømer, J.; Vrang, Niels

    Neurophysiology, neuroanatomy, overweight/obesity, hypothalamus, brainstem, food intake behaviour......Neurophysiology, neuroanatomy, overweight/obesity, hypothalamus, brainstem, food intake behaviour...

  8. Peptide YY3-36 and glucagon-like peptide-1 in functional dyspepsia. Secretion and role in symptom generation

    Witte, Anne-Barbara; Hilsted, Linda; Holst, Jens Juul;

    2016-01-01

    -36, GLP-1, dyspeptic symptoms, and satiety measurements. MATERIALS AND METHODS: Thirty-six patients with functional dyspepsia and 18 healthy controls consumed a liquid meal at two occasions. Firstly, a fixed amount of 250 mL (300 kcal) was consumed and gastric emptying was assessed using the paracetamol...... method. Secondly, participants drank 75 mL (90 kcal) per five min until maximal satiety. PYY3-36, GLP-1, glucose, and insulin concentrations were assessed. Satiety measures and dyspeptic symptoms were registered using visual analogue scales. RESULTS: Gastric emptying, glucose, PYY3-36, and GLP-1......-36 secretion is altered in functional dyspepsia, but postprandial GLP-1 secretion seems to correlate with nausea and PYY3-36 to the sensation of fullness, and therefore, these hormones might be involved in symptom generation....

  9. METABOLIC AND HORMONAL RESPONSES TO ADRENOCEPTOR ANTAGONISTS IN 48-HOUR-STARVED EXERCISING RATS

    BENTHEM, L; VANDERLEEST, J; STEFFENS, AB; ZIJLSTRA, WG

    1995-01-01

    The influence of 48 hours of starvation on sympathoadrenal regulation of nutrient utilization was investigated in rats. To assess the role of alpha- and beta-adrenoceptors, rats were studied during alpha- and beta-blockade. Energy metabolism was measured using indirect calorimetry before, during, an

  10. No effect of physiological concentrations of glucagon-like peptide-2 on appetite and energy intake in normal weight subjects

    Sørensen, L B; Flint, A; Raben, A;

    2003-01-01

    OBJECTIVE: To examine the effect of a GLP-2 infusion on appetite sensations and ad libitum energy intake in healthy, normal weight humans. DESIGN: The experiment was performed in a randomised, blinded, and placebo-controlled crossover design. Placebo or GLP-2 was infused (infusion rate of 25 pmol...... meals, or energy intake were different on the two occasions. Glucose, GLP-1, insulin, and GIP responses were also unaffected by the infusion, whereas glucagon levels were higher during the GLP-2 treatment (P<0.05). CONCLUSION: Circulating GLP-2 in physiological concentrations does not seem to play a...... significant role in human appetite regulation....

  11. Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study.

    Ahern, T

    2012-06-13

    Background  Diabetes and obesity are more prevalent amongst psoriasis patients as is disturbance of the innate immune system. GLP-1 analogue therapy considerably improves weight and glycaemic control in people with type 2 diabetes and its receptor is present on innate immune cells. Objective  We aimed to determine the effect of liraglutide, a GLP-1 analogue, on psoriasis severity. Methods  Before and after 10 weeks of liraglutide therapy (1.2 mg subcutaneously daily) we determined the psoriasis area and severity index (PASI) and the dermatology life quality index (DLQI) in seven people with both psoriasis and diabetes (median age 48 years, median body mass index 48.2 kg\\/m(2) ). We also evaluated the immunomodulatory properties of liraglutide by measuring circulating lymphocyte subset numbers and monocyte cytokine production. Results  Liraglutide therapy decreased the median PASI from 4.8 to 3.0 (P = 0.03) and the median DLQI from 6.0 to 2.0 (P = 0.03). Weight and glycaemic control improved significantly. Circulating invariant natural killer T (iNKT) cells increased from 0.13% of T lymphocytes to 0.40% (P = 0.03). Liraglutide therapy also effected a non-significant 54% decrease in the proportion of circulating monocytes that produced tumour necrosis factor alpha (P = 0.07). Conclusion  GLP-1 analogue therapy improves psoriasis severity, increases circulating iNKT cell number and modulates monocyte cytokine secretion. These effects may result from improvements in weight and glycaemic control as well as from direct immune effects of GLP-1 receptor activation. Prospective controlled trials of GLP-1 therapies are warranted, across all weight groups, in psoriasis patients with and without type 2 diabetes.

  12. The glucagon-like peptide 2 receptor is expressed in enteric neurons and not in the epithelium of the intestine

    Pedersen, Jens; B. Pedersen, Nis; Brix, Sophie W.;

    2015-01-01

    alone, (2) mucosa with lamina propria and epithelium, (3) the external muscle coat including myenteric plexus, (4) a compartment enriched for the myenteric plexus and (5) intestine without epithelium. Expression of Glp2r; chromogranin A; tubulin, beta 3; actin, gamma 2, smooth muscle, enteric and glial...

  13. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    Holst, JJ; Kielgast, Urd; Holst, Jens J;

    2009-01-01

    appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence for a...

  14. Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus--an adaptive response to hyperglycaemia?

    Hansen, A M K; Bödvarsdottir, T B; Nordestgaard, D N E;

    2011-01-01

    detected in the portal vein (9.8¿±¿1.5 vs 4.3¿±¿0.7 pmol/l, p¿<¿0.05), and in pancreas extracts (11.4¿±¿2.2 vs 5.1¿±¿1.3 pmol/g tissue, p¿<¿0.05). Freshly isolated islets from hyperglycaemic animals released more GLP-1 following 24 h culture than islets from control animals (28.2¿±¿4.4 pmol/l vs 5.......8¿±¿2.4, p¿<¿0.01). GLP-1 release was increased from healthy P. obesus islets following culture in high glucose for 6 days (91¿±¿9.1 pmol/l vs 28.8¿±¿6.6, p¿<¿0.01). High levels of GLP-1 were also found to be released from human islets. PC1/3 colocalised weakly with alpha cells. Conclusions...

  15. Absence of a memory effect for the insulinotropic action of glucagon-like peptide 1 (GLP-1) in healthy volunteers

    Meier, S; Hücking, K; Ritzel, R;

    2003-01-01

    and appropriate post hoc tests. RESULTS: GLP-1 plasma levels during the infusion periods were elevated to 89 +/- 9, 85 +/- 13, and 89 +/- 6 pmol/l (p enhanced negative rebound (p = 0.014), and insulin and C...... appears to exist for insulinotropic actions of GLP-1, in line with clinical data. 2). Reactive hypoglycemia causes a prompt rise in glucagon despite pharmacological circulating concentrations of GLP-1. 3). Similar studies should be performed in Type 2-diabetic patients, because exposure to GLP-1 might...

  16. Renal Extraction and Acute Effects of Glucagon-like peptide-1 on Central and Renal Hemodynamics in Healthy Men

    Asmar, Ali; Simonsen, Lene; Asmar, Meena;

    2015-01-01

    catheterization of a renal vein. The subjects remained supine during the experiments. During GLP-1 infusion, the systolic blood pressure and arterial pulse pressure both increased by 5 ± 1 mm Hg (p=0.015 and p=0.002, respectively). Heart rate increased by 5 ± 1 bpm (p=0.005) and cardiac output increased by 18...

  17. Temporal changes in the intestinal growth promoting effects of glucagon-like peptide 2 following intestinal resection

    Kaji, Tatsuru; Tanaka, Hiroaki; Redstone, Heather;

    2008-01-01

    expression (SGLT-1, GLUT-2, GLUT-5). In a separate study, the resection-induced effect on acute GLP-2 responsiveness was studied at d 3 and 10, in control or SBR animals, both supported with TPN. (n = 6). RESULTS: Bowel length, weight, and width were increased in SBR + TPN + GLP-2 (first wk) compared with...

  18. Effect of the glucagon-like peptide-1 receptor agonist lixisenatide on postprandial hepatic glucose metabolism in the conscious dog

    Moore, Mary Courtney; Werner, Ulrich; Smith, Marta S.; Farmer, Tiffany D.; Cherrington, Alan D.

    2013-01-01

    The impact of the GLP-1 receptor agonist lixisenatide on postprandial glucose disposition was examined in conscious dogs to identify mechanisms for its improvement of meal tolerance in humans and examine the tissue disposition of meal-derived carbohydrate. Catheterization for measurement of hepatic balance occurred ≈16 days before study. After being fasted overnight, dogs received a subcutaneous injection of 1.5 μg/kg lixisenatide or vehicle (saline, control; n = 6/group). Thirty minutes late...

  19. Reduction in bone resorption by exogenous glucagon-like peptide-2 administration requires an intact gastrointestinal tract

    Gottschalck, Ida B; Jeppesen, Palle B; Holst, Jens Juul; Henriksen, Dennis B

    2008-01-01

    1600 microg GLP-2, b) placebo and c) 3.8 MJ of a breakfast meal. Blood was sampled for measurements of s-CTX, s-osteocalcin and GLP-2 for 4 h after each intervention. RESULTS: After the GLP-2 injection, only control subjects showed a significant reduction in s-CTX (24% +/- 13%, p = 0.05, 120 min...

  20. Glucagon-like peptide 2 has limited efficacy to increase nutrient absorption in fetal and preterm pigs

    Sangild, Per Torp; Malo, Christiane; Schmidt, Mette;

    2007-01-01

    to exogenous GLP-2. This was accomplished using catheterized fetal pigs infused for 6 days (87-91% of gestation) with GLP-2 (25 nmol.kg(-1).day(-1) iv; n = 7) or saline (n = 7), and cesarean-delivered preterm pigs (92% of gestation) that received TPN with GLP-2 (25 nmol.kg(-1).day(-1) iv; n = 8) or...... circulating GLP-2 levels in fetuses, but did not increase intestinal mass or absorption of nutrients by intact tissues and brush border membrane vesicles, except for lysine. Administration of exogenous GLP-2 to preterm TPN-fed pigs similarly did not increase rates of nutrient absorption, yet nutrient...... exogenous GLP-2 to improve nutrient absorption by the intestine of fetal and preterm pigs is limited compared with term pigs and more mature animals and humans....

  1. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease

    Nyström, Thomas; Gutniak, Mark K; Zhang, Qimin;

    2004-01-01

    (I)) in two groups: 1) 12 type 2 diabetes patients with stable coronary artery disease and 2) 10 healthy subjects with normal endothelial function and S(I). Subjects underwent infusion of recombinant GLP-1 or saline in a random crossover study. Endothelial function was measured by postischemic FMD of...... brachial artery, using ultrasonography. S(I) [in (10(-4) dl.kg(-1).min(-1))/(muU/ml)] was measured by hyperinsulinemic isoglycemic clamp technique. In type 2 diabetic subjects, GLP-1 infusion significantly increased relative changes in brachial artery diameter from baseline FMD(%) (3.1 +/- 0.6 vs. 6.......6 +/- 1.0%, P < 0.05), with no significant effects on S(I) (4.5 +/- 0.8 vs. 5.2 +/- 0.9, P = NS). In healthy subjects, GLP-1 infusion affected neither FMD(%) (11.9 +/- 0.9 vs. 10.3 +/- 1.0%, P = NS) nor S(I) (14.8 +/- 1.8 vs. 11.6 +/- 2.0, P = NS). We conclude that GLP-1 improves endothelial dysfunction...

  2. Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets

    Burrin, Douglas G; Stoll, Barbara; Guan, Xinfu;

    2005-01-01

    height; however, stomach protein synthesis was decreased by GLP-2. Intestinal crypt and villus apoptosis decreased and crypt cell number increased linearly with GLP-2 infusion rates, whereas cell proliferation and protein synthesis were stimulated only at the high GLP-2 dose. The intestinal activities...... saline or GLP-2 at three rates (2.5, 5.0, and 10.0 nmol.kg(-1).d(-1)) for 7 d. Plasma GLP-2 concentrations ranged from 177 +/- 27 to 692 +/- 85 pM in the low- and high-infusion groups, respectively. GLP-2 infusion dose-dependently increased small intestinal weight, DNA and protein content, and villus...... of caspase-3 and -6 and active caspase-3 abundance decreased, yet procaspase-3 abundance increased markedly with increasing infusion rate and plasma concentration of GLP-2. The GLP-2-dose-dependent suppression of intestinal apoptosis and caspase-3 activity was associated with increased protein kinase B...

  3. Bone resorption is decreased postprandially by intestinal factors and glucagon-like peptide-2 is a possible candidate

    Holst, Jens Juul; Hartmann, Bolette; Gottschalck, Ida B;

    2007-01-01

    -bowel syndrome (SBS) or total gastrectomy in order to elucidate whether the signal for the meal-induced reduction of bone resorption is initiated from the stomach or the intestine. MATERIAL AND METHODS: Bone resorption was assessed from the serum concentration of collagen type I C-telopeptide cross-links (s...... and gastrectomy patients. GLP-2 concentrations increased significantly in all groups with the exception of the SBS plus colectomy group. CONCLUSIONS: An intestinal factor is responsible for the postprandial reduction in bone resorption, and our findings are compatible with such a function for GLP-2....

  4. Small molecule ago-allosteric modulators of the human glucagon-like peptide-1 (hGLP-1) receptor

    Teng, Min; Johnson, Michael D; Thomas, Christine;

    2007-01-01

    Following our previous publication describing the biological profiles, we herein describe the structure-activity relationships of a core set of quinoxalines as the hGLP-1 receptor agonists. The most potent and efficacious compounds are 6,7-dichloroquinoxalines bearing an alkyl sulfonyl group at the...... C-2 position and a secondary alkyl amino group at the C-3 position. These findings serve as a valuable starting point for the discovery of more drug-like small molecule agonists for the hGLP-1 receptor....

  5. Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists

    Madsbad, Sten

    2012-01-01

    Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians...... will start antidiabetic treatment with metformin, but adding a GLP-1 receptor agonist as the second drug seems to be optimal since more patients will reach an HbA1c below 7% than with a DPP-4 inhibitor or another oral antidiabetic agents and with minimal risk of hypoglycaemia. The GLP-1 receptor...... agonists are also more effective in weight and systolic blood pressure control than DPP-4 inhibitors. The side effects of the GLP-1 receptor agonists are primarily nausea and vomiting, which is less pronounced with the long acting agonists and often transient. A GLP-1 receptor agonist can be recommended...

  6. Cholecystokinin-Induced Gallbladder Emptying and Single-Dose Metformin Elicit Additive Glucagon-Like Peptide-1 Responses

    Rohde, Ulrich; Sonne, David Peick; Christensen, Mikkel; Hansen, Morten; Brønden, Andreas; Toräng, Signe; Rehfeld, Jens Frederik; Holst, Jens Juul; Vilsbøll, Tina; Knop, Filip Krag

    2016-01-01

    . PARTICIPANTS: Ten healthy male subjects with no family history of diabetes (aged 22 (range 20-32) years; body mass index 21.7 (19.3-24.2) kg/m(2); fasting plasma glucose 4.9 (4.7-5.3) mM; and HbA1c 5.1 (4.4-5.8) %). INTERVENTION: On 4 separate days, the subjects received metformin or placebo and a concomitant...

  7. Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome

    Jeppesen, Palle Bekker

    2012-01-01

    adaptation. Together, the symptoms of short bowel syndrome and the inconvenience and complications in relation to PS (e.g. catheter-related blood steam infections, central thrombosis and intestinal failure associated liver disease) may impair the quality of life of patients. The aim of treatment is to......Short bowel syndrome results from surgical resection, congenital defect or disease-associated loss of absorption. Parenteral support (PS) is lifesaving in patients with short bowel syndrome and intestinal failure who are unable to compensate for their malabsorption by metabolic or pharmacologic...... restoration of the structural and functional integrity of the remaining intestine with significant intestinotrophic and proabsorptive effects, facilitating a reduction in diarrhea and an equivalent reduction in the need for PS in patients with short bowel syndrome and intestinal failure....

  8. Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome

    Jeppesen, Palle Bekker

    2012-01-01

    Short bowel syndrome results from surgical resection, congenital defect or disease-associated loss of absorption. Parenteral support (PS) is lifesaving in patients with short bowel syndrome and intestinal failure who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Together, the symptoms of short bowel syndrome and the inconvenience and complications in relation to PS (e.g. catheter-related blood steam infections, central thrombosis and intestinal fai...

  9. Profile of care given to patients with blunt chest injuries within the first 48 hours

    E Nyangena

    2000-09-01

    Full Text Available This study was conducted in the trauma unit of a large academic hospital in Johannesburg, South Africa. The study aimed at describing the nature of care that patients with blunt chest injuries received during the first 48 hours after injury. A descriptive survey was chosen using retrospective and prospective record review to obtain data. The sample comprised 60 records of patients who were admitted to the hospital due to blunt chest injuries between January 1997 and June 1998. Descriptive statistics were used to present and analyse data. The study showed that: (i Blunt chest trauma victims received a thorough initial assessment and care. No missed injuries were identified on subsequent assessment; (ii More than half of the patients spent over one hour in the accident/emergency department before admission to the trauma ward or intensive care unit (ICU; (iii Motor vehicle accidents (MVA were the commonest cause of injury while pedestrian vehicle accidents (PVA were often fatal; (iv Nurses are good providers of care but poor in prescribing and documenting care; (v Pain assessment and psychosocial care was often neglected; (vi Less than half the patients developed complications during the first 48 hours; pain and pneumonia being the most common complications encountered.

  10. Two-dimensional, time dependent simulation of the planetary boundary layer over a 48-hour period

    This report presents results of a two-dimensional time-dependent simulation of the planetary boundary layer for a 48-hour period. These calculations are a continuation and expansion of one-dimensional simulations of the planetary boundary layer as described previously. The time-dependent evolution of a weather situation was simulated. It could be demonstrated that the main features of local ventilation systems can be simulated correctly. Two case studies are presented to show qualitatively, how local circulation systems can be influenced. One case assumes introduction of a hypothetical city, the other case uses arbitrarily introduced coverage of the sky as a pertubrbation. The problems connected with the verification of two-dimensional simulations using experimental data are discussed. Furthermore, proposals for a methodology to solve problems of model verification are discussed. (Auth.)

  11. The intestinal distribution pattern of appetite- and glucose regulatory peptides in mice, rats and pigs

    Albrechtsen, Nicolai Jacob Wewer; Kuhre, Rune Ehrenreich; Toräng, Signe;

    2016-01-01

    distribution analysis of the tissue content of the major appetite- and glucose regulatory peptides: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-1 (GLP-2), oxyntomodulin/glicentin, neurotensin, and peptide YY (PYY) from the duodenum to distal colon...... mouse the highest level was found in the distal colon. In rats and pigs, neurotensin was predominantly detected in mid and lower part of the small intestine, while the mouse showed the highest levels in the distal small intestine. In contrast, the distribution of GIP was restricted to the proximal small...

  12. Kardiologiske aspekter af glukagonlignende peptid 1

    Elvekjaer, Mikkel; Engstrøm, Thomas; Jensen, Jan Skov; Treiman, Marek

    2010-01-01

    Increasing experimental evidence points to direct effects of glucagon-like peptide-1 (GLP-1) and its analogs on the heart and circulatory system, in addition to the well-established, antidiabetic actions of these agents on glucose and on the energy metabolism. These effects are primarily...

  13. Functional ontogeny of the proglucagon-derived peptide axis in the premature human neonate

    Amin, Harish; Holst, Jens Juul; Hartmann, Bolette;

    2008-01-01

    BACKGROUND: The regulation of intestinal growth and development in human neonates is incompletely understood, which hinders the provision of nutrients enterally. The "hindgut" hormones glucagon-like peptides 1 and 2 have been shown to play an important role in the regulation of nutrient...... assimilation, intestinal growth, and function. OBJECTIVE: Our goal was to investigate the production of glucagon-like peptides 1 and 2 in premature human infants and examine the effects of prematurity and feeding on hormone release. PATIENTS AND METHODS: With informed consent, premature infants who were...... admitted to a tertiary neonatal intensive care nursery (gestational age: 28-32 weeks) were monitored with weekly determinations of postprandial glucagon-like peptide 1 and 2 levels. Comparison studies with groups of normal infants and adults were performed. Hormone levels were obtained by using specific...

  14. Pregnancy outcomes using stallion epididymal sperm stored at 5 °C for 24 or 48 hours before harvest.

    Stawicki, R J; McDonnell, S M; Giguère, S; Turner, R M

    2016-03-01

    The cryopreservation of epididymal sperm can be useful in a variety of circumstances for ensuring genetic preservation of a valued stallion. Although early studies have reported pregnancy rates significantly lower than those achieved with cryopreserved ejaculated sperm, two recent studies report over 60% one-cycle pregnancy rates with epididymal sperm stored for 24 hours at 5 °C before harvest and cryopreservation. The aims of this study were to: (1) attempt to replicate the one-cycle pregnancy rate of over 60% using epididymal sperm cooled and stored within the epididymis for 24 hours before harvest and cryopreservation and (2) evaluate pregnancy outcome with sperm cooled and stored within the epididymis for 48 hours before sperm harvest and cryopreservation. Testicles were obtained from 13 stallions undergoing routine castration. The epididymides were stored at 5 °C for either 24 or 48 hours before sperm harvest and cryopreservation in an egg yolk and dimethylformamide-based freezing extender. Thirteen mares were bred on one cycle with cryopreserved epididymal sperm stored for 24 hours before harvest, and 10 of those 13 mares were also bred on a previous or subsequent cycle with samples from the same stallion that had been stored for 48 hours before harvest. Pregnancy occurred in 7 of the 13 inseminations of sperm stored for 24 hours before harvest, and in 4 of the 10 inseminations of sperm stored for 48 hours before harvest. The pregnancy rate using epididymal sperm stored for 24 hours before harvest is consistent with that of previous reports. In addition, these results provide evidence that pregnancies can be achieved when the epididymides are cooled and stored for 48 hours before sperm harvest and cryopreservation. PMID:26559467

  15. Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding

    Korner, Judith; Bessler, Marc; Inabnet, William;

    2007-01-01

    glucose and insulin regulation after these procedures. METHODS: This was a cross-sectional study of 3 groups of women matched for age and body mass index: group 1, overweight controls (n = 13); group 2, BND (n = 10); and group 3, RYGB (n = 13). Venous blood was drawn with the patient in the fasted state...... and throughout a 3-hour period after a liquid meal. RESULTS: The fasting glucose level was similar between the 2 surgery groups; however, the fasting insulin concentrations were greater in the BND (10.0 microU/mL) than in the RYGB (6.2 microU/mL; P <0.05) group. The glucose level at 60 minutes was...... significantly lower in the RYGB group (70 mg/dL, range 38-82) than in the BND group (83 mg/dL, range 63-98). The GLP-1 levels at 30 minutes were more than threefold greater in the RYGB group (96 pmol/L) compared with the BND and overweight control (28 pmol/L) groups. The GLP-1 and insulin concentrations...

  16. Do Lactation-Induced Changes in Ghrelin, Glucagon-Like Peptide-1, and Peptide YY Influence Appetite and Body Weight Regulation during the First Postpartum Year?

    D. Enette Larson-Meyer

    2016-01-01

    Full Text Available To determine whether fasting and meal-induced appetite-regulating hormones are altered during lactation and associated with body weight retention after childbearing, we studied 24 exclusively breastfeeding women (BMI = 25.2 ± 3.6 kg/m2 at 4-5 weeks postpartum and 20 never-pregnant controls (BMI = 24.0 ± 3.1 kg/m2. Ghrelin, PYY, GLP-1, and appetite ratings were measured before/and 150 minutes after a standardized breakfast and 60 minutes after an ad libitum lunch. Body weight/composition were measured at 6 and 12 months. Fasting and area under-the-curve responses for appetite-regulating hormones did not differ between lactating and control groups; ghrelinacyl, however, tended to track higher after the standardized breakfast in lactating women and was higher (p6.0 kg. The retainers had greater (p<0.05 postmeal ghrelin rebound responses following breakfast. Overall these studies do not support the hypothesis that appetite-regulating hormones are altered during lactation and associated with postpartum weight retention. Altered ghrelin responses, however, deserve further exploration.

  17. Dietary fiber, gut peptides, and adipocytokines

    Sánchez, David; Miguel, Marta; Aleixandre, Amaya

    2012-01-01

    The consumption of dietary fiber (DF) has increased since it was related to the prevention of a range of illnesses and pathological conditions. DF can modify some gut hormones that regulate satiety and energy intake, thus also affecting lipid metabolism and energy expenditure. Among these gut hormones are ghrelin, glucagon-like peptide 1, peptide YY, and cholecystokinin. Adipose tissue is known to express and secrete a variety of products known as >adipocytokines,> which are also affected by ...

  18. Association Rule Mining and Classifier Approach for 48-Hour Rainfall Prediction Over Cuddalore Station of East Coast of India

    S. Meganathan; T.R. Sivaramakrishnan

    2013-01-01

    The methodology of data mining techniques has been presented for the rain forecasting models for the Cuddalore (11°43′ N/79°49′ E) station of Tamilnadu in East Coast of India. Data mining approaches like classification and association mining was applied to generate results for rain prediction before 48 hour of the actual occurrence of the rain. The objective of this study is to demonstrate what relationship models are there between various atmospheric variables and to interconnect these varia...

  19. The small bowel and functional dyspepsia - peptide hormones and neurotransmitters

    Witte, Anne-Barbara

    2013-01-01

    Functional dyspepsia (FD) is believed to be caused by pathophysiological changes in the upper gut. Gastro-intestinal motility, epithelial transport and signalling is associated with the metabolism of nutrients and the complex regulation of hunger and satiety. Glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) are considered “hot targets”. Both are anorexigenic, can induce nausea, and are involved in neuronal and hormonal feedback. Epithelial transport and signalling are partl...

  20. Radiolabelled peptides for oncological diagnosis

    Laverman, Peter; Boerman, Otto C.; Oyen, Wim J.G. [Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine, Nijmegen (Netherlands); Sosabowski, Jane K. [Queen Mary University of London, Centre for Molecular Oncology, Barts Cancer Institute, London (United Kingdom)

    2012-02-15

    Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The {sup 111}In-labelled somatostatin analogue octreotide (OctreoScan trademark) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours. (orig.)

  1. Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats

    Samantha L. Price, MRes

    2015-12-01

    Conclusions: The results indicate Glu-3 OXM-like analogues might not be suitable tools to investigate the mechanism of OXM analogue action in a rat model because they significantly increase body weight independent of food intake. Glu-3 OXM analogues are partial agonists at the rat GCGr and may also act as antagonists, possibly resulting in the observed increase in body weight.

  2. Glucagon-Like Peptide-1 Protects Human Islets against Cytokine-Mediated β-Cell Dysfunction and Death: A Proteomic Study of the Pathways Involved

    Rondas, Dieter; Bugliani, Marco; D’Hertog, Wannes;

    2013-01-01

    -treated human islets with GLP-1 resulted in a marked protection of β-cells against cytokine-induced apoptosis and significantly attenuated cytokine-mediated inhibition of glucose-stimulated insulin secretion. The cytoprotective effects of GLP-1 coincided with substantial alterations in the protein expression...... profile of cytokine-treated human islets, illustrating a counteracting effect on proteins from different functional classes such as actin cytoskeleton, chaperones, metabolic proteins, and islet regenerating proteins. In summary, GLP-1 alters in an integrated manner protein networks in cytokine......-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic...

  3. Blood glucose control in healthy subject and patients receiving intravenous glucose infusion or total parenteral nutrition using glucagon-like peptide 1

    Nauck, Michael A; Walberg, Jörg; Vethacke, Arndt;

    2004-01-01

    It was the aim of the study to examine whether the insulinotropic gut hormone GLP-1 is able to control or even normalise glycaemia in healthy subjects receiving intravenous glucose infusions and in severely ill patients hyperglycaemic during total parenteral nutrition.......It was the aim of the study to examine whether the insulinotropic gut hormone GLP-1 is able to control or even normalise glycaemia in healthy subjects receiving intravenous glucose infusions and in severely ill patients hyperglycaemic during total parenteral nutrition....

  4. Effects of microwave exposure on glucagon-like peptide-1 (GLP-1) and its receptor and the relationship with learning and memory injury

    In order to explore the effects of microwave exposure on GLP-1 and its receptor, the relationship between the changes of GLP-1 and its receptor and learning and memory injury induced by microwave exposure has been studied in this paper. Morris water maze was used to evaluate learning and memory ability of rats. The changes of the plasma GLP-1 level were measured by ELISA assay. Alteration of the GLP-1R mRNA expression in rat hippocampus was determined by RT-PCR and Apoptosis was detected by TUNEL. Our study showed that microwave exposure injured the learning and memory abilities of rats meanwhile plasma GLP-1 level was decreased and GLP-1R expression in hippocampus was down-regulated, which can be protected by pretreatment with GLP-1. Alterations in GLP-1 and GLP-1R are, at least partially, responsible for the microwave exposure induced learning and memory dysfunction and neuronal injury. These data provide some new clues to investigate the mechanisms of microwave exposure induced neuronal injury and develop clinical approaches for treatment of microwave exposure induced injury. It can provide some new ideals for investigation of related mechanism and development of clinical treatment under exposed microwave irradiation. (authors)

  5. Combination of soya protein and polydextrose reduces energy intake and glycaemic response via modulation of gastric emptying rate, ghrelin and glucagon-like peptide-1 in Chinese.

    Soong, Yean Yean; Lim, Wen Xin; Leow, Melvin Khee Shing; Siow, Phei Ching; Teh, Ai Ling; Henry, Christiani Jeyakumar

    2016-06-01

    The short-term effect of soya protein, polydextrose and their combination on energy intake (EI) was investigated in Chinese. In total, twenty-seven healthy, normotensive and lean Chinese men aged 21-40 years were given four different soyabean curd preloads with or without polydextrose. The study was a repeated-measure, randomised, cross-over design. The consumption of high-protein soyabean curd alone or in addition with polydextrose as a preload led to greater reduction in EI at a subsequent meal. A similar observation was also found after intake of low-protein soyabean curd with polydextrose. The gut hormone responses mirrored the reduction in food intake. It appears that incorporation of polydextrose either with low- or high-protein soyabean curd could be a potential strategy to reduce EI and assist with weight management. The popular consumption of soyabean curd in Chinese makes it an ideal vehicle for incorporation of polydextrose. This evidence-based dietary approach can serve as a guideline for developing functional foods for weight reduction and weight maintenance. PMID:27185412

  6. Insulin-like growth factor I and glucagon-like peptide-2 responses to fasting followed by controlled or ad libitum refeeding in rats

    Nelson, David W; Murali, Sangita G; Liu, Xiaowen;

    2008-01-01

    for 48 h and then refed for 2 or 4 days by continuous intravenous or intragastric infusion or ad libitum feeding. Fasting induced significant decreases in body weight, plasma concentrations of IGF-I and bioactive GLP-2, jejunal mucosal cellularity (mass, protein, DNA, and villus height), IGF-I m...... growth and prevented the increase in plasma IGF-I to fed levels; however, plasma GLP-2 and jejunal IGF-I mRNA were restored to fed levels. Intragastric refeeding restored intestinal cellularity and functional capacity (sucrase activity and sodium-glucose transporter-1 expression) to fed levels, whereas...

  7. Sustained glucagon-like peptide-2 infusion is required for intestinal adaptation, and cessation reverses increased cellularity in rats with intestinal failure

    Koopmann, Matthew C; Chen, Xueyan; Holst, Jens Juul;

    2010-01-01

    in duodenum and jejunum mucosal dry mass, protein, DNA, and sucrase activity compared with TPN control. The increased jejunum cellularity reflected significantly decreased apoptosis and increased crypt mitosis and crypt fission due to GLP-2. When GLP-2 infusion stopped at 7 days, these effects were...

  8. Fixed combination of insulin and a glucagon-like peptide-1 analog for the treatment of type 2 diabetes, exemplified by insulin degludec and liraglutide

    Vedtofte, Louise; Knop, Filip K; Vilsbøll, Tina

    2015-01-01

    Insulin therapy in the management of Type 2 diabetes is often postponed and/or not adequately intensified to maintain glycemic control because of the risk of weight gain and hypoglycemia. A fixed combination of the long-acting insulin degludec and liraglutide has recently been accepted by the EMA...

  9. Normal secretion of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 during gestational diabetes mellitus

    Cypryk, Katarzyna; Vilsbøll, Tina; Nadel, Iwona;

    2007-01-01

    Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of beta-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2. The aim of study was...

  10. Normal secretion of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 during gestational diabetes mellitus

    Cypryk, Katarzyna; Vilsbøll, Tina; Nadel, Iwona;

    2007-01-01

    BACKGROUND AND AIM: Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of beta-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2...... gestational women with diabetes mellitus in whom GDM was diagnosed according to the World Health Organization criteria (75-g oral glucose tolerance test (OGTT)). The control group consisted of 13 pregnant women with normal glucose tolerance (NGT), matched according to age and duration of pregnancy. For all...

  11. Short bowel patients treated for two years with glucagon-like Peptide 2: effects on intestinal morphology and absorption, renal function, bone and body composition, and muscle function

    Jeppesen, P B; Lund, P; Gottschalck, I B; Nielsen, H B; Holst, Jens Juul; Mortensen, J; Poulsen, S S; Quistorff, B; Mortensen, P B

    2009-01-01

    offered, to eleven SBS patients keeping parenteral support constant. 72-hour nutritional balance studies were performed at baseline, weeks 13, 26, 52 during two years intermitted by an 8-week washout period. In addition, mucosal morphometrics, renal function (by creatinine clearance), body composition and......, GLP-2 significantly reduced the fecal wet weight from approximately 3.0 to approximately 2.0 kg/day. This was accompanied by a decline in the oral wet weight intake, maintaining intestinal wet weight absorption and urinary weight constant. Renal function improved. No significant changes were...... demonstrated in energy intake or absorption, and GLP-2 did not significantly affect mucosal morphology, body composition, bone mineral density or muscle function. CONCLUSIONS: GLP-2 treatment reduces fecal weight by approximately 1000 g/d and enables SBS patients to maintain their intestinal fluid and...

  12. Effects of exendin-4, a glucagon like peptide-1 receptor agonist, on neutrophil count and inflammatory cytokines in a rat model of endotoxemia

    Yanay, Ofer; Bailey, Adam L; Kernan, Kelly; Zimmerman, Jerry J; Osborne, William R

    2015-01-01

    Background Sepsis remains a major cause of morbidity and mortality. A variety of strategies targeting modulation of the pro-inflammatory response associated with early sepsis have been reported without clinical success. GLP-1 enhances glucose-stimulated insulin secretion. In addition, it was shown to have anti-inflammatory effects. We hypothesized that treatment with exendin-4, a GLP-1 receptor agonist, would attenuate inflammation and improve glucose control in a lipopolysaccharide (LPS) rat model of inflammation. Methods Two-month-old male Wistar rats were randomly assigned to one of the following four groups: 1) treatment: intraperitoneal (IP) injection of LPS 10 mg/kg followed by exendin-4, 30 μg/kg, 10 minutes later; 2) control-1: IP injection of LPS 10 mg/kg, followed by normal saline (NS); 3) control-2: IP NS injection followed by exendin-4; 4) sham: IP injection of NS followed by another NS injection. Glucose concentration, total white blood count with absolute neutrophil count, and pro- and anti-inflammatory cytokine concentrations were measured at 0, 3, 6, and 10 hours following LPS injection. Results At 3 hours, rats injected with LPS developed neutropenia, elevated pro- and anti-inflammatory cytokines, and mild hypoglycemia. Treatment with exendin-4 significantly modulated neutropenia, and decreased pro-inflammatory cytokine concentrations (IL-1α, IL-1β, IL-6, TNFα, and IFNγ). However, exendin-4 had no effect on IL-10 concentrations. LPS injection led to mild hypoglycemia, that was not observed in rats treated with exendin-4. Sham animals exhibited no significant change from baseline in all parameters. Conclusion In this LPS model of acute early phase inflammation, treatment with exendin-4 decreased pro-inflammatory cytokine concentrations without changing IL-10 blood levels and improved neutropenia. Following LPS injection, rats developed a tendency toward hypoglycemia that improved with exendin-4. Overall our data suggest that exogenous exendin-4 mediates anti-inflammatory effects early in this rat model of endotoxin-induced inflammation. PMID:26244029

  13. Women with bulimia nervosa exhibit attenuated secretion of glucagon-like peptide 1, pancreatic polypeptide, and insulin in response to a meal

    Naessén, Sabine; Carlström, Kjell; Holst, Jens Juul;

    2011-01-01

    The eating disorder bulimia nervosa (BN) is characterized by frequent episodes of binge eating, followed regularly by inappropriate compensatory behavior, such as self-induced vomiting.......The eating disorder bulimia nervosa (BN) is characterized by frequent episodes of binge eating, followed regularly by inappropriate compensatory behavior, such as self-induced vomiting....

  14. Protein kinase C pathway mediates the protective effects of glucagon-like peptide-1 on the apoptosis of islet β-cells.

    Zhang, Lihai; Wang, Yuesheng; Wang, Jiao; Liu, Yinglan; Yin, Yanbin

    2015-11-01

    The incidence of diabetes has been increasing over previous years. It is hypothesized that promoting the survival of islet β-cells is a key direction for the treatment of diabetes. Although gastric bypass surgery improves certain types of diabetes and attenuates its progression, there are certain associated disadvantages (including intestinal obstruction and anastomotic leakage), and quality of life and physical status (such as malnutrition) are significantly affected by gastric bypass surgery. Therefore, it is important to determine the mechanisms underlying the improvement of diabetes by gastric bypass surgery and identify novel gene targets for diabetes therapeutics. In the present study, glucagon‑like peptide‑1 (GLP‑1), whose secretion was markedly increased following gastric bypass surgery, increased the activity of protein kinase C (PKC) in islet β‑cells in a dose‑dependent manner. Additionally, treatment with GLP‑1 boosted cell viability and decreased cell death in starved islet β‑cells, and inhibited mitochondria‑dependent apoptosis by regulating the expression levels of Bcl‑2/Bax. These effects were reversed by inhibiting the PKC pathway using hypericin. Therefore, the present study concluded that GLP‑1 may promote the survival and inhibit the apoptosis of islet β‑cells at least in part by activating the PKC pathway, which is an important underlying mechanism and may be exploited in the treatment of diabetes. PMID:26459881

  15. The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion

    El-Ouaghlidi, Andrea; Rehring, Erika; Holst, Jens Juul;

    2007-01-01

    glibenclamide (5 mg), was administered 30 min before 75 g oral glucose. Blood was sampled to measure glucose, and total (sum of active and inactive) GLP-1 and GIP. Statistical evaluation was done using repeated-measures ANOVA. RESULTS: Glibenclamide provoked hypoglycemia (

  16. No effect of beta-adrenergic blockade on hypoglycaemic effect of glucagon-like peptide-1 (GLP-1) in normal subjects

    Toft-Nielsen, M; Hvidberg, A; Hilsted, Jannik;

    1996-01-01

    GLP-1 administration decreases blood glucose levels in normal subjects and non-insulin-dependent diabetes mellitus patients and is therefore proposed as a treatment for diabetic hyperglycaemia. The glucose lowering effect of GLP-1 is glucose dependent and therefore self-limiting, but it is not...... min-1). In a control experiment, saline and propranolol were infused. Hepatic glucose production was measured and blood was analysed for plasma glucose, insulin, glucagon, catecholamines, and radioactivity. Plasma GLP-1 levels were similar on the two GLP-1 infusion days and resulted in: (1) a...... significant decrease in plasma glucose from 5.2 +/- 0.2 to 4.1 +/- 0.1 mmol l-1 with GLP-1/propranolol infusion, and from 5.2 +/- 0.1 to 4.0 +/- 0.1 mmol l-1 with GLP-1/saline infusion (NS); (2) a corresponding significant increase in plasma insulin from 58.0 +/- 6.3 to 144.5 +/- 22.3 pmol l-1 and from 61...

  17. NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs

    Ribel, Ulla; Larsen, Marianne O; Rolin, Bidda; Carr, Richard D; Wilken, Michael; Sturis, Jeppe; Westergaard, Lisbet; Deacon, Carolyn F; Knudsen, Lotte Bjerre

    2002-01-01

    2211 (15,367 +/- 5,438 vs. 9,014 +/- 2,952 pmol l(-1) min), and glucagon levels were suppressed (P < 0.05). Once-daily injections of NN2211 (3.3 micrograms kg(-1) s.c.) reduced the glucose excursion during an oral glucose tolerance test, to 59 +/- 15% of pre-treatment values by 4 weeks (P < 0...... hyperglycaemic glucose clamp and chronic treatment results in better daily metabolic control. Therefore, NN2211, a GLP-1 derivative that can be administered once daily, holds promise as a new anti-diabetic drug with a minimal risk of hypoglycaemia....

  18. Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide

    Cani, Patrice D.; Montoya, Maite Lasa; Neyrinck, Audrey M; Delzenne, Nathalie M.; Lambert, Didier

    2004-01-01

    The CB1 cannabinoid receptor antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant; SR141716A), and oleoylethanolamide (OEA) are known to reduce food consumption, by, at least partially, a peripheral regulation of feeding. The effects of systemic SR141716A or OEA (5 mg/kg) administrations on food consumption in 24 h food-deprived and fed rats were investigated. In fasted rats, SR141716A and OEA produced an inhibition in food intake measu...

  19. Expression of mRNA for proglucagon and glucagon-like peptide-2 (GLP-2) receptor in the ruminant gastrointestinal tract and the influence of energy intake

    Taylor-Edwards, C C; Burrin, D G; Matthews, J C;

    2010-01-01

    from the forestomachs (rumen, omasum, and abomasum) and intestines (duodenum, jejunum, ileum, and colon) of 18 forage-fed Angus steers (260 kg BW). In Experiments 1 and 2, real-time polymerase chain reaction showed that expression of GCG and GLP2R mRNA was detectable in forestomach tissues......, but expression was greater (P intestinal and colon tissue. High energy intake tended (P = 0.07) to increase plasma GLP-2 during the acute period and was paralleled by a 78% increase (P = 0.07) in ileal GCG mRNA expression. After this initial adaptation, duodenal GCG mRNA expression increased (P...... demonstrate that cattle express GCG and GLP2R mRNA primarily in small intestinal and colon tissues. Increased nutrient intake increases ileal GCG mRNA and plasma GLP-2, suggesting that GLP-2 may play a role in the trophic response of the ruminant gastrointestinal tract to increased feed intake....

  20. Elimination and degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with end-stage renal disease

    Idorn, Thomas; Knop, Filip K; Jørgensen, Morten B; Christensen, Mikkel; Holst, Jens Juul; Hornum, Mads; Feldt-Rasmussen, Bo

    2014-01-01

    repeatedly. Plasma half-life (T1/2), metabolic clearance rate (MCR), area under curve and volume of distribution for intact and metabolite levels of GLP-1 and GIP were calculated. Results: Fasting concentrations of intact GLP-1 and GIP were increased in dialysis patients (P < 0.001), whereas fasting levels...

  1. Glukagonlignende peptid-analoger i behandlingen af type 2-diabetes mellitus--en gennemgang af et Cochranereview

    Beck-Nielsen, Henning

    2012-01-01

    A Cochrane analysis concluded that glucagon-like peptide-1 (GLP-1) analogues were effective for the improvement of glycaemic control in patients with type 2 diabetes. What is the significance for the treatment of Danish patients with type 2 diabetes? In Denmark, two drugs exist, exenatid and...

  2. Studies on some biochemical aspects in the toad after 48 hours of exposure to simulated high altitude

    Biswas, H. M.; Boral, M. C.

    1983-06-01

    Blood glucose, tissue carbohydrate, total plasma and tissue protein and plasma electrolyte concentrations were estimated in male toads, exposed to simulated high altitude of 12,000, 18,000 and 24,000 feet respectively for 48 hours of continuous exposure in a decompression chamber. Blood glucose and muscle carbohydrate were decreased significantly in animals exposed to 18,000 and 24,000 feet altitude, without having any change in the liver carbohydrate. Muscle carbohydrate was also decreased in 12,000 feet altitude exposed animals. Plasma protein content was increased significantly in 18,000 and 24,000 feet altitude exposed animals, whereas no such change was noted in tissue protein content. A slight increase of plasma sodium concentration was found in animals exposed to 24,000 feet, and a decrease of potassium concentration was also noted in 18,000 and 24,000 feet exposed animals. Magnesium concentration of the plasma was increased in 18,000 and 24,000 feet exposed animals. This animal had also shown an eosinopenia, lymphopenia and neutrophilia when exposed at 24,000 feet high altitude.

  3. Association Rule Mining and Classifier Approach for 48-Hour Rainfall Prediction Over Cuddalore Station of East Coast of India

    S. Meganathan

    2013-04-01

    Full Text Available The methodology of data mining techniques has been presented for the rain forecasting models for the Cuddalore (11°43′ N/79°49′ E station of Tamilnadu in East Coast of India. Data mining approaches like classification and association mining was applied to generate results for rain prediction before 48 hour of the actual occurrence of the rain. The objective of this study is to demonstrate what relationship models are there between various atmospheric variables and to interconnect these variables according to the pattern obtained out of data mining technique. Using this approach rainfall estimates can be obtained to support the decisions to launch cloud-seeding operations. There are 3 main parts in this study. First, the obtained raw data was filtered using discretization approach based on the best fit ranges. Then, association mining has been performed on it using Predictive Apriori algorithm. Thirdly, the data has been validated using K* classifier approach. Results show that the overall classification accuracy of the data mining technique is satisfactory

  4. Gut-brain peptides in corticostriatal-limbic circuitry and alcohol use disorders

    Doo-SupChoi

    2014-09-01

    Full Text Available Peptides synthesized in endocrine cells in the gastrointestinal tract and neurons are traditionally considered regulators of metabolism, energy intake, and appetite. However, recent work has demonstrated that many of these peptides act on corticostriatal-limbic circuitry and, in turn, regulate addictive behaviors. Given that alcohol is a source of energy and an addictive substance, it is not surprising that increasing evidence supports a role for gut-brain peptides specifically in alcohol use disorders (AUD. In this review, we discuss the effects of several gut-brain peptides on alcohol-related behaviors and the potential mechanisms by which these gut-brain peptides may interfere with alcohol-induced changes in corticostriatal-limbic circuitry. This review provides a summary of current knowledge on gut-brain peptides focusing on five peptides: neurotensin, glucagon-like peptide 1, ghrelin, substance P, and neuropeptide Y. Our review will be helpful to develop novel therapeutic targets for AUD.

  5. Interactions of Gastrointestinal Peptides: Ghrelin and Its Anorexigenic Antagonists

    Anna-Sophia Wisser

    2010-01-01

    Full Text Available Food intake behaviour and energy homeostasis are strongly regulated by a complex system of humoral factors and nerval structures constituting the brain-gut-axis. To date the only known peripherally produced and centrally acting peptide that stimulates food intake is ghrelin, which is mainly synthesized in the stomach. Recent data indicate that the orexigenic effect of ghrelin might be influenced by other gastrointestinal peptides such as cholecystokinin (CCK, bombesin, desacyl ghrelin, peptide YY (PYY, as well as glucagon-like peptide (GLP. Therefore, we will review on the interactions of ghrelin with several gastrointestinal factors known to be involved in appetite regulation in order to elucidate the interdependency of peripheral orexigenic and anorexigenic peptides in the control of appetite.

  6. Regulation des Na+-D-Glucose Kotranporters SGLT1 im Dünndarm nach bariatrischen Operation und durch von Protein RS1 (RSC1A1) abgeleitete Peptide

    Rikkala, Prashanth Reddy

    2016-01-01

    Bariatrische Operationen repräsentieren die Behandlung erster Wahl bei krankhafter Fettleibigkeit, resultierend in Gewichtsverlust und verbesserter Diabetes-Kontrolle. Der positive Effekt bariatrischer Operationen auf den Typ-2 Diabetes ist unklar. Erhöhte Sekretion von Insulin, welches das Enterohormon „Glucagon-like-peptide 1“ (GLP-1) reguliert, wurde beobachtet bei Ratten mit experimentellem Typ 2-ähnlichem Diabetes nach duodenalem-jejunalem Bypass (DJB) und ilealer Transposition (IT). Der...

  7. Control of Insulin Secretion by Production of Reactive Oxygen Species: Study Performed in Pancreatic Islets from Fed and 48-Hour Fasted Wistar Rats

    Riva, Patrícia; Simões, Daniel; Curi, Rui; Carpinelli, Angelo Rafael

    2016-01-01

    Mitochondria and NADPH oxidase are important sources of reactive oxygen species in particular the superoxide radical (ROS) in pancreatic islets. These molecules derived from molecular oxygen are involved in pancreatic β-cells signaling and control of insulin secretion. We examined the involvement of ROS produced through NADPH oxidase in the leucine- and/or glucose-induced insulin secretion by pancreatic islets from fed or 48-hour fasted rats. Glucose-stimulated insulin secretion (GSIS) in isolated islets was evaluated at low (2.8 mM) or high (16.7 mM) glucose concentrations in the presence or absence of leucine (20 mM) and/or NADPH oxidase inhibitors (VAS2870–20 μM or diphenylene iodonium—DPI—5 μM). ROS production was determined in islets treated with dihydroethidium (DHE) or MitoSOX Red reagent for 20 min and dispersed for fluorescence measurement by flow cytometry. NADPH content variation was examined in INS-1E cells (an insulin secreting cell line) after incubation in the presence of glucose (2.8 or 16.7 mM) and leucine (20 mM). At 2.8 mM glucose, VAS2870 and DPI reduced net ROS production (by 30%) and increased GSIS (by 70%) in a negative correlation manner (r = -0.93). At 16.7 mM glucose or 20 mM leucine, both NADPH oxidase inhibitors did not alter insulin secretion neither net ROS production. Pentose phosphate pathway inhibition by treatment with DHEA (75 μM) at low glucose led to an increase in net ROS production in pancreatic islets from fed rats (by 40%) and induced a marked increase (by 144%) in islets from 48-hour fasted rats. The NADPH/NADP+ ratio was increased when INS-1E cells were exposed to high glucose (by 4.3-fold) or leucine (by 3-fold). In conclusion, increased ROS production through NADPH oxidase prevents the occurrence of hypoglycemia in fasting conditions, however, in the presence of high glucose or high leucine levels, the increased production of NADPH and the consequent enhancement of the activity of the antioxidant defenses

  8. Radiopharmaceutical development of radiolabelled peptides

    Fani, Melpomeni; Maecke, Helmut R. [University Hospital Freiburg, Department of Nuclear Medicine, Freiburg (Germany)

    2012-02-15

    Receptor targeting with radiolabelled peptides has become very important in nuclear medicine and oncology in the past few years. The overexpression of many peptide receptors in numerous cancers, compared to their relatively low density in physiological organs, represents the molecular basis for in vivo imaging and targeted radionuclide therapy with radiolabelled peptide-based probes. The prototypes are analogs of somatostatin which are routinely used in the clinic. More recent developments include somatostatin analogs with a broader receptor subtype profile or with antagonistic properties. Many other peptide families such as bombesin, cholecystokinin/gastrin, glucagon-like peptide-1 (GLP-1)/exendin, arginine-glycine-aspartic acid (RGD) etc. have been explored during the last few years and quite a number of potential radiolabelled probes have been derived from them. On the other hand, a variety of strategies and optimized protocols for efficient labelling of peptides with clinically relevant radionuclides such as {sup 99m}Tc, M{sup 3+} radiometals ({sup 111}In, {sup 86/90}Y, {sup 177}Lu, {sup 67/68}Ga), {sup 64/67}Cu, {sup 18}F or radioisotopes of iodine have been developed. The labelling approaches include direct labelling, the use of bifunctional chelators or prosthetic groups. The choice of the labelling approach is driven by the nature and the chemical properties of the radionuclide. Additionally, chemical strategies, including modification of the amino acid sequence and introduction of linkers/spacers with different characteristics, have been explored for the improvement of the overall performance of the radiopeptides, e.g. metabolic stability and pharmacokinetics. Herein, we discuss the development of peptides as radiopharmaceuticals starting from the choice of the labelling method and the conditions to the design and optimization of the peptide probe, as well as some recent developments, focusing on a selected list of peptide families, including somatostatin

  9. Effects of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concentrations in healthy subjects

    Hlebowicz, Joanna; Hlebowicz, Anna; Lindstedt, Sandra;

    2009-01-01

    BACKGROUND: A previous study of healthy subjects showed that intake of 6 g cinnamon with rice pudding reduced postprandial blood glucose and the gastric emptying rate (GER) without affecting satiety. OBJECTIVE: The objective was to study the effect of 1 and 3 g cinnamon on GER, postprandial blood...... and without 1 or 3 g cinnamon. Fifteen healthy subjects were assessed in a crossover trial. RESULTS: The addition of 1 or 3 g cinnamon had no significant effect on GER, satiety, glucose, GIP, or the ghrelin response. The insulin response at 60 min and the area under the curve (AUC) at 120 min were...... significantly lower after ingestion of rice pudding with 3 g cinnamon (P = 0.05 and P = 0.036, respectively, after Bonferroni correction). The change in GLP-1 response (DeltaAUC) and the change in the maximum concentration (DeltaC(max)) were both significantly higher after ingestion of rice pudding with 3 g...

  10. Disrupted dynamics of F-actin and insulin granule fusion in INS-1 832/13 beta-cells exposed to glucotoxicity: partial restoration by glucagon-like peptide 1.

    Quinault, Aurore; Gausseres, Blandine; Bailbe, Danielle; Chebbah, Nella; Portha, Bernard; Movassat, Jamileh; Tourrel-Cuzin, Cecile

    2016-08-01

    Actin dynamics in pancreatic β-cells is involved in insulin exocytosis but the molecular mechanisms of this dynamics and its role in biphasic insulin secretion in pancreatic β-cells is largely unknown. Moreover, the impact of a glucotoxic environment on the sub-cortical actin network dynamics is poorly studied. In this study, we investigate the behavior of insulin granules and the subcortical actin network dynamics in INS-1 832/13 β-cells submitted to a normal or glucotoxic environment. Our results show that glucose stimulation leads to a reorganization of the subcortical actin network with a rupture of its interactions with t-SNARE proteins (Syntaxin 1A and SNAP-25), promoting insulin secretion in INS-1 832/13 β-cells. Prolonged exposure of INS-1 832/13 β-cells to high-glucose levels (glucotoxicity) leads to the densification of the cortical actin network, which prevents its reorganization under acute glucose, and diminishes the glucose-stimulated insulin secretion, as shown by the decreased number of fusion events. The most interesting in our results is the partial restoration by GLP-1 of the insulin secretion ability from high-glucose treated INS-1 832/13 cells. This improved insulin exocytosis is associated with partial restored actin dynamics and fusion events during the two phases of the secretion, with a preferential involvement of Epac2 signaling in the first phase and a rather involvement of PKA signaling in the second phase of insulin exocytosis. All these data provide some new insights into the mechanism by which current therapeutics may be improving insulin secretion. PMID:27101990

  11. Lower glucose-dependent insulinotropic polypeptide (GIP) response but similar glucagon-like peptide 1 (GLP-1), glycaemic, and insulinaemic response to ancient wheat compared to modern wheat depends on processing

    Bakhøj, S; Flint, A; Holst, Jens Juul;

    2003-01-01

    to the responses to bread of modern wheat (Triticum aestivum). DESIGN: The 3-h postprandial insulinaemic, glycaemic, GIP, and GLP-1 responses to bread made from Einkorn were compared to responses to a traditional Danish wheat loaf. The bread from Einkorn was prepared by 3 different processing methods...

  12. 胰高血糖素样肽-2及其受体与胃肠道的发育%Glucagon like peptide-2, its recptor as well as gastrointestinal development

    王丽娜; 陈杰; 赵茹茜

    2006-01-01

    胰高血糖素样肽-2(GLP-2)是由胰高血糖素原基因表达并切割得到的一种33肽.它在肠道、胰腺及脑中都有表达,组织特异性的加工过程使得胰高血糖素原在不同的组织表达产物不同,肠道中以GLP-1和GLP-2为主.肠道中GLP在营养物质、神经系统及内分泌激素的调控下由L细胞分泌,最终又被二酰肽肽酶Ⅳ(DPPⅣ)降解经肾脏代谢掉.经DPPⅣ降解后得到的产物GLP-2(3-33)可以作为GLP-2的拮抗剂使用.GLP-2能通过抑制胃肠的运动和分泌,加快营养的转运,从而增强肠道对营养物质的吸收能力.此外GLP-2还被报道有抑制摄食的作用.GLP-2对肠道的营养作用主要表现为刺激隐窝细胞的增殖,抑制黏膜细胞的凋亡.GLP-2是通过G蛋白偶联受体发挥作用的,而GLP-2受体(GLP-2R)在肠道主要在神经元细胞和内分泌细胞上,其中的信号转导机制目前看来包含多种途径.从其对胃肠道的作用出发,有广阔的应用前景.

  13. Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes – a randomized, single-blinded, cross-over pilot study

    Faber, Rebekka; Zander, Mette; Pena, Adam;

    2015-01-01

    either the GLP-1 analogue liraglutide or received no treatment for 10 weeks, in a randomized, single-blinded, cross-over setup with a 2 weeks wash-out period. The effect of liraglutide on coronary microcirculation was evaluated using non-invasive trans-thoracic Doppler-flow echocardiography during...... 33.1 ± 4.4, mean baseline CFR 2.35 ± 0.45). There was a small increase in CFR following liraglutide treatment (change 0.18, CI95% [-0.01; 0.36], p = 0.06) but no difference in effect in comparison with no treatment (difference between treatment allocation 0.16, CI95% [-0.08; 0.40], p = 0...

  14. 胰高血糖素样肽-1的生物学及相关药物研究%Botanical and pharmaceutical research on glucagon-like peptide-1

    李磊; 李立安

    2012-01-01

    19 世纪60 年代发现了肠道对葡萄糖具有调节作用.这种生理现象主要是由两个被称为"肠促胰素"的肠内因子:胰高糖素样肽-1(7-37)/(7-36)酰胺和葡萄糖依赖性促胰岛素多肽(1-42)介导的.GLP-1 与GLP-1 受体的结合,刺激cAMP 生成,增加葡萄糖依赖性胰岛素分泌.研究还证明在体外人的胰岛制备中,GLP-1 介导β- 细胞凋亡的减弱和胰岛素反应性增强.很明显GLP-1/GLP-1 受体轴是葡萄糖代谢的关键性生理调节器,因此GLP-1 受体激动剂和DPP-4 抑制剂成为治疗糖尿病药物研发的焦点.

  15. A randomised controlled trial of opioid only versus combined opioid and non-steroidal anti inflammatory analgesics for pain relief in the first 48 hours after Caesarean section

    Natalia Adamou

    2014-01-01

    Full Text Available Background: Post-Caesarean section pain is complex in nature, requiring a combination of pharmacological and non-pharmacological methods. Effective management of postoperative pain will reduce postoperative morbidity, hospital stay and cost. The objective of this study was to compare the clinical effectiveness and adverse effects of a combination of non-selective cyclooxygenase (COX inhibitor (Diclofenac sodium 50 mg and opioid (Pentazocine 60 mg to opiod only (Pentazocine 60 mg for pain management after Caesarean section (CS at Aminu Kano Teaching Hospital (AKTH. Materials and Methods: This was a randomised double-blind controlled study conducted at AKTH, Kano, Nigeria. A total of 166 patients scheduled to undergo either emergency or elective Caesarean section were studied. Group I received a combination of COX inhibitor and opiod while Group II received opiod only for pain management after CS. Results: The average age of the patients was 28.35 years (SD ± 6.426 in the group I and 26.9(SD ± 6.133 in group II. The mean parity was 3.27(SD ± 2.67 and 2.75(SD ± 2.14 while the mean gestational age at admission was 37.68(SD ± 2.69 and 38.18(SD ± 2.63 weeks in the first and second groups, respectively. Comparison of the level of pain experienced and patients satisfaction during the first 48 hours postoperatively revealed that the level of pain was statistically significantly less and patient′s satisfaction significantly better in group I compared to group II (P-value 0.00001. Conclusion: The use of combined compared to single agent analgesia is safe, significantly reduced pain and improved patient satisfaction after a caesarian section (CS.

  16. Updates in weight loss surgery and gastrointestinal peptides

    Svane, Maria Saur; Bojsen-Møller, Kirstine N; Madsbad, Sten;

    2015-01-01

    PURPOSE OF REVIEW: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy are referred to as 'metabolic surgery' due to hormonal shifts with impacts on diabetes remission and weight loss. The purpose of this review is to summarize recent findings in mechanisms underlying beneficial effects of...... weight loss surgery. RECENT FINDINGS: Importantly, gut hormone secretion is altered after RYGB and sleeve gastrectomy due to accelerated transit of nutrients to distal parts of the small intestine, leading to excessive release of L-cell peptide hormones [e.g. glucagon-like peptide-1 (GLP-1), peptide YY...... demonstrated by relapse of impaired glucose tolerance in studies blocking the GLP-1 receptor by exendin 9-39, and later after major weight loss increased peripheral insulin sensitivity. Gut hormone secretion changes towards a more anorectic profile and is likely important for less caloric intake and weight...

  17. Lessons learned from the clinical development of oral peptides.

    Karsdal, Morten Asser; Riis, Bente Juul; Mehta, Nozer; Stern, William; Arbit, Ehud; Christiansen, Claus; Henriksen, Kim

    2015-05-01

    The oral delivery of peptides and proteins has been hampered by an array of obstacles. However, several promising novel oral delivery systems have been developed. This paper reviews the most advanced oral formulation technologies, and highlights key lessons and implications from studies undertaken to date with these oral formulations. Special interest is given to oral salmon calcitonin (CT), glucagon-like peptide-1 (GLP-1), insulin, PYY-(3-36), recombinant human parathyroid hormone (rhPTH(1-31)-NH2) and PTH(1-34), by different technologies. The issues addressed include (i) interaction with water, (ii) interaction with food, (iii) diurnal variation, (iv) inter- and intra-subject variability, (v) correlation between efficacy and exposure and (vi) key deliverables of different technologies. These key lessons may aid research in the development of other oral formulations. PMID:25408230

  18. GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow

    Guan, Xinfu; Karpen, Heidi E; Stephens, John;

    2006-01-01

    BACKGROUND & AIMS: Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive hormone that exerts diverse actions in the gastrointestinal tract, including enhancing epithelial cell survival and proliferation, mucosal blood flow, and nutrient uptake and suppressing gastric motility and secretion...... in the gut. METHODS: Intestinal cellular GLP-2R localization was determined with real-time, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of laser capture microdissected subtissue and fluorescence in situ hybridization and also with double and/or triple immunostaining of...

  19. Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1.

    Horner, Katy; Lee, SoJung

    2015-11-01

    During childhood and adolescence, a number of factors, including age, puberty, sex, race, and body composition, may contribute to differences in satiety, food intake, and appetite-related peptides. These peptides include the orexigenic peptide ghrelin and anorexigenic gut peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). For example, lower fasting ghrelin levels, lower postprandial ghrelin suppression, and blunted PYY and GLP-1 responses to food intake could contribute to a dysregulation of appetite in already obese children and adolescents. Whereas, changes in these peptides observed during puberty could facilitate growth. A greater understanding of the major moderating factors of appetite-related peptides in the pediatric population is essential to improve interpretation of study findings and for effective tailoring of strategies targeting appetite control to individuals. While more studies are needed, there is some evidence to suggest that exercise-based lifestyle interventions could be a potential therapeutic strategy to improve appetite-peptide profiles in overweight and obese children and adolescents. The aim of this review is (i) to discuss the potential moderating factors of ghrelin, PYY, and GLP-1, including age and puberty, sex, race and body composition; and (ii) to examine the effects of exercise interventions on these appetite-related gut peptides in children and adolescents. PMID:26466085

  20. Relationships among tonic and episodic aspects of motivation to eat, gut peptides, and weight before and after bariatric surgery

    Bryant, Eleanor J; King, Neil A; Falkén, Ylva;

    2012-01-01

    BACKGROUND: The interaction between motivation to eat, eating behavior traits, and gut peptides after Roux-en-Y gastric bypass (RYGB) surgery is not fully understood. METHODS: Appetite and hormone responses to a fixed liquid preload were assessed in 12 obese (body mass index 45±1.9 kg/m(2......)) participants immediately before and 3 days, 2 months, and 1 year after RYGB surgery. Subjective appetite and plasma levels of ghrelin, leptin, insulin, and glucagon-like peptide-1 (GLP-1) were measured for a 3-hour postprandial period. Eating behavior traits were also measured using the Three Factor Eating...... subjective appetite ratings and alterations in appetite peptides favoring an anorectic response. Presurgery EE was significantly related to fasting and area under the curve (AUC) ghrelin; UE was associated with AUC desire to eat, and there was a significant association between fasting desire to eat and...

  1. Heterogeneity of glucagonomas due to differential processing of proglucagon-derived peptides

    Challis, Benjamin G; Albrechtsen, Nicolai J Wewer; Bansiya, Vishakha;

    2015-01-01

    was increased production of intact glucagon-like peptide 1 (GLP-1) and GLP-2, similar to that of the enteroendocrine L cell. In case 2, pancreatic glucagon was elevated due to a pancreatic α-cell-like proglucagon processing profile. In summary, we describe two patients with pNETs and heterogeneous......UNLABELLED: Pancreatic neuroendocrine tumours (pNETs) secreting proglucagon are associated with phenotypic heterogeneity. Here, we describe two patients with pNETs and varied clinical phenotypes due to differential processing and secretion of proglucagon-derived peptides (PGDPs). Case 1, a 57-year...... clinical phenotypes due to differential processing and secretion of PGDPs. This is the first description of a patient with symptomatic hyperinsulinaemic hypoglycaemia and marked gastrointestinal dysfunction due to, in part, a proglucagon-expressing pNET. LEARNING POINTS: PGDPs exhibit a diverse range of...

  2. Imaging tumors with peptide-based radioligands

    Behr, T. M.; Gotthardt, M.; Barth, A.; Behe, M. [Philipps-University of Marburg, Dept. of Nuclear Medicine, Marburg (Germany)

    2001-06-01

    derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands, e.g. among many others, gastrin-releasing peptide/bombesin, neurotensin, substance-P, pan-somatostatin (somatostatin derivatives which bind to all five receptor subtypes) or glucagon-like peptide-1 (glp-1) analogs (the latter for the specific detection of insulinomas), is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Future work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.

  3. Peptide production and secretion in GLUTag, NCI-H716 and STC-1 cells: a comparison to native L-cells

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Deacon, Carolyn F.;

    2016-01-01

    samples; n=9 from different passage numbers) or peptide secretion in response to buffer (baseline), and after stimulation with 50 mM KCl or 10 mM glucose + 10 µM forskolin/3-isobutyl-1-methylxanthine (n=6 also different passage numbers). All cell lines produced and processed proglucagon into GLP-1, GLP-2......GLUTag, NCI-H716 and STC-1 are cell lines that are widely used to study mechanisms underlying secretion of glucagon-like peptide (GLP-1), but the extent to which they resemble native L-cells is unknown. We used validated immunoassays for 14 different hormones to analyze peptide content (lysis......, glicentin and oxyntomodulin in a pattern (prohormone convertase (PC)1/3 dependent) similar to that described for human gut. All three cell lines showed basal secretion of GLP-1 and -2 which increased after stimulation. In contrast to freshly isolated murine L-cells, all lines also expressed PC2 and secreted...

  4. In vitro activity of naturally occurring peptides (defensins against Listeria monocytogenes

    Nascimento Maria da Graça F.

    1994-01-01

    Full Text Available Autoclaved distilled water samples were inoculated with L. monocytogenes strain V7 and strain VPH-1, and incubated aerobically, at 30 C for 48 hours. Each strain was tested individually, and growth curves were determined at 1, 2, 3, 4, 5, 21, 24, and 48 hours. The growth or survival of L. monocytogenes was similar for both strains, with survivors at 24 hour-incubation. The microbicidal activity of one synthetic cationic peptide (NP-2 was examined against L. monocytogenes strain V7, in a water system. Antibacterial activity of NP-2 (1, 5, and 10 g/ml was best expressed at 60 minute-incubation, with 10 g/ml of peptide, at 30 C.

  5. B-Type Natriuretic Peptide in the Critically Ill with Acute Kidney Injury

    Massimo de Cal; Mikko Haapio; Cruz, Dinna N.; Paolo Lentini; Andrew A. House; Ilona Bobek; Grazia M. Virzì; Valentina Corradi; Flavio Basso; Pasquale Piccinni; Angela D'Angelo; Chang, Jamie W.; Rosner, Mitchell H.; Claudio Ronco

    2011-01-01

    Introduction. Acute kidney injury (AKI) is common in the intensive care unit (ICU) and associated with poor outcome. Plasma B-type natriuretic peptide (BNP) is a biomarker related to myocardial overload, and is elevated in some ICU patients. There is a high prevalence of both cardiac and renal dysfunction in ICU patients. Aims. To investigate whether plasma BNP levels in the first 48 hours were associated with AKI in ICU patients. Methods. We studied a cohort of 34 consecutive ICU patients. P...

  6. Endogenous Bioactive Peptides as Potential Biomarkers for Atherosclerotic Coronary Heart Disease

    Tsutomu Hirano

    2012-04-01

    Full Text Available Cardiovascular disease is the leading cause of death worldwide, with high medical costs and rates of disability. It is therefore important to evaluate the use of cardiovascular biomarkers in the early diagnosis of coronary artery disease (CAD. We have screened a variety of recently identified bioactive peptides candidates in anticipation that they would allow detection of atherosclerotic CAD. Especially, we have focused on novel anti-atherogenic peptides as indicators and negative risk factors for CAD. In vitro, in vivo and clinical studies indicated that human adiponectin, heregulin-β1, glucagon-like peptide-1 (GLP-1, and salusin-α, peptides of 244, 71, 30, and 28 amino acids, respectively, attenuate the development and progression of atherosclerotic lesions by suppressing macrophage foam cell formation via down-regulation of acyl-coenzyme A: cholesterol acyltransferase-1. Circulating levels of these peptides in the blood are significantly decreased in patients with CAD compared to patients without CAD. Receiver operating characteristic analyses showed that salusin-α is a more useful biomarker, with better sensitivity and specificity, compared with the others for detecting CAD. Therefore, salusin-α, heregulin-β1, adiponectin, and/or GLP-1, alone or in various combinations, may be useful as biomarkers for atherosclerotic CAD.

  7. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose- and non-glucose-induced insulin secretion in patients with type 2 diabetes mellitus

    Aaboe, Kasper; Knop, Filip Krag; Vilsbøll, Tina; Deacon, Carolyn F.; Holst, Jens Juul; Madsbad, Sten; Krarup, Thure

    2010-01-01

    AIM: To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients...... with type 2 diabetes. METHOD: A double-blinded, placebo-controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add-on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90-min 20 m......M hyperglycaemic clamp with 5 g of l-arginine infusion. Main outcome measure was postprandial total glucagon-like peptide 1 (GLP-1) concentration. Additional measures were insulin and C-peptide, glycaemic control, intact and total peptide YY (PYY) and glucose-dependent insulinotropic polypeptide (GIP), and intact...

  8. Improved glucose control and reduced body weight in rodents with dual mechanism of action peptide hybrids.

    Trevaskis, James L; Mack, Christine M; Sun, Chengzao; Soares, Christopher J; D'Souza, Lawrence J; Levy, Odile E; Lewis, Diane Y; Jodka, Carolyn M; Tatarkiewicz, Krystyna; Gedulin, Bronislava; Gupta, Swati; Wittmer, Carrie; Hanley, Michael; Forood, Bruce; Parkes, David G; Ghosh, Soumitra S

    2013-01-01

    Combination therapy is being increasingly used as a treatment paradigm for metabolic diseases such as diabetes and obesity. In the peptide therapeutics realm, recent work has highlighted the therapeutic potential of chimeric peptides that act on two distinct receptors, thereby harnessing parallel complementary mechanisms to induce additive or synergistic benefit compared to monotherapy. Here, we extend this hypothesis by linking a known anti-diabetic peptide with an anti-obesity peptide into a novel peptide hybrid, which we termed a phybrid. We report on the synthesis and biological activity of two such phybrids (AC164204 and AC164209), comprised of a glucagon-like peptide-1 receptor (GLP1-R) agonist, and exenatide analog, AC3082, covalently linked to a second generation amylin analog, davalintide. Both molecules acted as full agonists at their cognate receptors in vitro, albeit with reduced potency at the calcitonin receptor indicating slightly perturbed amylin agonism. In obese diabetic Lep(ob)/Lep (ob) mice sustained infusion of AC164204 and AC164209 reduced glucose and glycated haemoglobin (HbA1c) equivalently but induced greater weight loss relative to exenatide administration alone. Weight loss was similar to that induced by combined administration of exenatide and davalintide. In diet-induced obese rats, both phybrids dose-dependently reduced food intake and body weight to a greater extent than exenatide or davalintide alone, and equal to co-infusion of exenatide and davalintide. Phybrid-mediated and exenatide + davalintide-mediated weight loss was associated with reduced adiposity and preservation of lean mass. These data are the first to provide in vivo proof-of-concept for multi-pathway targeting in metabolic disease via a peptide hybrid, demonstrating that this approach is as effective as co-administration of individual peptides. PMID:24167604

  9. Improved glucose control and reduced body weight in rodents with dual mechanism of action peptide hybrids.

    James L Trevaskis

    Full Text Available Combination therapy is being increasingly used as a treatment paradigm for metabolic diseases such as diabetes and obesity. In the peptide therapeutics realm, recent work has highlighted the therapeutic potential of chimeric peptides that act on two distinct receptors, thereby harnessing parallel complementary mechanisms to induce additive or synergistic benefit compared to monotherapy. Here, we extend this hypothesis by linking a known anti-diabetic peptide with an anti-obesity peptide into a novel peptide hybrid, which we termed a phybrid. We report on the synthesis and biological activity of two such phybrids (AC164204 and AC164209, comprised of a glucagon-like peptide-1 receptor (GLP1-R agonist, and exenatide analog, AC3082, covalently linked to a second generation amylin analog, davalintide. Both molecules acted as full agonists at their cognate receptors in vitro, albeit with reduced potency at the calcitonin receptor indicating slightly perturbed amylin agonism. In obese diabetic Lep(ob/Lep (ob mice sustained infusion of AC164204 and AC164209 reduced glucose and glycated haemoglobin (HbA1c equivalently but induced greater weight loss relative to exenatide administration alone. Weight loss was similar to that induced by combined administration of exenatide and davalintide. In diet-induced obese rats, both phybrids dose-dependently reduced food intake and body weight to a greater extent than exenatide or davalintide alone, and equal to co-infusion of exenatide and davalintide. Phybrid-mediated and exenatide + davalintide-mediated weight loss was associated with reduced adiposity and preservation of lean mass. These data are the first to provide in vivo proof-of-concept for multi-pathway targeting in metabolic disease via a peptide hybrid, demonstrating that this approach is as effective as co-administration of individual peptides.

  10. Pancreatic and intestinal processing of proglucagon in man

    Holst, J J; Poulsen, Steen Seier

    1987-01-01

    acids. With these tools, we studied the localisation and molecular nature of glucagon-like immunoreactivity in human pancreas, small intestine and plasma. By immunohistochemistry glucagon-like peptide-1, and glucagon-like peptide-2 immunoreactivity coexisted with glucagon in pancreatic islet cells and...... with enteroglucagon in small intestinal enteroglucagon-producing cells. By chromatography of tissue extracts we found that glucagon-like peptide-1 and glucagon-like peptide-2-immunoreactivities in the human pancreas (307 +/- 51 and 107 +/- 37 pmol/g tissue) were mainly contained in a large peptide...

  11. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

    Madsbad, Sten; Schmitz, Ole; Ranstam, Jonas;

    2004-01-01

    .0003) compared with placebo. Improvement in glycemic control was evident after 1 week. Body weight decreased by 1.2 kg in the 0.45-mg liraglutide group (P = 0.0184) compared with placebo. The proinsulin-to-insulin ratio decreased in the 0.75-mg liraglutide group (-0.18; P = 0.0244) compared with placebo...

  12. 治疗糖尿病的中国药物专利分析——以胰高血糖素样肽-1(GLP-1)类药物为例%Chinese Medicines Patent Analysis for Diabetes——for Glucagon-like Peptide-1 (GLP-1)

    王冲

    2014-01-01

    利用国家知识产权局专利信息服务平台对GLP-1类药物的中国专利进行数据检索、清洗和分析,对时间序列数据采用“累计分析”方法,并对两个在中国上市的GLP-1药品进行专利分析.结果发现,目前GLP-1类药物的专利申请受市场发展影响非常大,专利申请处于快速增长期,中国申请人的专利申请比例在不断增加,GLP-1相关技术目前还主要掌握在诺和诺德和礼来这两家有GLP-1药品上市的公司手中.该专利分析能为GLP-1技术的进一步开发及完善提供参考和依据.

  13. Short-term aerobic exercise training improves gut peptide regulation in nonalcoholic fatty liver disease.

    Kullman, Emily L; Kelly, Karen R; Haus, Jacob M; Fealy, Ciaran E; Scelsi, Amanda R; Pagadala, Mangesh R; Flask, Chris A; McCullough, Arthur J; Kirwan, John P

    2016-05-15

    Obesity-related nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease. Exercise and diet are uniformly prescribed treatments for NAFLD; however, there are limited empirical data on the effects of exercise training on metabolic function in these patients. The purpose of this study was to investigate the fasting and glucose-stimulated adaptation of gut peptides to short-term aerobic exercise training in patients with NAFLD. Twenty-two obese subjects, 16 with NAFLD [body mass index (BMI), 33.2 ± 1.1 (SE) kg/m(2)] and 6 obese controls (BMI, 31.3 ± 1.2 kg/m(2)), were enrolled in a supervised aerobic exercise program (60 min/day, 85% of their heart rate maximum, for 7 days). Fasting and glucose-stimulated glucagon-like peptide-1 (GLP-17-36) and peptide tyrosine tyrosine (PYYTotal) concentrations in plasma were assessed before and after the exercise program. Initially, the NAFLD group had higher fasting PYY (NAFLD = 117 ± 18.6, control = 47.2 ± 6.4 pg/ml, P obese adults with NAFLD. PMID:27032902

  14. Effect of abomasal glucose infusion on plasma concentrations of gut peptides in periparturient dairy cows

    Larsen, Mogens; Relling, A E; Reynolds, C K;

    2010-01-01

    Six Holstein cows fitted with ruminal cannulas and permanent indwelling catheters in the portal vein, hepatic vein, mesenteric vein, and an artery were used to study the effects of abomasal glucose infusion on splanchnic plasma concentrations of gut peptides. The experimental design was a randomi......Six Holstein cows fitted with ruminal cannulas and permanent indwelling catheters in the portal vein, hepatic vein, mesenteric vein, and an artery were used to study the effects of abomasal glucose infusion on splanchnic plasma concentrations of gut peptides. The experimental design...... was a randomized block design with repeated measurements. Cows were assigned to one of 2 treatments: control or infusion of 1,500 g of glucose/d into the abomasum from the day of parturition to 29 d in milk. Cows were sampled 12 ± 6 d prepartum and at 4, 15, and 29 d in milk. Concentrations of glucose......-dependent insulinotropic polypeptide, glucagon-like peptide 1(7-36) amide, and oxyntomodulin were measured in pooled samples within cow and sampling day, whereas active ghrelin was measured in samples obtained 30 min before and after feeding at 0800 h. Postpartum, dry matter intake increased at a lower rate with infusion...

  15. Psyllium fiber-enriched meal strongly attenuates postprandial gastrointestinal peptide release in healthy young adults

    Karhunen, Leila J.; Juvonen, Kristiina R.; Flander, Sanna M.;

    2010-01-01

    Dietary fiber (DF) and protein are essential constituents of a healthy diet and are well known for their high satiety impact. However, little is known about their influence on postprandial gastrointestinal (GI) peptide release. Our aim in this single-blind, randomized, cross-over study was to.......8 g) and fiber (7.6 g); 2) low in protein (2.6 g) and high in soluble fiber (psyllium, 23.0 g); 3) high in protein (soy, 19.7 g) and low in fiber (6.2 g); 4) high in protein (18.4 g) and fiber (23.0 g); and 5) white wheat bread. Serum insulin and plasma glucose, ghrelin, glucagon-like peptide 1 (GLP-1......), and peptide YY (PYY) concentrations were determined for 2 h following the meals. In addition, hunger and satiety ratings were collected. Postprandial glucose, insulin, ghrelin, GLP-1, and PYY responses all differed among the meals (P 0.05). Fiber-enriched meals decreased glucose, insulin, ghrelin, and...

  16. Peptide dendrimers

    Niederhafner, Petr; Šebestík, Jaroslav; Ježek, Jan

    2005-01-01

    Roč. 11, - (2005), 757-788. ISSN 1075-2617 R&D Projects: GA ČR(CZ) GA203/03/1362 Institutional research plan: CEZ:AV0Z40550506 Keywords : multiple antigen peptides * peptide dendrimers * synthetic vaccine * multipleantigenic peptides Subject RIV: CC - Organic Chemistry Impact factor: 1.803, year: 2005

  17. Peptide inhibition of human cytomegalovirus infection

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  18. Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides.

    Steinert, Robert E; Frey, Florian; Töpfer, Antonia; Drewe, Jürgen; Beglinger, Christoph

    2011-05-01

    In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250 ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy-d-glucose. Glucose stimulated GLP-1 (P = 0·002) and peptide tyrosine tyrosine (PYY; P = 0·046) secretion and reduced fasting plasma ghrelin (P = 0·046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucose. PMID:21255472

  19. 48-hour ambulatory electrocardiography in dynamite workers and controls

    Hogstedt, C; Söderholm, B; Bodin, L

    1980-01-01

    ABSTRACT Sudden deaths and chronic cardiovascular diseases have been reported in excess frequency from the explosives industry. Forty-two active dynamite workers and 43 healthy, unexposed workers have been studied by ambulatory electrocardiographic monitoring during two 24-hour periods covering an exposed shift and the “abstinence phase,” 40-64 hours after the last exposure to dynamite. To achieve comparability the non-exposed individuals were screened for risk factors of heart disease in the...

  20. Glucose turnover in 48-hour-fasted running rats

    In fed rats, hyperglycemia develops during exercise. This contrasts with the view based on studies of fasted human and dog that euglycemia is maintained in exercise and glucose production (R/sub a/) controlled by feedback mechanisms. Forty-eight-hour-fasted rats (F) were compared to fed rats (C) and overnight food-restricted (FR) rats. [3-3H]- and [U-14C]glucose were infused and blood and tissue sampled. During running (21 m/min, 0% grade) R/sub a/ increased most in C and least in F and only in F did R/sub a/ not significantly exceed glucose disappearance. Plasma glucose increased more in C (3.3 mmol/1) than in FR (1.6 mmol/l) and only modestly (0.6 mmol/l) and transiently in F. Resting liver glycogen and exercise glycogenolysis were highest in C and similar in FR and F. Resting muscle glycogen and exercise glycogenolysis were highest in C and lowest in F. During running, lactate production and gluconeogenesis were higher in FR than in F. At least in rats, responses of production and plasma concentration of glucose to exercise depend on size of liver and muscle glycogen stores; glucose production matches increase in clearance better in fasted than in fed states. Probably glucose production is stimulated by feedforward mechanisms and feedback mechanisms are added if plasma glucose decreases

  1. NUTRALYS® pea protein: characterization of in vitro gastric digestion and in vivo gastrointestinal peptide responses relevant to satiety

    Joost Overduin

    2015-04-01

    Design: Under in vitro simulated gastric conditions, the digestion of NUTRALYS® pea protein was compared to that of two dairy proteins, slow-digestible casein and fast-digestible whey. In vivo, blood glucose and gastrointestinal hormonal (insulin, ghrelin, cholecystokinin [CCK], glucagon-like peptide 1 [GLP-1], and peptide YY [PYY] responses were monitored in nine male Wistar rats following isocaloric (11 kcal meals containing 35 energy% of either NUTRALYS® pea protein, whey protein, or carbohydrate (non-protein. Results: In vitro, pea protein transiently aggregated into particles, whereas casein formed a more enduring protein network and whey protein remained dissolved. Pea-protein particle size ranged from 50 to 500 µm, well below the 2 mm threshold for gastric retention in humans. In vivo, pea-protein and whey-protein meals induced comparable responses for CCK, GLP-1, and PYY, that is, the anorexigenic hormones. Pea protein induced weaker initial, but equal 3-h integrated ghrelin and insulin responses than whey protein, possibly due to the slower gastric breakdown of pea protein observed in vitro. Two hours after meals, CCK levels were more elevated in the case of protein meals compared to that of non-protein meals. Conclusions: These results indicate that 1 pea protein transiently aggregates in the stomach and has an intermediately fast intestinal bioavailability in between that of whey and casein; 2 pea-protein- and dairy-protein-containing meals were comparably efficacious in triggering gastrointestinal satiety signals.

  2. Shock of birth evaluation of neurologic status of term newborn in the first 48 hours of life Choque do nascimento: avaliação do vigor neurológico do recém-nascido a termo nas primeiras 48 horas de vida

    Rudimar Dos Santos Riesgo

    1996-09-01

    Full Text Available The shock of birth is a transient depression of muscle tone and deep tendon reflexes seen in newborn babies shortly after birth. We evaluated the shock of birth in a sample of 313 consecutive term newborns at 4, 24 and 48 hours of life. We correlated neurologic findings on examination with maternal, obstetric and perinatal data. Special attention was given to the relationship between the mode of delivery and shock of birth. Of the maternal data, factors associated with the shock of birth were obstetric gestational age, previous gestations, abortions or previous vaginal deliveries. Presence of stained amniotic fluid at birth was associated with the shock of birth. There was also a correlation between shock of birth and newborn sex, birth weight, thoracic circumference and the Battaglia and Lubchenco classification. The shock of birth lasted less than 24 hours in 70% of the newborns and less than 48 hours in 84.3%. We conclude that the mode of delivery, vaginal or cesarean section, did not influence the shock of birth. We also established the duration and factors associated with this phenomenon.O choque do nascimento é uma depressão temporária do tono muscular e reflexos em recém-nascidos. Nós o avaliamos em uma amostra de 313 recém-nascidos a termo, de partos consecutivos, examinados com 4,24 e 48 horas de vida. Correlacionamos os achados do exame neurológico com dados maternos, do parto e do recém-nascido, com ênfase na relação entre o tipo de parto e o choque do nascimento. Dentre os dados maternos, estiveram associados com o choque do nascimento: idade gestacional obstétrica, gestações, abortamentos e partos vaginais prévios. O único dado do parto que esteve associado foi a presença de líquido amniótico não claro. Sexo, peso ao nascimento, perímetro torácico e classificação de Battaglia & Lubchenco foram os dados do recém-nascido que estiveram associados com o evento. O choque do nascimento durou menos de 24 horas em

  3. Administration of a dipeptidyl peptidase IV inhibitor enhances the intestinal adaptation in a mouse model of short bowel syndrome

    Okawada, Manabu; Holst, Jens Juul; Teitelbaum, Daniel H

    2011-01-01

    Glucagon-like peptide-2 induces small intestine mucosal epithelial cell proliferation and may have benefit for patients who suffer from short bowel syndrome. However, glucagon-like peptide-2 is inactivated rapidly in vivo by dipeptidyl peptidase IV. Therefore, we hypothesized that selectively...... inhibiting dipeptidyl peptidase IV would prolong the circulating life of glucagon-like peptide-2 and lead to increased intestinal adaptation after development of short bowel syndrome....

  4. The Effects of Combined and Separate Application of YY3-36 and/or Glucagons-like Peptide-17-36 on the Appetite and the Blood Glucose in Health Population%肽YY3-36、胰升糖素样肽-1 7-36联合及单独用药对健康人群食欲和血糖的影响

    王芳; 朱大菊; 胡清; 孙明谨; 陈世清

    2005-01-01

    目的探讨肽YY3-36(PYY3-36)、胰升糖素样肽-17-36GLP-17-36)联合及单独用药对食欲和血糖的影响.方法健康志愿者行双盲对照,分别注射盐水(saline)、PYY3-36、GLP-17-36、PYY3-36+GLP-l7-36,观察其能量摄入情况.留取血样测定肽YY(PYY)、胰升糖素样肽-1(GLP-1)、葡萄糖、胰岛素.结果同盐水组比较,PYY3-36+GLP-17-36组、PYY3-36组及GLP-17-36组摄取食物能量明显减少(对能量摄取与盐水组相比较,其百分比依次为PYY3-36+GLP-17-36(-28±2%),PYY3-36(-15±6%),GLP-17-36(-5±5%);在PYY3-36+GLP-17-36组、PYY3-36组PYY浓度增加,GLP-17-36组下降.PYY3-36+GLP-17-36组、GLP-17-36组GLP-1浓度增加,PYY3-36组无明显变化;在GLP-17-36组、PYY3-36+GLP-17-36组输入90min时胰岛素浓度增加,PYY3Ⅳ组无明显变化.GLP-17-36组、PYY3-36GLP-17-36组输入90 min时血糖浓度降低,PYY3-36组无明显变化.结论PYY3-36+GLP-17-36有明显抑制食欲作用,其程度依次高于PYY3-36、GLP-17-36,且PYY3-36+GLP-17-36及GLP-17-36能降低血糖.

  5. Production of peptide antibiotics by Bacillus sp. GU 057 indigenously isolated from saline soil.

    Amin, Adnan; Khan, Muhammad Ayaz; Ehsanullah, Malik; Haroon, Uzma; Azam, Sheikh Muhammad Farooq; Hameed, Abdul

    2012-10-01

    A total of 112 soil samples were taken from differents areas of district D.I.Khan and Kohat (KPK) Pakistan and screened for production of antibiotics against the Micrococcus luteus and Staphylococcus aureus. Widest zone of inhibition (18mm) was produced by microorganism isolated from saline soil. The strain was later identified as Bacillus GU057 by standard biochemical assays. Maximum activity (18mm inhibition zone) was observed against Staphylococcus aureus after 48 hours of incubation at pH 8 and 4% concentration of glucose. The antibiotic was identified by autobiography as bacitracin. The Bacillus strain GU057 was confirmed as good peptide antibiotic producer and can effectively be indulged as biocontrol agent. PMID:24031962

  6. Production of peptide antibiotics by Bacillus sp: GU 057 indigenously isolated from saline soil

    Adnan Amin

    2012-12-01

    Full Text Available A total of 112 soil samples were taken from differents areas of district D.I.Khan and Kohat (KPK Pakistan and screened for production of antibiotics against the Micrococcus luteus and Staphylococcus aureus. Widest zone of inhibition (18mm was produced by microorganism isolated from saline soil. The strain was later identified as Bacillus GU057 by standard biochemical assays. Maximum activity (18mm inhibition zone was observed against Staphylococcus aureus after 48 hours of incubation at pH 8 and 4% concentration of glucose. The antibiotic was identified by autobiography as bacitracin. The Bacillus strain GU057 was confirmed as good peptide antibiotic producer and can effectively be indulged as biocontrol agent.

  7. Anticipatory and consummatory effects of (hedonic chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Antonello E. Rigamonti

    2015-11-01

    Full Text Available Background: Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods: To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1, peptide YY (PYY, anandamide (AEA, 2-AG, palmitoylethanolamide (PEA, and oleoylethanolamide (OEA in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results: The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions: When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  8. The Drosophila ortholog of TMEM18 regulates insulin and glucagon-like signaling.

    Wiemerslage, Lyle; Gohel, Priya A; Maestri, Giulia; Hilmarsson, Torfi G; Mickael, Michel; Fredriksson, Robert; Williams, Michael J; Schiöth, Helgi B

    2016-06-01

    Transmembrane protein 18 (TMEM18) is an ill-described, obesity-related gene, but few studies have explored its molecular function. We found single-nucleotide polymorphism data, suggesting that TMEM18 may be involved in the regulation/physiology of metabolic syndrome based on associations with insulin, homeostatic model assessment-β (HOMAβ), triglycerides, and blood sugar. We then found an ortholog in the Drosophila genome, knocked down Drosophila Tmem18 specifically in insulin-producing cells, and tested for its effects on metabolic function. Our results suggest that TMEM18 affects substrate levels through insulin and glucagon signaling, and its downregulation induces a metabolic state resembling type 2 diabetes. This work is the first to experimentally describe the metabolic consequences of TMEM18 knockdown, and further supports its association with obesity. PMID:27029472

  9. Human peptide transporters

    Nielsen, Carsten Uhd; Brodin, Birger; Jørgensen, Flemming Steen;

    2002-01-01

    Peptide transporters are epithelial solute carriers. Their functional role has been characterised in the small intestine and proximal tubules, where they are involved in absorption of dietary peptides and peptide reabsorption, respectively. Currently, two peptide transporters, PepT1 and PepT2, wh...

  10. Pituitary Adenlylate Cyclase Activating Peptide Protects Adult Neural Stem Cells from a Hypoglycaemic milieu.

    Mansouri, Shiva; Lietzau, Grazyna; Lundberg, Mathias; Nathanson, David; Nyström, Thomas; Patrone, Cesare

    2016-01-01

    Hypoglycaemia is a common side-effect of glucose-lowering therapies for type-2 diabetic patients, which may cause cognitive/neurological impairment. Although the effects of hypoglycaemia in the brain have been extensively studied in neurons, how hypoglycaemia impacts the viability of adult neural stem cells (NSCs) has been poorly investigated. In addition, the cellular and molecular mechanisms of how hypoglycaemia regulates NSCs survival have not been characterized. Recent work others and us have shown that the pituitary adenylate cyclase-activating polypeptide (PACAP) and the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 stimulate NSCs survival against glucolipoapoptosis. The aim of this study was to establish an in vitro system where to study the effects of hypoglycaemia on NSC survival. Furthermore, we determine the potential role of PACAP and Exendin-4 in counteracting the effect of hypoglycaemia. A hypoglycaemic in vitro milieu was mimicked by exposing subventricular zone-derived NSC to low levels of glucose. Moreover, we studied the potential involvement of apoptosis and endoplasmic reticulum stress by quantifying protein levels of Bcl-2, cleaved caspase-3 and mRNA levels of CHOP. We show that PACAP via PAC-1 receptor and PKA activation counteracts impaired NSC viability induced by hypoglycaemia. The protective effect induced by PACAP correlated with endoplasmic reticulum stress, Exendin-4 was ineffective. The results show that hypoglycaemia decreases NSC viability and that this effect can be substantially counteracted by PACAP via PAC-1 receptor activation. The data supports a potential therapeutic role of PAC-1 receptor agonists for the treatment of neurological complications, based on neurogenesis impairment by hypoglycaemia. PMID:27305000

  11. Peptidic exenatide and herbal catalpol mediate neuroprotection via the hippocampal GLP-1 receptor/β-endorphin pathway.

    Jia, Yu; Gong, Nian; Li, Teng-Fei; Zhu, Bin; Wang, Yong-Xiang

    2015-12-01

    Both peptidic agonist exenatide and herbal agonist catalpol of the glucagon-like peptide-1 receptor (GLP-1R) are neuroprotective. We have previously shown that activation of spinal GLP-1Rs expresses β-endorphin in microglia to produce antinociception. The aim of this study was to explore whether exenatide and catalpol exert neuroprotection via activation of the hippocampal GLP-1R/β-endorphin pathway. The rat middle cerebral artery occlusion model was employed, and the GLP-1R immunofluorescence staining and β-endorphin measurement were assayed in the hippocampus and primary cultures of microglia, neurons and astrocytes. The immunoreactivity of GLP-1Rs on microglia in the hippocampus was upregulated after ischemia reperfusion. Intracerebroventricular (i.c.v.) injection of exenatide and catalpol produced neuroprotection in the rat transient ischemia/reperfusion model, reflected by a marked reduction in brain infarction size and a mild recovery in neurobehavioral deficits. In addition, i.c.v. injection of exenatide and catalpol significantly stimulated β-endorphin expression in the hippocampus and cultured primary microglia (but not primary neurons or astrocytes). Furthermore, exenatide and catalpol neuroprotection was completely blocked by i.c.v. injection of the GLP-1R orthosteric antagonist exendin (9-39), specific β-endorphin antiserum, and selective opioid receptor antagonist naloxone. Our results indicate, for the first time, that the neuroprotective effects of catalpol and exenatide are GLP-1R-specific, and that these effects are mediated by β-endorphin expression probably in hippocampal microglia. We postulate that in contrast to the peripheral tissue, where the activation of GLP-1Rs in pancreas islet β-cells causes secretion of insulin to perform glucoregulation, it leads to β-endorphin expression in microglial cells to produce neuroprotection and analgesia in the central nervous system. PMID:26546042

  12. Regulation of feeding behavior and food intake by appetite-regulating peptides in wild-type and growth hormone-transgenic coho salmon.

    White, Samantha L; Volkoff, Helene; Devlin, Robert H

    2016-08-01

    Survival, competition, growth and reproductive success in fishes are highly dependent on food intake, food availability and feeding behavior and are all influenced by a complex set of metabolic and neuroendocrine mechanisms. Overexpression of growth hormone (GH) in transgenic fish can result in greatly enhanced growth rates, feed conversion, feeding motivation and food intake. The objectives of this study were to compare seasonal feeding behavior of non-transgenic wild-type (NT) and GH-transgenic (T) coho salmon (Oncorhynchus kisutch), and to examine the effects of intraperitoneal injections of the appetite-regulating peptides cholecystokinin (CCK-8), bombesin (BBS), glucagon-like peptide-1 (GLP-1), and alpha-melanocyte-stimulating hormone (α-MSH) on feeding behavior. T salmon fed consistently across all seasons, whereas NT dramatically reduced their food intake in winter, indicating the seasonal regulation of appetite can be altered by overexpression of GH in T fish. Intraperitoneal injections of CCK-8 and BBS caused a significant and rapid decrease in food intake for both genotypes. Treatment with either GLP-1 or α-MSH resulted in a significant suppression of food intake for NT but had no effect in T coho salmon. The differential response of T and NT fish to α-MSH is consistent with the melanocortin-4 receptor system being a significant pathway by which GH acts to stimulate appetite. Taken together, these results suggest that chronically increased levels of GH alter feeding regulatory pathways to different extents for individual peptides, and that altered feeding behavior in transgenic coho salmon may arise, in part, from changes in sensitivity to peripheral appetite-regulating signals. PMID:27149948

  13. Chronic infusion of opiate peptides to rat cerebrospinal fluid with osmotic minipumps.

    Saland, L C; Ortiz, E; Samora, A

    1984-09-01

    Beta-endorphin-related opiate peptides or the opiate antagonist naloxone were chronically infused for periods of 24 to 48 hours to the lateral cerebral ventricle of adult male rats using Alza osmotic minipumps. Previous studies have suggested a "chemotactic"-like effect of opiate peptides for supraependymal macrophages in the region of the third ventricle of the brain. The present study demonstrates a stimulatory effect of beta-endorphin infusion on the appearance of lymphocyte and neutrophil-like cells, in addition to macrophages, in the region of the third ventricle, suggestive of an intracerebral inflammatory response. None of the other molecules, including alpha-endorphin, methionine-enkephalin, naloxone, or sterile saline produced similar cellular responses after infusion, although some of the latter substances may have induced the appearance of supraependymal neuron-like cells in the area. Observations suggest that the chronic presence of beta-endorphin, a biologically active opiate peptide, will interact with cells of the immune system, which have the ability to gain access to the cerebrospinal fluid. PMID:6091499

  14. Peptide-Carrier Conjugation

    Hansen, Paul Robert

    To produce antibodies against synthetic peptides it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide-carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined.......To produce antibodies against synthetic peptides it is necessary to couple them to a protein carrier. This chapter provides a nonspecialist overview of peptide-carrier conjugation. Furthermore, a protocol for coupling cysteine-containing peptides to bovine serum albumin is outlined....

  15. PeptideAtlas

    U.S. Department of Health & Human Services — PeptideAtlas is a multi-organism, publicly accessible compendium of peptides identified in a large set of tandem mass spectrometry proteomics experiments. Mass...

  16. Peptider holder krabben rask

    Buchmann, Kurt

    Antimikrobielle Peptider har hos mere primitive dyr en vigtig funktion i organismernes immunforsvar Udgivelsesdato: 1. februar......Antimikrobielle Peptider har hos mere primitive dyr en vigtig funktion i organismernes immunforsvar Udgivelsesdato: 1. februar...

  17. Peptide Nucleic Acid Synthons

    2004-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  18. Peptide Nucleic Acids

    2003-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  19. Peptide Nucleic Acids

    1998-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  20. Peptide Nucleic Acids (PNA)

    2002-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  1. Antimicrobial Peptides in 2014

    Guangshun Wang

    2015-03-01

    Full Text Available This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms.

  2. PH dependent adhesive peptides

    Tomich, John; Iwamoto, Takeo; Shen, Xinchun; Sun, Xiuzhi Susan

    2010-06-29

    A novel peptide adhesive motif is described that requires no receptor or cross-links to achieve maximal adhesive strength. Several peptides with different degrees of adhesive strength have been designed and synthesized using solid phase chemistries. All peptides contain a common hydrophobic core sequence flanked by positively or negatively charged amino acids sequences.

  3. Inhibition of atrial natriuretic peptide-induced natriuresis by plasma hydrolysates containing pepsanurin.

    Borić, M P; Croxatto, H R; Albertini, R; Roblero, J S

    1992-02-01

    The specificity of antidiuretic actions of pepsanurin, a peptidic fraction obtained by pepsin hydrolysis of plasma, was studied in anesthetized rats and in isolated perfused rat kidneys. Pepsanurin was obtained from fresh dialyzed human plasma digested with pepsin (2,400 units/ml, 18 hours at 37 degrees C, pH 2.5), deproteinized (10 minutes at 80 degrees C), and centrifuged. In the rat, intraperitoneal injections of pepsanurin (0.5 ml/100 g body wt) significantly inhibited the effects of an intravenous bolus of atrial natriuretic peptide (ANP) (0.5 micrograms) on water, sodium, and potassium excretion without altering systemic blood pressure. In addition, pepsanurin abolished the peak in glomerular filtration rate and reduced the ANP-induced rise in fractional sodium excretion. Pepsanurin also inhibited the natriuretic effects of amiloride (10 micrograms/100 g body wt i.v.) without changing glomerular filtration rate, but it did not inhibit the potassium-retaining effect of amiloride. In contrast, pepsanurin had no effect on basal urinary excretion, and it did not affect the diuretic response induced by furosemide (doses of 25, 50, or 100 micrograms i.v.). Control peptidic hydrolysates prepared from human plasma preincubated 48 hours at 37 degrees C (PIPH), bovine albumin (BSAH), or human albumin did not inhibit ANP, amiloride, or furosemide. In perfused kidneys, pepsanurin significantly and reversibly reduced sodium and water excretion. Furthermore, pepsanurin, but not PIPH or BSAH, blocked the natriuretic and diuretic effects of ANP. These results support the existence of a specific plasma substrate able to release a peptide or peptides that counteract distal tubule diuresis and natriuresis by an intrarenal mechanism. PMID:1531208

  4. Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes

    Deacon, Carolyn F; Holst, Jens J

    2005-01-01

    of appetite. Glucagon-like peptide-1 is, however, extremely rapidly inactivated by the serine peptidase, dipeptidyl peptidase IV, so that the native peptide is not useful clinically. A new approach to utilise the beneficial effects of glucagon-like peptide-1 in the treatment of type 2 diabetes has...... been the development of orally active dipeptidyl peptidase IV inhibitors. Preclinical studies have demonstrated that this approach is effective in enhancing endogenous levels of glucagon-like peptide-1, resulting in improved glucose tolerance in glucose-intolerant and diabetic animal models. In recent...

  5. Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration.

    El-Jamal, Noura; Erdual, Edmone; Neunlist, Michel; Koriche, Dine; Dubuquoy, Caroline; Maggiotto, Francois; Chevalier, Julien; Berrebi, Dominique; Dubuquoy, Laurent; Boulanger, Eric; Cortot, Antoine; Desreumaux, Pierre

    2014-08-01

    The glucagon-like peptide 2 (GLP-2) is an intestinotrophic hormone with growth promoting and anti-inflammatory actions. However, the full biological functions of GLP-2 and the localization of its receptor (GLP-2R) remain controversial. Among cell lines tested, the expression of GLP-2R transcript was detected in human colonic myofibroblasts (CCD-18Co) and in primary culture of rat enteric nervous system but not in intestinal epithelial cell lines, lymphocytes, monocytes, or endothelial cells. Surprisingly, GLP-2R was expressed in murine (GLUTag), but not human (NCI-H716) enteroendocrine cells. The screening of GLP-2R mRNA in mice organs revealed an increasing gradient of GLP-2R toward the distal gut. An unexpected expression was detected in the mesenteric fat, mesenteric lymph nodes, bladder, spleen, and liver, particularly in hepatocytes. In two mice models of trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis, the colonic expression of GLP-2R mRNA was decreased by 60% compared with control mice. Also, GLP-2R mRNA was significantly downregulated in intestinal tissues of inflammatory bowel disease patients. Therapeutically, GLP-2 showed a weak restorative effect on intestinal inflammation during TNBS-induced colitis as assessed by macroscopic score and inflammatory markers. Finally, GLP-2 treatment accelerated mouse liver regeneration following partial hepatectomy as assessed by histological and molecular analyses. In conclusion, the limited therapeutic effect of GLP-2 on colonic inflammation dampens its utility in the management of severe inflammatory intestinal disorders. However, the role of GLP-2 in liver regeneration is a novelty that might introduce GLP-2 into the management of liver diseases and emphasizes on the importance of elucidating other extraintestinal functions of GLP-2. PMID:24875097

  6. [Plant signaling peptides. Cysteine-rich peptides].

    Ostrowski, Maciej; Kowalczyk, Stanisław

    2015-01-01

    Recent bioinformatic and genetic analyses of several model plant genomes have revealed the existence of a highly abundant group of signaling peptides that are defined as cysteine-rich peptides (CRPs). CRPs are usually in size between 50 and 90 amino acid residues, they are positively charged, and they contain 4-16 cysteine residues that are important for the correct conformational folding. Despite the structural differences among CRP classes, members from each class have striking similarities in their molecular properties and function. The present review presents the recent progress in research on signaling peptides from several families including: EPF/EPFL, SP11/SCR, PrsS, RALF, LURE, and some other peptides belonging to CRP group. There is convincing evidence indicating multiple roles for these CRPs as signaling molecules during the plant life cycle, ranging from stomata development and patterning, self-incompatibility, pollen tube growth and guidance, reproductive processes, and nodule formation. PMID:26281357

  7. Plant signalling peptides

    Wiśniewska, Justyna; Trejgell, Alina; Tretyn, Andrzej

    2003-01-01

    Biochemical and genetic studies have identified peptides that play crucial roles in plant growth and development, including defence mechanisms in response to wounding by pests, the control of cell division and expansion, and pollen self-incompatibility. The first two signalling peptides to be described in plants were tomato systemin and phytosulfokine (PSK). There is also biochemical evidence that natriuretic peptide-like molecules, immunologically-relatedt o those found ...

  8. The effect of synthesized RGD peptide on the secretion of extracellular matrix (ECM) by the hepatic stellate cell

    Objective: To study the effect of RGD peptide on the secretion of extracellular matrix by primary hepatic stellate cells. Methods: The RGD peptide was synthesized by chemical method. HSCs were isolated from SD rat by in situ perfusion of liver and cultured for 48 hours. The culture was divided into 4 parts: 1)Control (no agent added) 2) TGF β1 added ( TGF β1 5ng/ml), 3)RGD added (RGD 100 μg/ml), 4)Combined agents added (TGF β1 5ng/ ml and RGD 100 μg/ml). Afterwards , they were further cultured for 3 days. The levels of ECM in the culture supernatant were detected with radioimmunoassay. Results: The levels of HA, LN and PC III in the parts with TGF β1 and combined agent were significantly higher than those in the control, while the levels in culture with RGD remained unchanged. The levels of LN and PCIII in the culture with combined agents were significantly lower than those in the culture with TGF β1. Conclusion: RGD peptide could decrease the levels of LN and PCIII in HSCs culture, suggesting inhibition of secretion of ECM by primary HSCs. The probable mechanism involved might be a competitive combination with integrin. (authors)

  9. Polycyclic peptide therapeutics.

    Baeriswyl, Vanessa; Heinis, Christian

    2013-03-01

    Owing to their excellent binding properties, high stability, and low off-target toxicity, polycyclic peptides are an attractive molecule format for the development of therapeutics. Currently, only a handful of polycyclic peptides are used in the clinic; examples include the antibiotic vancomycin, the anticancer drugs actinomycin D and romidepsin, and the analgesic agent ziconotide. All clinically used polycyclic peptide drugs are derived from natural sources, such as soil bacteria in the case of vancomycin, actinomycin D and romidepsin, or the venom of a fish-hunting coil snail in the case of ziconotide. Unfortunately, nature provides peptide macrocyclic ligands for only a small fraction of therapeutic targets. For the generation of ligands of targets of choice, researchers have inserted artificial binding sites into natural polycyclic peptide scaffolds, such as cystine knot proteins, using rational design or directed evolution approaches. More recently, large combinatorial libraries of genetically encoded bicyclic peptides have been generated de novo and screened by phage display. In this Minireview, the properties of existing polycyclic peptide drugs are discussed and related to their interesting molecular architectures. Furthermore, technologies that allow the development of unnatural polycyclic peptide ligands are discussed. Recent application of these technologies has generated promising results, suggesting that polycyclic peptide therapeutics could potentially be developed for a broad range of diseases. PMID:23355488

  10. Insulin C-peptide test

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin produced by the body and insulin injected ...

  11. Peptide Nucleic Acids

    2004-01-01

    A novel class of compounds known as peptide nucleic acids, bind complementary DNA and RNA strands, and generally do so more strongly than the corresponding DNA or RNA strands while exhibiting increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from a...

  12. PNA Peptide chimerae

    Koch, T.; Næsby, M.; Wittung, P.; Jørgensen, M.; Larsson, C.; Buchardt, O.; Stanly, C.J.; Norden, B.; Nielsen, P.E.; Ørum, H.

    1995-01-01

    Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields.......Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields....

  13. In vitro activity of naturally occurring peptides (defensins against Listeria monocytogenes Ação in vitro de peptídeos naturais (defensinas sobre Listeria monocytogenes

    Maria da Graça F. Nascimento

    1994-12-01

    Full Text Available Autoclaved distilled water samples were inoculated with L. monocytogenes strain V7 and strain VPH-1, and incubated aerobically, at 30 C for 48 hours. Each strain was tested individually, and growth curves were determined at 1, 2, 3, 4, 5, 21, 24, and 48 hours. The growth or survival of L. monocytogenes was similar for both strains, with survivors at 24 hour-incubation. The microbicidal activity of one synthetic cationic peptide (NP-2 was examined against L. monocytogenes strain V7, in a water system. Antibacterial activity of NP-2 (1, 5, and 10 g/ml was best expressed at 60 minute-incubation, with 10 g/ml of peptide, at 30 C.Amostras de água destilada, autoclavadas, foram inoculadas com L. monocytogenes cepa V7 e cepa VPH-1, e incubadas, aerobicamente, a 30ºC por 48 horas. Cada cepa foi testada individualmente, e determinou-se curvas de crescimento a 1, 2, 3, 4, 5, 21, 24, e 48 horas. O crescimento ou sobrevivência das duas cepas foi semelhante e encontrou-se sobreviventes em 24 horas de incubação. Examinou-se a atividade bactericida de um dos peptídeos catiônicos sintéticos (NP-2 contra L. monocytogenes cepa V7, em sistema aquoso. A atividade antibacteriana de NP-2 (1, 5, and 10µg/ml foi melhor aos 60 minutos de incubação, com 10µg/ml de peptídeo, a 30 C.

  14. The effects of fluorouracil, epirubicin, and cyclophosphamide (FEC60 on the intestinal barrier function and gut peptides in breast cancer patients: an observational study

    Russo Francesco

    2013-02-01

    Full Text Available Abstract Background Several GI peptides linked to intestinal barrier function could be involved in the modification of intestinal permeability and the onset of diarrhea during adjuvant chemotherapy. The aim of the study was to evaluate the circulating levels of zonulin, glucagon-like peptide-2 (GLP-2, epidermal growth factor (EGF and ghrelin and their relationship with intestinal permeability and chemotherapy induced diarrhea (CTD. Methods Sixty breast cancer patients undergoing an FEC60 regimen were enrolled, 37 patients completed the study. CTD(+ patients were discriminated by appropriate questionnaire and criteria. During chemotherapy, intestinal permeability was assessed by lactulose/mannitol urinary test on day 0 and day 14. Zonulin, GLP-2, EGF and ghrelin circulating levels were evaluated by ELISA tests at five time-points (days 0, 3, 10, 14, and 21. Results During FEC60 administration, the lactulose/mannitol ratio was significantly higher on day 14 than at baseline. Zonulin levels were not affected by chemotherapy, whereas GLP-2 and EGF levels decreased significantly. GLP-2 levels on day 14 were significantly lower than those on day 0 and day 3, while EGF values were significantly lower on day 10 than at the baseline. In contrast, the total concentrations of ghrelin increased significantly at day 3 compared to days 0 and 21, respectively. Ten patients (27% suffered from diarrhea. On day 14 of chemotherapy, a significant increase of the La/Ma ratio occurred in CTD(+ patients compared to CTD(− patients. With regards to circulating gut peptides, the AUCg of GLP-2 and ghrelin were significantly lower and higher in CTD(+ patients than CTD(− ones, respectively. Finally in CTD(+ patients a significant and inverse correlation between GLP-2 and La/Ma ratio was found on day 14. Conclusions Breast cancer patients undergoing FEC60 showed alterations in the intestinal permeability, which was associated with modifications in the levels of GLP-2

  15. Descriptors for antimicrobial peptides

    Jenssen, Håvard

    2011-01-01

    Introduction: A frightening increase in the number of isolated multidrug resistant bacterial strains linked to the decline in novel antimicrobial drugs entering the market is a great cause for concern. Cationic antimicrobial peptides (AMPs) have lately been introduced as a potential new class of...... antimicrobial drugs, and computational methods utilizing molecular descriptors can significantly accelerate the development of new peptide drug candidates. Areas covered: This paper gives a broad overview of peptide and amino-acid scale descriptors available for AMP modeling and highlights which of these are...

  16. PNA Peptide chimerae

    Koch, T.; Næsby, M.; Wittung, P.;

    1995-01-01

    Radioactive labelling of PNA has been performed try linking a peptide segment to the PNA which is substrate for protein kinase A. The enzymatic phosphorylation proceeds in almost quantitative yields....

  17. Tumor penetrating peptides

    ErkkiRuoslahti

    2013-08-01

    Full Text Available Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC, contains the integrin-binding RGD motif. RGD mediates tumor homing through binding to αv integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue-penetrating peptides, and the primary receptor can also be a vascular “zip code” of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is

  18. Introduction to Peptide Synthesis

    Stawikowski, Maciej; Fields, Gregg B.

    2002-01-01

    A number of synthetic peptides are significant commercial or pharmaceutical products, ranging from the dipeptide sugar-substitute aspartame to clinically used hormones, such as oxytocin, adrenocorticotropic hormone, and calcitonin. This unit provides an overview of the field of synthetic peptides and proteins. It discusses selecting the solid support and common coupling reagents. Additional information is provided regarding common side reactions and synthesizing modified residues.

  19. Antimicrobial Peptides from Plants

    Tam, James P.; Wang, Shujing; Wong, Ka H.; Tan, Wei Liang

    2015-01-01

    Plant antimicrobial peptides (AMPs) have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs) of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic), lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms. PMID:26580629

  20. Antimicrobial Peptides from Plants

    James P. Tam

    2015-11-01

    Full Text Available Plant antimicrobial peptides (AMPs have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic, lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms.

  1. Electromembrane extraction of peptides.

    Balchen, Marte; Reubsaet, Léon; Pedersen-Bjergaard, Stig

    2008-06-20

    Rapid extraction of eight different peptides using electromembrane extraction (EME) was demonstrated for the first time. During an extraction time of 5 min, the model peptides migrated from a 500 microL aqueous acidic sample solution, through a thin supported liquid membrane (SLM) of an organic liquid sustained in the pores in the wall of a porous hollow fiber, and into a 25 microL aqueous acidic acceptor solution present inside the lumen of the hollow fiber. The driving force of the extraction was a 50 V potential sustained across the SLM, with the positive electrode in the sample and the negative electrode in the acceptor solution. The nature and the composition of the SLM were highly important for the EME process, and a mixture of 1-octanol and 15% di(2-ethylhexyl) phosphate was found to work properly. Using 1mM HCl as background electrolyte in the sample and 100 mM HCl in the acceptor solution, and agitation at 1050 rpm, enrichment up to 11 times was achieved. Recoveries were found to be dependent on the structure of the peptide, indicating that the polarity and the number of ionized groups were important parameters affecting the extraction efficiency. The experimental findings suggested that electromembrane extraction of peptides is possible and may be a valuable tool for future extraction of peptides. PMID:18479691

  2. Modern treatment of short bowel syndrome

    Jeppesen, Palle B

    2013-01-01

    Recently, the US Food and Drug Administration and the European Medicines Agency approved the glucagon-like peptide 2 analogue, teduglutide, for the treatment of short bowel syndrome (SBS), and this review describes the physiological basis for its clinical use.......Recently, the US Food and Drug Administration and the European Medicines Agency approved the glucagon-like peptide 2 analogue, teduglutide, for the treatment of short bowel syndrome (SBS), and this review describes the physiological basis for its clinical use....

  3. TCF7L2 rs7903146-macronutrient interaction in obese individuals' responses to a 10-wk randomized hypoenergetic diet

    Grau, Katrine; Cauchi, Stephane; Holst, Claus; Astrup, Arne; Martinez, J. Alfredo; Saris, Wim H.M.; Blaak, Ellen E; Oppert, Jean-Michel; Arner, Peter; Rössner, Stephan; Macdonald, Ian A.; Klimcakova, Eva; Langin, Dominique; Pedersen, Oluf; Froguel, Philippe; Sørensen, Thorkild I.A.

    2010-01-01

    Transcription factor 7-like 2 (TCF7L2) rs7903146 associates with type 2 diabetes and may operate via impaired glucagon-like peptide 1 secretion, which is stimulated more by fat than by carbohydrate ingestion.......Transcription factor 7-like 2 (TCF7L2) rs7903146 associates with type 2 diabetes and may operate via impaired glucagon-like peptide 1 secretion, which is stimulated more by fat than by carbohydrate ingestion....

  4. Synthetic antibiofilm peptides.

    de la Fuente-Núñez, César; Cardoso, Marlon Henrique; de Souza Cândido, Elizabete; Franco, Octavio Luiz; Hancock, Robert E W

    2016-05-01

    Bacteria predominantly exist as multicellular aggregates known as biofilms that are associated with at least two thirds of all infections and exhibit increased adaptive resistance to conventional antibiotic therapies. Therefore, biofilms are major contributors to the global health problem of antibiotic resistance, and novel approaches to counter them are urgently needed. Small molecules of the innate immune system called host defense peptides (HDPs) have emerged as promising templates for the design of potent, broad-spectrum antibiofilm agents. Here, we review recent developments in the new field of synthetic antibiofilm peptides, including mechanistic insights, synergistic interactions with available antibiotics, and their potential as novel antimicrobials against persistent infections caused by biofilms. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID:26724202

  5. One-dimensional, time dependent simulation of the planetary boundary layer over a 48-hour period

    Results of a one-dimensional, time dependent simulation of the planetary boundary layer are given. First, a description of the mathematical model used is given and its approximations are discussed. Then a description of the initial and boundary conditions used for the simulation is given. Results are discussed with respect to their agreement with observed data and their precision. It can be demonstrated that a simulation of the planetary boundary layer is possible with satisfactory precision. The incompleteness of observed data gives, however, problems with their use and thus introduces uncertainties into the simulation. As a consequence, the report tries to point to the inherent limitations of such a simulation. (Auth.)

  6. Quantitative baseline renography 48 hours after renal transplantation predicts long-term graft survival

    Technetium-99m mercaptoacetylglycine (99mTc-MAG3) renography is a successful non-invasive method for the evaluation of renal transplants. In this study we prospectively studied 256 patients after renal transplantation, using the MAG3 uptake capacity in the first 10 min (MUC10), which is an index of renal function representing kidney activity as a fraction of the injected dose. Renal scintigraphy was performed in all patients within 48 h of transplantation. Renograms were obtained over 20 min, after bolus injection of ±100 MBq 99mTc-MAG3. MUC10 ranged between 0.0 and 94.9. The patients were divided into five groups: group 1, MUC10 <1; group 2, 1≤MUC10<5; group 3, 5≤MUC10<10; group 4, 10≤MUC10<30; group 5, MUC10 ≥30. In 235 patients, follow-up for 5 years was completed. Considering all the renal transplants, 30% of the grafts ceased functioning within the first 5 years. Six grafts showed a MUC10 of <1, and none survived the first year. After 5 years, 43% of the grafts with a MUC10 of 1-5 still functioned, as compared with 63% of those with a MUC10 of 5-10, 72% of those with a MUC10 of 10-30 and 83% of those with a MUC10 of ≥30. Kaplan-Meier survival analysis showed significant differences between the five different patient groups based on MUC10 in terms of the percentage of kidneys that ceased to function within 5 years. The period of cold ischaemia and the donor age were known in 178 patients. In contrast to cold ischaemia time, the MUC10 and the donor age showed a significant effect (P<0.05) on graft survival. This study indicates that the MUC10 early after renal transplantation is useful as a prognostic factor in the evaluation of kidney transplants and that a MUC10 of <1 indicates a dismal prognosis for the renal transplant. (orig.)

  7. The effect of 48-hour fasting on taurine status in healthy adult dogs.

    Gray, K; Alexander, L G; Staunton, R; Colyer, A; Watson, A; Fascetti, A J

    2016-06-01

    Low circulating taurine concentrations may be a risk factor for dilated cardiomyopathy (DCM) in dogs. Circulating taurine is typically measured in the clinic 4-5 h after feeding, largely because the impact of later sampling is not known. The objective of this study was to measure taurine in the blood during a 48-h fast in 12 healthy adult Labrador Retrievers to refine sampling methodology for determination of taurine status. Plasma and whole blood (WB) taurine concentrations did not fall to levels indicative of clinical deficiency throughout fasting; WB was the more reliable indicator of taurine status. This study shows that blood samples can be taken for assessment of taurine status any time up to 48 h after ingestion of a meal in healthy adult dogs. PMID:26250395

  8. 48-Hour Forecast of Precipitation Amounts from the National Weather Service's National Digital Forecast Database (NDFD)

    National Oceanic and Atmospheric Administration, Department of Commerce — The National Digital Forecast Database (NDFD) contains a seamless mosaic of the National Weather Service's (NWS) digital forecasts of precipitation amounts. In...

  9. Biomimetic peptide nanosensors.

    Cui, Yue; Kim, Sang N; Naik, Rajesh R; McAlpine, Michael C

    2012-05-15

    The development of a miniaturized sensing platform tailored for sensitive and selective detection of a variety of biochemical analytes could offer transformative fundamental and technological opportunities. Due to their high surface-to-volume ratios, nanoscale materials are extremely sensitive sensors. Likewise, peptides represent robust substrates for selective recognition due to the potential for broad chemical diversity within their relatively compact size. Here we explore the possibilities of linking peptides to nanosensors for the selective detection of biochemical targets. Such systems raise a number of interesting fundamental challenges: What are the peptide sequences, and how can rational design be used to derive selective binders? What nanomaterials should be used, and what are some strategies for assembling hybrid nanosensors? What role does molecular modeling play in elucidating response mechanisms? What is the resulting performance of these sensors, in terms of sensitivity, selectivity, and response time? What are some potential applications? This Account will highlight our early attempts to address these research challenges. Specifically, we use natural peptide sequences or sequences identified from phage display as capture elements. The sensors are based on a variety of nanomaterials including nanowires, graphene, and carbon nanotubes. We couple peptides to the nanomaterial surfaces via traditional surface functionalization methods or self-assembly. Molecular modeling provides detailed insights into the hybrid nanostructure, as well as the sensor detection mechanisms. The peptide nanosensors can distinguish chemically camouflaged mixtures of vapors and detect chemical warfare agents with sensitivities as low as parts-per-billion levels. Finally, we anticipate future uses of this technology in biomedicine: for example, devices based on these sensors could detect disease from the molecular components in human breath. Overall, these results provide a

  10. Therapeutic HIV Peptide Vaccine

    Fomsgaard, Anders

    2015-01-01

    Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

  11. Cationic Antimicrobial Peptide Cytotoxicity

    Laverty, Garry; Gilmore, Brendan

    2014-01-01

    Fluorescence microscopy serves as a valuable tool for assessing the structural integrity and viability of eukaryotic cells. Through the use of calcein AM and the DNA stain 4,6-diamidino-2 phenylindole (DAPI), cell viability and membrane integrity can be qualified. Our group has previously shown the ultra-short cationic antimicrobial peptide H-OOWW-NH2; the amphibian derived 27-mer peptide Maximin-4and the ultra-short lipopeptide C12-OOWW-NH2 to be effective against a range of bacterial biofil...

  12. Biosynthesis of cardiac natriuretic peptides

    Goetze, Jens Peter

    2010-01-01

    Cardiac-derived peptide hormones were identified more than 25 years ago. An astonishing amount of clinical studies have established cardiac natriuretic peptides and their molecular precursors as useful markers of heart disease. In contrast to the clinical applications, the biogenesis of cardiac p...... competent endocrine cells. The structurally related atrial natriuretic peptide will be mentioned where appropriate, whereas C-type natriuretic peptide will not be considered as a cardiac peptide of relevance in mammalian physiology....... characterized. An ongoing characterization of the molecular heterogeneity will help appreciate the biosynthetic capacity of the endocrine heart and could introduce new diagnostic possibilities. Notably, different biosynthetic products may not be equal markers of the same pathophysiological processes. An...... inefficient post-translational prohormone maturation will also affect the biology of the cardiac natriuretic peptide system. This review aims at summarizing the myocardial synthesis of natriuretic peptides focusing on B-type natriuretic peptide, where new data has disclosed cardiac myocytes as highly...

  13. Biosynthesis of cardiac natriuretic peptides

    Goetze, Jens Peter

    2010-01-01

    Cardiac-derived peptide hormones were identified more than 25 years ago. An astonishing amount of clinical studies have established cardiac natriuretic peptides and their molecular precursors as useful markers of heart disease. In contrast to the clinical applications, the biogenesis of cardiac...... inefficient post-translational prohormone maturation will also affect the biology of the cardiac natriuretic peptide system. This review aims at summarizing the myocardial synthesis of natriuretic peptides focusing on B-type natriuretic peptide, where new data has disclosed cardiac myocytes as highly...... competent endocrine cells. The structurally related atrial natriuretic peptide will be mentioned where appropriate, whereas C-type natriuretic peptide will not be considered as a cardiac peptide of relevance in mammalian physiology....

  14. Biochemical functionalization of peptide nanotubes with phage displayed peptides

    Swaminathan, Swathi; Cui, Yue

    2016-09-01

    The development of a general approach for the biochemical functionalization of peptide nanotubes (PNTs) could open up existing opportunities in both fundamental studies as well as a variety of applications. PNTs are spontaneously assembled organic nanostructures made from peptides. Phage display has emerged as a powerful approach for identifying selective peptide binding motifs. Here, we demonstrate for the first time the biochemical functionalization of PNTs via peptides identified from a phage display peptide library. The phage-displayed peptides are shown to recognize PNTs. These advances further allow for the development of bifunctional peptides for the capture of bacteria and the self-assembly of silver particles onto PNTs. We anticipate that these results could provide significant opportunities for using PNTs in both fundamental studies and practical applications, including sensors and biosensors nanoelectronics, energy storage devices, drug delivery, and tissue engineering.

  15. Direct and indirect radioiodination of protein: comparative study of chemotactic peptide labeling

    chemotactic peptide labeled by direct and indirect methods. The ATE was obtained with satisfactory yield (90,7%). The conditions for ATE radioiodination were p H 3 - 4, 50 μmol of t-butylhydroperoxide and 30 minutes of reaction. The SIB was purified to remove the unreacted ATE and some radiochemical impurities presented in the reaction mixture. The peptide radioiodinated by direct method was obtained in a short reaction time (10 minutes), with high radiochemical purity (> 96%) and in vitro stability (48 hours under refrigeration). The biodistribution studies developed in normal Swiss mice and in mice with inflammatory focus developed by the administration of turpentine in the right thigh showed the ability of the compound to concentrate in the inflammatory focus as evidenced by the higher uptake in the inflamed thigh when compared to the normal thigh (p 99%) and was stable in vitro (24 hours under refrigeration). Despite the indirect labeling procedure was laborious, time consuming and the product was obtained with low radiochemical yield (26,3%), the labeled peptide showed specificity by inflammatory focus and in vivo stability confirmed by the lower thyroid uptake when compared with the peptide labeled by direct method. The great in vivo stability of the peptide labeled by indirect method justifies the study of new and alternative purification procedure that reduces process time and increases the final yield. (author)

  16. Peptide iodination on phenylalanine residues

    Peptide labelling with radioactive isotopes is always a compromise between peptide chemistry, labelling chemistry, and biological receptor tolerance. Therefore new ways for isotope introduction are always useful. The present contribution describes the introduction of iodine isotopes onto synthetic polypeptides by means of the Gattermann/ Sandmeyer reactions. Peptides containing the nitrophenylalanyl residue are reduced to the corresponding aminophenylalanyl, diazolized to the diazonium phenylalanyl peptide and converted to the iodophenylalanyl peptide in the presence of copper. Two examples are presented: angiotensin II and enkephalin. In both cases, the iodophenylalanyl residue is well accepted by the biological target. (author). 13 refs.; 4 figs

  17. Antimicrobial Peptides (AMPs

    Mehrzad Sadredinamin

    2016-04-01

    Full Text Available Antimicrobial peptides (AMPs are extensive group of molecules that produced by variety tissues of invertebrate, plants, and animal species which play an important role in their immunity response. AMPs have different classifications such as; biosynthetic machines, biological sources, biological functions, molecular properties, covalent bonding patterns, three dimensional structures, and molecular targets.These molecules have multidimensional properties including antimicrobial activity, antiviral activity, antifungal activity, anti-parasite activity, biofilm control, antitumor activity, mitogens activity and linking innate to adaptive immunity that making them promising agents for therapeutic drugs. In spite of this advantage of AMPs, their clinical developments have some limitation for commercial development. But some of AMPs are under clinical trials for the therapeutic purpose such as diabetic foot ulcers, different bacterial infections and tissue damage. In this review, we emphasized on the source, structure, multidimensional properties, limitation and therapeutic applications of various antimicrobial peptides.

  18. Antimicrobial peptides in crustaceans

    RD Rosa; MA Barracco

    2010-01-01

    Crustaceans are a large and diverse invertebrate animal group that mounts a complex and efficient innate immune response against a variety of microorganisms. The crustacean immune system is primarily related to cellular responses and the production and release of important immune effectors into the hemolymph. Antimicrobial proteins and/or peptides (AMPs) are key components of innate immunity and are widespread in nature, from bacteria to vertebrate animals. In crustaceans, 15 distinct AMP fam...

  19. [Brain natriuretic peptide].

    La Villa, G; Lazzeri, C; Fronzaroli, C; Franchi, F; Gentilini, P

    1995-01-01

    Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis. PMID:8718658

  20. Accurate Peptide Fragment Mass Analysis: Multiplexed Peptide Identification and Quantification

    Weisbrod, Chad R.; Eng, Jimmy K.; Hoopmann, Michael R.; Baker, Tahmina; Bruce, James E.

    2012-01-01

    FT All Reaction Monitoring (FT-ARM) is a novel approach for the identification and quantification of peptides that relies upon the selectivity of high mass accuracy data and the specificity of peptide fragmentation patterns. An FT-ARM experiment involves continuous, data-independent, high mass accuracy MS/MS acquisition spanning a defined m/z range. Custom software was developed to search peptides against the multiplexed fragmentation spectra by comparing theoretical or empirical fragment ion...

  1. NCAM Mimetic Peptides: An Update

    Berezin, Vladimir; Bock, Elisabeth

    2008-01-01

    pharmacological tools interfering with NCAM functions. Recent progress in our understanding of the structural basis of NCAM-mediated cell adhesion and signaling has allowed a structure-based design of NCAM mimetic peptides. Using this approach a number of peptides termed P2, P1-B, P-3-DE and P-3-G, whose...... sequences contain one or several NCAM homophilic binding sites involved in NCAM binding to itself, have been identified. By means of NMR titration analysis and molecular modeling a number of peptides derived from NCAM and targeting NCAM heterophilic ligands such as the fibroblast growth factor receptor and...... heparan sulfate proteoglycans (HSPG) have been identified. The FGL, dekaCAM, FRM/EncaminA, BCL, EncaminC and EncaminE peptides all target the FGF receptor whereas the heparin binding peptide HBP targets HSPG. Moreover, a number of NCAM binding peptides have been identified employing screening of...

  2. The PeptideAtlas Project

    Deutsch, Eric W.

    2010-01-01

    PeptideAtlas is a multi-species compendium of peptides observed with tandem mass spectrometry methods. Raw mass spectrometer output files are collected from the community and reprocessed through a uniform analysis and validation pipeline that continues to advance. The results are loaded into a database and the information derived from the raw data is returned to the community via several web-based data exploration tools. The PeptideAtlas resource is useful for experiment planning, improving g...

  3. Human Antimicrobial Peptides and Proteins

    Guangshun Wang

    2014-01-01

    As the key components of innate immunity, human host defense antimicrobial peptides and proteins (AMPs) play a critical role in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. This article provides an overview on the identification, activity, 3D structure, and mechanism of action of human AMPs selected from the antimicrobial peptide database. Over 100 such peptides have been identified ...

  4. A Stochastic Model by the Fourier Transform of Pde for the Glp - 1

    Dr. P. Senthilkumar

    2015-05-01

    Full Text Available The peptide hormone glucagon like peptide GLP -1 has most important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP -1 has to be administered by injection. A few small-molecule agonists to peptide hormone receptors have been described.

  5. Improving Peptide Applications Using Nanotechnology.

    Narayanaswamy, Radhika; Wang, Tao; Torchilin, Vladimir P

    2016-01-01

    Peptides are being successfully used in various fields including therapy and drug delivery. With advancement in nanotechnology and targeted delivery carrier systems, suitable modification of peptides has enabled achievement of many desirable goals over-riding some of the major disadvantages associated with the delivery of peptides in vivo. Conjugation or physical encapsulation of peptides to various nanocarriers, such as liposomes, micelles and solid-lipid nanoparticles, has improved their in vivo performance multi-fold. The amenability of peptides to modification in chemistry and functionalization with suitable nanocarriers are very relevant aspects in their use and have led to the use of 'smart' nanoparticles with suitable linker chemistries that favor peptide targeting or release at the desired sites, minimizing off-target effects. This review focuses on how nanotechnology has been used to improve the number of peptide applications. The paper also focuses on the chemistry behind peptide conjugation to nanocarriers, the commonly employed linker chemistries and the several improvements that have already been achieved in the areas of peptide use with the help of nanotechnology. PMID:26279082

  6. Peptides that influence membrane topology

    Wong, Gerard C. L.

    2014-03-01

    We examine the mechanism of a range of polypeptides that influence membrane topology, including antimicrobial peptides, cell penetrating peptides, viral fusion peptides, and apoptosis proteins, and show how a combination of geometry, coordination chemistry, and soft matter physics can be used to approach a unified understanding. We will also show how such peptides can impact biomedical problems such as auto-immune diseases (psoriasis, lupus), infectious diseases (viral and bacterial infections), and mitochondrial pathologies (under-regulated apoptosis leads to neurodegenerative diseases whereas over-regulated apoptosis leads to cancer.)

  7. Polyclonal Peptide Antisera.

    Pihl, Tina H; Illigen, Kristin E; Houen, Gunnar

    2015-01-01

    Polyclonal antibodies are relatively easy to produce and may supplement monoclonal antibodies for some applications or even have some advantages. The choice of species for production of (peptide) antisera is based on practical considerations, including availability of immunogen (vaccine) and animals. Two major factors govern the production of antisera: the nature of adaptive immune responses, which take place over days/weeks and ethical guidelines for animal welfare. Here, simple procedures for immunization of mice, rabbits, sheep, goats, pigs, horses, and chickens are presented. PMID:26424267

  8. Phytosulfokine peptide signalling.

    Sauter, Margret

    2015-08-01

    Phytosulfokine (PSK) belongs to the group of plant peptide growth factors. It is a disulfated pentapeptide encoded by precursor genes that are ubiquitously present in higher plants, suggestive of universal functions. Processing of the preproprotein involves sulfonylation by a tyrosylprotein sulfotransferase in the trans-golgi and proteolytic cleavage in the apoplast. The secreted peptide is perceived at the cell surface by a membrane-bound receptor kinase of the leucine-rich repeat family. The PSK receptor PSKR1 from Arabidopsis thaliana is an active kinase and has guanylate cyclase activity resulting in dual-signal outputs. Receptor activity is regulated by calmodulin. While PSK may be an autocrine growth factor, it also acts non-cell autonomously by promoting growth of cells that are receptor-deficient. In planta, PSK has multiple functions. It promotes cell growth, acts in the quiescent centre cells of the root apical meristem, contributes to funicular pollen tube guidance, and differentially alters immune responses depending on the pathogen. It has been suggested that PSK integrates growth and defence signals to balance the competing metabolic costs of these responses. This review summarizes our current understanding of PSK synthesis, signalling, and activity. PMID:25754406

  9. Urinary Peptides in Rett Syndrome.

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  10. Peptide-LNA oligonucleotide conjugates

    Astakhova, I Kira; Hansen, Lykke Haastrup; Vester, Birte; Wengel, Jesper

    2013-01-01

    Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical...

  11. Solid-phase peptide synthesis

    Jensen, Knud Jørgen

    This chapter provides an introduction to and overview of peptide chemistry with a focus on solid-phase peptide synthesis. The background, the most common reagents, and some mechanisms are presented. This chapter also points to the different chapters and puts them into perspective....

  12. Radiolabelled peptides for oncological diagnosis.

    Laverman, P.; Sosabowski, J.K.; Boerman, O.C.; Oyen, W.J.G.

    2012-01-01

    Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of resea

  13. Conus venom peptide pharmacology.

    Lewis, Richard J; Dutertre, Sébastien; Vetter, Irina; Christie, MacDonald J

    2012-04-01

    Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (≈ 0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (ω-, μ-, μO-, δ-, ι-, and κ-conotoxins), ligand-gated ion channels (α-conotoxins, σ-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (ρ-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (χ-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies. PMID:22407615

  14. Peptide primary messengers in plants

    2001-01-01

    The peptide primary messengers regulate embryonic development,cell growth and many other activities in animal cells. But recent evidence verified that peptide primary messengers are also involved in plant defense responses, the recognition between pollen and stigma and keep the balance between cell proliferation and differentiations in shoot apical meristems. Those results suggest that plants may actually make wide use of peptide primary messengers, both in embryonic development and late life when they rally their cells to defend against pathogens and insect pests. The recent advance in those aspects is reviewed.

  15. Screening of TACE Peptide Inhibitors from Phage Display Peptide Library

    2005-01-01

    To obtain the recombinant tumor necrosis factor-α converting enzyme (TACE) ectodomain and use it as a selective molecule for the screening of TACE peptide inhibitors, the cDNA coding catalytic domain (T800) and full-length ectodomain (T1300) of TACE were amplified by RTPCR, and the expression plasmids were constructed by inserting T800 and T1300 into plasmid pET28a and pET-28c respectively. The recombinant T800 and T1300 were induced by IPTG, and SDSPAGE and Western blotting analysis results revealed that T800 and T1300 were highly expressed in the form of inclusion body. After Ni2+-NTA resin affinity chromatography, the recombinant proteins were used in the screening of TACE-binding peptides from phage display peptide library respectively. After 4 rounds of biopanning, the positive phage clones were analyzed by ELISA, competitive inhibition assay and DNA sequencing. A common amino acid sequence (TRWLVYFSRPYLVAT) was found and synthesized. The synthetic peptide could inhibit the TNF-α release from LPS-stimulated human peripheral blood mononuclear cells (PBMC) up to 60.3 %. FACS analysis revealed that the peptide mediated the accumulation of TNF-α on the cell surface. These results demonstrate that the TACE-binding peptide is an effective antagonist of TACE.

  16. The Equine PeptideAtlas

    Bundgaard, Louise; Jacobsen, Stine; Sorensen, Mette A.;

    2014-01-01

    Progress in MS-based methods for veterinary research and diagnostics is lagging behind compared to the human research, and proteome data of domestic animals is still not well represented in open source data repositories. This is particularly true for the equine species. Here we present a first...... current release comprises 24 131 distinct peptides representing 2636 canonical proteins observed at false discovery rates of 0.2% at the peptide level and 1.4% at the protein level. Data from the Equine PeptideAtlas are available for experimental planning, validation of new datasets, and as a proteomic...... data mining resource. The advantages of the Equine PeptideAtlas are demonstrated by examples of mining the contents for information on potential and well-known equine acute phase proteins, which have extensive general interest in the veterinary clinic. The extracted information will support further...

  17. Peptide nanostructures in biomedical technology.

    Feyzizarnagh, Hamid; Yoon, Do-Young; Goltz, Mark; Kim, Dong-Shik

    2016-09-01

    Nanostructures of peptides have been investigated for biomedical applications due to their unique mechanical and electrical properties in addition to their excellent biocompatibility. Peptides may form fibrils, spheres and tubes in nanoscale depending on the formation conditions. These peptide nanostructures can be used in electrical, medical, dental, and environmental applications. Applications of these nanostructures include, but are not limited to, electronic devices, biosensing, medical imaging and diagnosis, drug delivery, tissue engineering and stem cell research. This review offers a discussion of basic synthesis methods, properties and application of these nanomaterials. The review concludes with recommendations and future directions for peptide nanostructures. WIREs Nanomed Nanobiotechnol 2016, 8:730-743. doi: 10.1002/wnan.1393 For further resources related to this article, please visit the WIREs website. PMID:26846352

  18. Production and characterization of peptide antibodies

    Trier, Nicole Hartwig; Hansen, Paul Robert; Houen, Gunnar

    2012-01-01

    Proteins are effective immunogens for generation of antibodies. However, occasionally the native protein is known but not available for antibody production. In such cases synthetic peptides derived from the native protein are good alternatives for antibody production. These peptide antibodies are...... powerful tools in experimental biology and are easily produced to any peptide of choice. A widely used approach for production of peptide antibodies is to immunize animals with a synthetic peptide coupled to a carrier protein. Very important is the selection of the synthetic peptide, where factors such as......, including solid-phase peptide-carrier conjugation and peptide-carrier conjugation in solution. Upon immunization, adjuvants such as Al(OH)(3) are added together with the immunogenic peptide-carrier conjugate, which usually leads to high-titred antisera. Following immunization and peptide antibody...

  19. Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats

    Thiele, Todd E.; Dijk, Gertjan van; Campfield, L. Arthur; Smith, Francoise J.; Burn, Paul; Woods, Stephen C.; Bernstein, Ilene L.; Seeley, Randy J.

    1997-01-01

    Leptin (ob protein) and glucagon-like peptide-1-(7-36) amide (GLP-1) are peptides recently proposed to be involved in the regulation of food intake. Although the ability of exogenous leptin and GLP-1 to modulate consummatory behavior is consistent with the suggestion that these peptides are endogeno

  20. Targeting cancer with peptide aptamers

    Seigneuric, Renaud; Gobbo, Jessica; Colas, Pierre; Garrido, Carmen

    2011-01-01

    A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but also peptide aptamers are relatively recent agents. Peptide aptamers are seldom described but represent attractive agents that can inhibit a growing panel of oncotargets including Heat Shock Proteins. Potential pitfalls and coming challenges towards succe...

  1. Manufacturing of peptides exhibiting biological activity

    Zambrowicz, Aleksandra; Timmer, Monika; Polanowski, Antoni; Lubec, Gert; Trziszka, Tadeusz

    2012-01-01

    Numerous studies have shown that food proteins may be a source of bioactive peptides. Those peptides are encrypted in the protein sequence. They stay inactive within the parental protein until release by proteolytic enzymes (Mine and Kovacs-Nolan in Worlds Poult Sci J 62(1):87–95, 2006; Hartman and Miesel in Curr Opin Biotechnol 18:163–169, 2007). Once released the bioactive peptides exhibit several biofunctionalities and may serve therapeutic roles in body systems. Opioid peptides, peptides ...

  2. Peptides and proteins

    Bachovchin, W.W.; Unkefer, C.J.

    1994-12-01

    Advances in magnetic resonance and vibrational spectroscopy make it possible to derive detailed structural information about biomolecular structures in solution. These techniques are critically dependent on the availability of labeled compounds. For example, NMR techniques used today to derive peptide and protein structures require uniformity {sup 13}C-and {sup 15}N-labeled samples that are derived biosynthetically from (U-6-{sup 13}C) glucose. These experiments are possible now because, during the 1970s, the National Stable Isotope Resource developed algal methods for producing (U-6-{sup 13}C) glucose. If NMR techniques are to be used to study larger proteins, we will need sophisticated labelling patterns in amino acids that employ a combination of {sup 2}H, {sup 13}C, and {sup 15}N labeling. The availability of these specifically labeled amino acids requires a renewed investment in new methods for chemical synthesis of labeled amino acids. The development of new magnetic resonance or vibrational techniques to elucidate biomolecular structure will be seriously impeded if we do not see rapid progress in labeling technology. Investment in labeling chemistry is as important as investment in the development of advanced spectroscopic tools.

  3. Antimicrobial peptides in annelids

    A Tasiemski

    2008-06-01

    Full Text Available Gene encoded antimicrobial peptides (AMPs are widely distributed among living organisms including plants, invertebrates and vertebrates. They constitute important effectors of the innate immune response by exerting multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cytokine release, cell proliferation, angiogenesis, wound healing, chemotaxis and immune induction. In invertebrates, most of the data describe the characterization and/or the function of AMPs in the numerically and economically most representative group which are arthropods. Annelids are among the first coelomates and are therefore of special phylogenetic interest. Compared to other invertebrate groups, data on annelid’s immunity reveal heavier emphasis on the cellular than on the humoral response suggesting that immune defense of annelids seems to be principally developed as cellular immunity.This paper gives an overview of the variety of AMPs identified in the three classes of annelids, i.e. polychaetes, oligochaetes and achaetes. Their functions, when they have been studied, in the humoral or cellular response of annelids are also mentioned.

  4. Kinins and peptide receptors.

    Regoli, Domenico; Gobeil, Fernand

    2016-04-01

    This paper is divided into two sections: the first contains the essential elements of the opening lecture presented by Pr. Regoli to the 2015 International Kinin Symposium in S. Paulo, Brazil on June 28th and the second is the celebration of Dr. Regoli's 60 years of research on vasoactive peptides. The cardiovascular homeostasis derives from a balance of two systems, the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS). The biologically active effector entity of RAS is angiotensin receptor-1 (AT-1R), and that of KKS is bradykinin B2 receptor (B2R). The first mediates vasoconstriction, the second is the most potent and efficient vasodilator. Thanks to its complex and multi-functional mechanism of action, involving nitric oxide (NO), prostacyclin and endothelial hyperpolarizing factor (EDHF). B2R is instrumental for the supply of blood, oxygen and nutrition to tissues. KKS is present on the vascular endothelium and functions as an autacoid playing major roles in cardiovascular diseases (CVDs) and diabetes. KKS exerts a paramount role in the prevention of thrombosis and atherosclerosis. Such knowledge emphasizes the already prominent value of the ACE-inhibitors (ACEIs) for the treatment of CVDs and diabetes. Indeed, the ACEIs, thanks to their double action (block of the RAS and potentiation of the KKS) are the ideal agents for a rational treatment of these diseases. PMID:26408609

  5. Antimicrobial peptides in crustaceans

    RD Rosa

    2010-11-01

    Full Text Available Crustaceans are a large and diverse invertebrate animal group that mounts a complex and efficient innate immune response against a variety of microorganisms. The crustacean immune system is primarily related to cellular responses and the production and release of important immune effectors into the hemolymph. Antimicrobial proteins and/or peptides (AMPs are key components of innate immunity and are widespread in nature, from bacteria to vertebrate animals. In crustaceans, 15 distinct AMP families are currently recognized, although the great majority (14 families comes from members of the order Decapoda. Crustacean AMPs are generally cationic, gene-encoded molecules that are mainly produced by circulating immune-competent cells (hemocytes or are derived from unrelated proteins primarily involved in other biological functions. In this review, we tentatively classified the crustacean AMPs into four main groups based on their amino acid composition, structural features and multi-functionality. We also attempted to summarize the current knowledge on their implication both in an efficient response to microbial infections and in crustacean survival.

  6. Material Binding Peptides for Nanotechnology

    Urartu Ozgur Safak Seker

    2011-02-01

    Full Text Available Remarkable progress has been made to date in the discovery of material binding peptides and their utilization in nanotechnology, which has brought new challenges and opportunities. Nowadays phage display is a versatile tool, important for the selection of ligands for proteins and peptides. This combinatorial approach has also been adapted over the past decade to select material-specific peptides. Screening and selection of such phage displayed material binding peptides has attracted great interest, in particular because of their use in nanotechnology. Phage display selected peptides are either synthesized independently or expressed on phage coat protein. Selected phage particles are subsequently utilized in the synthesis of nanoparticles, in the assembly of nanostructures on inorganic surfaces, and oriented protein immobilization as fusion partners of proteins. In this paper, we present an overview on the research conducted on this area. In this review we not only focus on the selection process, but also on molecular binding characterization and utilization of peptides as molecular linkers, molecular assemblers and material synthesizers.

  7. Collagen-like antimicrobial peptides.

    Masuda, Ryo; Kudo, Masakazu; Dazai, Yui; Mima, Takehiko; Koide, Takaki

    2016-11-01

    Combinatorial library composed of rigid rod-like peptides with a triple-helical scaffold was constructed. The component peptides were designed to have various combinations of basic and neutral (or hydrophobic) amino acid residues based on collagen-like (Gly-Pro-Yaa)-repeating sequences, inspired from the basic and amphiphilic nature of naturally occurring antimicrobial peptides. Screening of the peptide pools resulted in identification of antimicrobial peptides. A structure-activity relationship study revealed that the position of Arg-cluster at N-terminus and cystine knots at C-terminus in the triple helix significantly contributed to the antimicrobial activity. The most potent peptide RO-A showed activity against Gram-negative Escherichia coli and Gram-positive Bacillus subtilis. In addition, Escherichia coli exposed to RO-A resulted in abnormal elongation of the cells. RO-A was also shown to have remarkable stability in human serum and low cytotoxicity to mammalian cells. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 453-459, 2016. PMID:27271210

  8. Automated solid-phase peptide synthesis to obtain therapeutic peptides

    Veronika Mäde

    2014-05-01

    Full Text Available The great versatility and the inherent high affinities of peptides for their respective targets have led to tremendous progress for therapeutic applications in the last years. In order to increase the drugability of these frequently unstable and rapidly cleared molecules, chemical modifications are of great interest. Automated solid-phase peptide synthesis (SPPS offers a suitable technology to produce chemically engineered peptides. This review concentrates on the application of SPPS by Fmoc/t-Bu protecting-group strategy, which is most commonly used. Critical issues and suggestions for the synthesis are covered. The development of automated methods from conventional to essentially improved microwave-assisted instruments is discussed. In order to improve pharmacokinetic properties of peptides, lipidation and PEGylation are described as covalent conjugation methods, which can be applied by a combination of automated and manual synthesis approaches. The synthesis and application of SPPS is described for neuropeptide Y receptor analogs as an example for bioactive hormones. The applied strategies represent innovative and potent methods for the development of novel peptide drug candidates that can be manufactured with optimized automated synthesis technologies.

  9. Perspectives and Peptides of the Next Generation

    Brogden, Kim A.

    Shortly after their discovery, antimicrobial peptides from prokaryotes and eukaryotes were recognized as the next potential generation of pharmaceuticals to treat antibiotic-resistant bacterial infections and septic shock, to preserve food, or to sanitize surfaces. Initial research focused on identifying the spectrum of antimicrobial agents, determining the range of antimicrobial activities against bacterial, fungal, and viral pathogens, and assessing the antimicrobial activity of synthetic peptides versus their natural counterparts. Subsequent research then focused on the mechanisms of antimicrobial peptide activity in model membrane systems not only to identify the mechanisms of antimicrobial peptide activity in microorganisms but also to discern differences in cytotoxicity for prokaryotic and eukaryotic cells. Recent, contemporary work now focuses on current and future efforts to construct hybrid peptides, peptide congeners, stabilized peptides, peptide conjugates, and immobilized peptides for unique and specific applications to control the growth of microorganisms in vitro and in vivo.

  10. Exploration of the Medicinal Peptide Space.

    Gevaert, Bert; Stalmans, Sofie; Wynendaele, Evelien; Taevernier, Lien; Bracke, Nathalie; D'Hondt, Matthias; De Spiegeleer, Bart

    2016-01-01

    The chemical properties of peptide medicines, known as the 'medicinal peptide space' is considered a multi-dimensional subset of the global peptide space, where each dimension represents a chemical descriptor. These descriptors can be linked to biofunctional, medicinal properties to varying degrees. Knowledge of this space can increase the efficiency of the peptide-drug discovery and development process, as well as advance our understanding and classification of peptide medicines. For 245 peptide drugs, already available on the market or in clinical development, multivariate dataexploration was performed using peptide relevant physicochemical descriptors, their specific peptidedrug target and their clinical use. Our retrospective analysis indicates that clusters in the medicinal peptide space are located in a relatively narrow range of the physicochemical space: dense and empty regions were found, which can be explored for the discovery of novel peptide drugs. PMID:26876881

  11. Peptide-enhanced oral delivery of therapeutic peptides and proteins

    Kristensen, Mie; Foged, Camilla; Berthelsen, Jens;

    2013-01-01

    such as the cell penetrating peptides (CPPs) and the tight junction modulating peptides (TJMPs), which are able to translocate across the cellular membranes in a non-disruptive way or reversibly modulate the integrity of intercellular tight junctions (TJs), respectively. However, because of the harsh...... believed that CPP-mediated translocation involves transcytosis and/or direct translocation through the epithelial cells; whereas TJMP-mediated translocation is dependent on interaction with transmembrane or peripheral TJ proteins. This review focuses on the CPPs and the TJMPs currently employed as...

  12. Double-Stranded Peptide Nucleic Acids

    2001-01-01

    A novel class of compounds, known as peptide nucleic acids, form double-stranded structures with one another and with ssDNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker.......A novel class of compounds, known as peptide nucleic acids, form double-stranded structures with one another and with ssDNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  13. Recent development of peptide self-assembly

    Xiubo Zhao; Fang Pan; Jian R. Lu

    2008-01-01

    Amino acids are the building blocks to build peptides and proteins. Recent development in peptide synthesis has however enabled us to mimic this natural process by preparing various long and short peptides possessing different conformations and biological functions. The self-assembly of short designed peptides into molecular nanostructures is becoming a growing interest in nanobiotechnology. Self-assembled peptides exhibit several attractive features for applications in tissue regeneration, drug delivery, biological surface engineering as well as in food science, cosmetic industry and antibiotics. The aim of this review is to introduce the readers to a number of representative studies on peptide self-assembly.

  14. Antiviral active peptide from oyster

    Zeng, Mingyong; Cui, Wenxuan; Zhao, Yuanhui; Liu, Zunying; Dong, Shiyuan; Guo, Yao

    2008-08-01

    An active peptide against herpes virus was isolated from the enzymic hydrolysate of oyster ( Crassostrea gigas) and purified with the definite direction hydrolysis technique in the order of alcalase and bromelin. The hydrolysate was fractioned into four ranges of molecular weight (>10 kDa, 10 5 kDa, 5 1 kDa and <1 kDa) using ultrafiltration membranes and dialysis. The fraction of 10 5 kDa was purified using consecutive chromatographic methods including DEAE Sephadex A-25 column, Sephadex G-25 column, and high performance liquid chromatogram (HPLC) by activity-guided isolation. The antiviral effect of the obtained peptide on herpetic virus was investigated in Vero cells by observing cytopathic effect (CPE). The result shows that the peptide has high inhibitory activity on herpetic virus.

  15. Radioactive labelling of peptidic hormones

    The labelling of peptidic hormones requires stability, specificity and sensitivity of the label. Introduction of a radioactive atome is one way to satisfy these criteria. Several processes have been described to prepare radioactive TRF: synthesis of the peptide with labelled aminoacids or introduction of the label into the hormone. In that approach, tritium can be substituted in the imidazole ring, via precursors activating the proper carbon. Monoiodo TRF leads essentially to tritium labelling of the 5 positions whereas monoazo TRF allows the preparation of 3H TRF labelled in the 2 positions. Di-substituted TRF leads to labelling into the 2 and 5 carbons. Labelled analogs of TRF can be prepared with labelled iodine; further developments of peptide labelling, will be presented. In particular, the homolytic scission of the C-iodine, bond by photochemical activation. The nascent carbon radical can be stabilized by a tritiated scavenger. This approach eliminates the use of heavy metal catalysts

  16. Antiviral active peptide from oyster

    2008-01-01

    An active peptide against herpes virus was isolated from the enzymic hydrolysate of oyster (Crassostrea gigas) and purified with the definite direction hydrolysis technique in the order of alcalase and bromelin. The hydrolysate was fractioned into four ranges of molecular weight (>10 kDa, 10-5 kDa, 5-1 kDa and <1 kDa) using ultrafiltration membranes and dialysis. The fraction of 10?5 kDa was purified using consecutive chromatographic methods including DEAE Sephadex A-25 column, Sephadex G-25 column, and high performance liquid chromatogram (HPLC) by activity-guided isolation. The antiviral effect of the obtained peptide on herpetic virus was investigated in Vero cells by observing cytopathic effect (CPE). The result shows that the peptide has high inhibitory activity on herpetic virus.

  17. Direct and indirect radioiodination of protein: comparative study of chemotactic peptide labeling; Radioiodacao de proteina por via direta e indireta: estudo comparativo da marcacao de peptideo quimiotatico

    Lavinas, Tatiana

    2004-07-01

    of the chemotactic peptide labeled by direct and indirect methods. The ATE was obtained with satisfactory yield (90,7%). The conditions for ATE radioiodination were p H 3 - 4, 50 {mu}mol of t-butylhydroperoxide and 30 minutes of reaction. The SIB was purified to remove the unreacted ATE and some radiochemical impurities presented in the reaction mixture. The peptide radioiodinated by direct method was obtained in a short reaction time (10 minutes), with high radiochemical purity (> 96%) and in vitro stability (48 hours under refrigeration). The biodistribution studies developed in normal Swiss mice and in mice with inflammatory focus developed by the administration of turpentine in the right thigh showed the ability of the compound to concentrate in the inflammatory focus as evidenced by the higher uptake in the inflamed thigh when compared to the normal thigh (p< 0.05, Student t) in all studied time. However, the uptake in thyroid increased in time due to the in vivo dehalogenation of the compound. The peptide radioiodinated by indirect method was also obtained with high radiochemical purity but only after high performance liquid chromatography purification (> 99%) and was stable in vitro (24 hours under refrigeration). Despite the indirect labeling procedure was laborious, time consuming and the product was obtained with low radiochemical yield (26,3%), the labeled peptide showed specificity by inflammatory focus and in vivo stability confirmed by the lower thyroid uptake when compared with the peptide labeled by direct method. The great in vivo stability of the peptide labeled by indirect method justifies the study of new and alternative purification procedure that reduces process time and increases the final yield. (author)

  18. Peptide Antibiotics for ESKAPE Pathogens

    Thomsen, Thomas Thyge

    developed from a cecropin-mellitin hybrid peptide and proved effective in killing colistin resistant Gram-negative A. baumannii in vitro. The molecule was improved with regard to toxicity, as measured by hemolytic ability. Further, this peptide is capable of specifically killing non-growing cells of...... colistin resistant A. baumannii, also known as persisters. Using D. melanogaster as an in vivo efficacy model it was demonstrated that the Lantibiotic NAI- 107, currently undergoing pre-clinical studies, rescues D. melanogaster from MRSA infection with similar efficacy to last resort antimicrobial...

  19. Novel Formulations for Antimicrobial Peptides

    Ana Maria Carmona-Ribeiro

    2014-10-01

    Full Text Available Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy.

  20. Peptides and the new endocrinology

    Schwyzer, Robert

    1982-01-01

    The discovery of regulatory peptides common to the nervous and the endocrine systems (brain, gut, and skin) has brought about a revolution in our concepts of endocrinology and neurology. We are beginning to understand some of the complex interrelationships between soma and psyche that might, someday, be important for an integrated treatment of diseases. Examples of the actions of certain peptides in the periphery and in the central nervous system are given, and their biosynthesis and molecular anatomy as carriers for information are discussed.