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Sample records for 48-hour glucagon-like peptide

  1. Glucagon-like peptide-1

    Holst, Jens Juul

    2006-01-01

    The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal...

  2. 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...

  3. 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.

  4. 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 the peptide....

  5. 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 inve......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...

  6. 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...

  7. Acylation of Glucagon-like peptide-2

    Trier, Sofie; Linderoth, Lars; Bjerregaard, Simon;

    2014-01-01

    These results show that membrane interactions play a prominent role during intestinal translocation of an acylated peptide. Acylation benefits permeation for shorter and medium chains due to increased membrane interactions, however, for longer chains insertion in the membrane becomes dominant and...... and hinders translocation, i.e. the peptides get 'stuck' in the cell membrane. Applying a transcellular absorption enhancer increases the dynamics of membrane insertion and detachment by fluidizing the membrane, thus facilitating its effects primarily on membrane associated peptides....

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

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

    2008-01-01

    Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor beta-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects...... as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here....

  9. The discovery of glucagon-like peptide 1.

    Lund, P Kay

    2005-06-15

    The discovery of glucagon-like peptide 1 (GLP-1) began more than two decades ago with the observations that anglerfish islet proglucagon messenger RNAs (mRNAs) contained coding sequences for two glucagon-related peptides arranged in tandem. Subsequent analyses revealed that mammalian proglucagon mRNAs encoded a precursor containing the sequence of pancreatic glucagon, intestinal glicentin and two glucagon-related peptides termed GLP-1 and GLP-2. Multidisciplinary approaches were then required to define the structure of biologically active GLP-1 7-36 amide and its role as an incretin, satiety hormone and, most recently, a neuroprotective peptide. This historial perspective outlines the use of traditional recombinant DNA approaches to derive the GLP-1 sequence and highlights the challenges and combination of clinical and basic science approaches required to define the physiology and pathophysiology of bioactive peptides discovered through genomics.

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

    Thulesen, Jesper; Hartmann, B.; Kissow, H.;

    2001-01-01

    Anatomy, glucagon-like peptide 2, small intestine, short bowel, intestinal adaptation, growth factors, rat......Anatomy, glucagon-like peptide 2, small intestine, short bowel, intestinal adaptation, growth factors, rat...

  11. Bioactivity of a modified human Glucagon-like peptide-1

    Xu, Fangfang; Wang, Kevin Yueju; Wang, Nan; Li, Gangqiang; Liu, Dehu

    2017-01-01

    Diabetes has become the third largest cause of death in humans worldwide. Therefore, effective treatment for this disease remains a critical issue. Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis, and therefore represents a promising candidate to use for the treatment of diabetes. Native GLP-1, however, is quickly degraded in in the circulatory system; which limits its clinical application. In the present study, a chemically-synthesized, modified analogue of human GLP-1 (mGLP-1) was designed. Our analyses indicated that, relative to native GLP-1, mGLP-1 is more resistant to trypsin and pancreatin degradation. mGLP-1 promotes mouse pancreatic β-cell proliferation by up-regulating the expression level of cyclin E, CDK2, Bcl-2 and down-regulating Bax, p21, and stimulates insulin secretion. An oral glucose tolerance test indicated that mGLP-1 significantly improved glucose tolerance in mice. Intraperitoneal injections of mGLP-1 into streptozotocin (STZ)-induced type 2 diabetic mice significantly reduced blood sugar levels and stimulated insulin secretion. Oral gavages of mGLP-1 in diabetic mice did not result in significant hypoglycemic activity. PMID:28152036

  12. 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....

  13. Evaluation of beta-cell secretory capacity using glucagon-like peptide 1

    Vilsbøll, Tina; Nielsen, Mette Toft; Krarup, T

    2000-01-01

    Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients.......Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients....

  14. Enteral supplementation with glutamine, fiber, and oligosaccharide modulates incretin and glucagon-like peptide-2 secretion

    2014-01-01

    Aims/Introduction: A dietary supplementation product enriched with glutamine, dietary fiber and oligosaccharide (GFO) is widely applied for enteral nutrition support in Japan. The aim of the present study was to evaluate the effects of GFO ingestion on secretion of incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2). Materials and Methods: We carried out a cross-over study involving 20 healthy Japanese volunteers. The partic...

  15. 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.......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....

  16. 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

    2007-01-01

    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. ...

  17. 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 concent...

  18. The effect of glucagon-like Peptide-2 receptor agonists on colonic anastomotic wound healing

    Redstone, Heather A; Buie, William D; Hart, David A;

    2010-01-01

    Background. Glucagon-like peptide 2 (GLP-2) is an intestinal specific trophic hormone, with therapeutic potential; the effects on intestinal healing are unknown. We used a rat model of colonic healing, under normoxic, and stress (hypoxic) conditions to examine the effect of GLP-2 on intestinal he...

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

    Ripken, D.; Wielen, N. van der; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F.; Hendriks, H.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 fo

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

    Ripken, Dina; Wielen, van der Nikkie; 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

  1. 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 ...

  2. Decreased Hypothalamic Glucagon-Like Peptide-1 Receptor Expression in Type 2 Diabetes Patients

    Ten Kulve, Jennifer S; van Bloemendaal, Liselotte; Balesar, Rawien; IJzerman, Richard G; Swaab, Dick F; Diamant, Michaela; la Fleur, Susanne E; Alkemade, Anneke

    2016-01-01

    CONTEXT: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonist treatment in type 2 diabetes (T2DM) reduce blood glucose and food intake. It has been suggested that these effects are partly mediated through central GLP-1 receptors (GLP-1Rs). The rodent and nonhuman primate hypothalamus show clea

  3. 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)....

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

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

    2014-01-01

    The gut hormone glucagon-like peptide-1 (GLP-1) is an insulinotropic incretin with significant cardiovascular impact. Two classes of medication, GLP-1 analogues and DPP-4 inhibitors, have been developed that circumvent the rapid degradation of GLP-1 by the enzyme dipeptidyl peptidase-4 (DPP-4), b...

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

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

    2007-01-01

    BACKGROUND: Glucagon-like peptide-2 (GLP-2) seems to be a highly specific intestinotrophic mediator. From animal studies, GLP-2 is known to increase in the early neonatal period before it falls to adult level. No studies in newborn infants addressing this specific subject have been published so f...

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

    Sigalet, David L; de Heuvel, Elaine; Wallace, Laurie;

    2014-01-01

    BACKGROUND: The enteroendocrine hormone glucagon like peptide-2 (GLP-2) and its ligands are under development as therapeutic agents for a variety of intestinal pathologies. A number of these conditions occur in neonates and infants, and thus a detailed understanding of the effects of GLP-2 during...

  7. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

    Ellenbroek, J.H.; Tons, H.A.; Westerouen van Meeteren, M.J.; de Graaf, N.; Hanegraaf, M.A.; Rabelink, T.J.; Carlotti, F.; de Koning, E.J.

    2013-01-01

    AIMS/HYPOTHESIS: Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular di

  8. 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…

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

    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 in...

  10. 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...... 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...... were studied with the intravenous infusion of GLP-2 (2 pmol l(-1) min(-1)) or placebo over 120 min in the fasting state. Plasma concentrations of glucose, insulin, C-peptide, glucagon, intact GLP-2 and ghrelin were determined. RESULTS: During the infusion of GLP-2, plasma concentrations of intact GLP-2...

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

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

    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...

  12. 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...

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

    Bak, Monika Judyta; Albrechtsen, Nicolai Jacob Wewer; Pedersen, Jens;

    2014-01-01

    AIMS: To evaluate performances of commercially available glucagon-like peptide-1 (GLP-1) assays and implications for clinical studies. MATERIALS AND METHODS: Known concentrations (5-300 pmol/l) of synthetic GLP-1 isoforms (GLP-1 1-36NH2 , 7-36NH2 , 9-36NH2 , 1-37, 7-37 and 9-37) were added to the...

  14. Intracerebroventricular administration of novel glucagon-like peptide suppresses food intake in chicks.

    Honda, Kazuhisa; Saneyasu, Takaoki; Yamaguchi, Takuya; Shimatani, Tomohiko; Aoki, Koji; Nakanishi, Kiwako; Kamisoyama, Hiroshi

    2014-02-01

    Glucagon-related peptides such as glucagon, glucagon-like peptide-1, and oxyntomodulin suppress food intake in mammals and birds. Recently, novel glucagon-like peptide (GCGL) was identified from chicken brain, and a comparatively high mRNA expression level of GCGL was detected in the hypothalamus. A number of studies suggest that the hypothalamus plays a critical role in the regulation of food intake in mammals and birds. In the present study, we investigated whether GCGL is involved in the central regulation of food intake in chicks. Male 8-day-old chicks (Gallus gallus) were used in all experiments. Intracerebroventricular administration of GCGL in chicks significantly suppressed food intake. Plasma glucose level was significantly decreased by GCGL, whereas plasma corticosterone level was not affected. Central administration of a corticotrophin-releasing factor (CRF) receptor antagonist, α-helical CRF, attenuated GCGL-suppressed food intake. It seems likely that CRF receptor is involved in the GCGL-induced anorexigenic pathway. All our findings suggest that GCGL functions as an anorexigenic peptide in the central nervous system of chicks.

  15. 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.

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

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

    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 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...... of gastrointestinal function in a group of children with autism....

  17. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Body Weight: A Meta-Analysis

    Matteo Monami; Ilaria Dicembrini; Niccolò Marchionni; Rotella, Carlo M.; Edoardo Mannucci

    2012-01-01

    Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for “exenatide,” “liraglutide,” “albiglutide,” “semaglutide,” and “lixisenatide” was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or...

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

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

    2014-01-01

    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......) 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

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

    Madsbad, S

    2014-01-01

    The hormone glucagon-like peptide-1 (GLP-1) is released from the gut in response to food intake. It acts as a satiety signal, leading to reduced food intake, and also as a regulator of gastric emptying. Furthermore, GLP-1 functions as an incretin hormone, stimulating insulin release and inhibiting...... glucagon secretion from the pancreas in response to food ingestion. Evidence suggests that the action or effect of GLP-1 may be impaired in obese subjects, even in those with normal glucose tolerance. GLP-1 impairment may help explain the increased gastric emptying and decreased satiety signalling seen...

  20. 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...... and protein contents and increased total protein synthesis rate in SBS+GLP-2 vs. SBS pigs (+100%, P fluid and macronutrients. GLP-2 treatment may...... be a promising therapy to enhance intestinal adaptation and improve digestive function in preterm infants with jejunostomy following intestinal resection....

  1. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System

    Muscogiuri, Giovanna; DeFronzo, Ralph A; Gastaldelli, Amalia

    2017-01-01

    Glucagon-like peptide-1 (GLP-1) is released in response to meals and exerts important roles in the maintenance of normal glucose homeostasis. GLP-1 is also important in the regulation of neurologic and cognitive functions. These actions are mediated via neurons in the nucleus of the solitary trac...... human trials report a neuroprotective effect of GLP-1-RAs in Alzheimer's and Parkinson's disease. In this review, we discuss the role of GLP-1 and GLP-1-RAs in the nervous system with focus on GLP-1 actions on appetite regulation, glucose homeostasis, and neuroprotection....

  2. Glucagon-like peptide-2 increases mesenteric blood flow in humans

    Bremholm, Lasse; Hornum, Mads; Henriksen, Birthe Merete;

    2008-01-01

    OBJECTIVE: Mesenteric blood flow is believed to be influenced by digestion and absorption of ingested macronutrients. We hypothesized that the intestinotrophic hormone, GLP-2 (glucagons-like peptide 2), may be involved in the regulation of mesenteric blood flow. Changes in mesenteric blood flow...... were measured by Doppler ultrasound scanning of the superior mesenteric artery (SMA). The aim of the study was to demonstrate the influence of GLP-2 on this flow, expressed as changes in resistance index (RI). MATERIAL AND METHODS: A homogeneous group of 10 fasting healthy volunteers completed a 2-day...... support the hypothesis that GLP-2 is an important regulator of mesenteric blood flow....

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

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

    2007-01-01

    described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor...... and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also......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...

  4. Crystal Structure of Glucagon-like Peptide-1 in Complex with the Extracellular Domain of the Glucagon-like Peptide-1 Receptor

    Underwood, Christina Rye; Garibay, P.; Knudsen, L.B.;

    2010-01-01

    GLP-1 (glucagon-like peptide-1) is an incretin released from intestinal L-cells in response to food intake. Activation of the GLP-1 receptor potentiates the synthesis and release of insulin from pancreatic beta-cells in a glucose-dependent manner. The GLP-1 receptor belongs to class B of the G......-protein-coupled receptors, a subfamily characterized by a large N-terminal extracellular ligand binding domain. Exendin-4 and GLP-1 are 50% identical, and exendin-4 is a full agonist with similar affinity and potency for the GLP-1 receptor. We recently solved the crystal structure of the GLP-1 receptor extracellular domain...... in complex with the competitive antagonist exendin-4(9-39). Interestingly, the isolated extra-cellular domain binds exendin-4 with much higher affinity than the endogenous agonist GLP-1. Here, we have solved the crystal structure of the extracellular domain in complex with GLP-1 to 2.1 angstrom resolution...

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

    Hansen, Lene; Lampert, Sarah; Mineo, Hitoshi

    2004-01-01

    Glucagon-like peptide (GLP)-1 is secreted rapidly from the intestine postprandially. We therefore investigated its possible neural regulation. With the use of isolated perfused porcine ileum, GLP-1 secretion was measured in response to electrical stimulation of the mixed, perivascular nerve supply...... and infusions of neuroactive agents alone and in combination with different blocking agents. Electrical nerve stimulation inhibited GLP-1 secretion, an effect abolished by phentolamine. Norepinephrine inhibited secretion, and phentolamine abolished this effect. GLP-1 secretion was stimulated by isoproterenol...... and weak effects on glucose-dependent insulinotropic peptide and somatostatin secretion, although this elicited a marked atropine-resistant release of the neuropeptide vasoactive intestinal polypeptide to the portal circulation. Thus GLP-1 secretion is inhibited by the sympathetic nerves to the gut and may...

  6. 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.

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

    Snyder, Eric M; Carr, Richard D; Deacon, Carolyn F

    2008-01-01

    Altitude exposure has been associated with loss of appetite and weight loss in healthy humans; however, the endocrine factors that contribute to these changes remain unclear. Leptin and glucagon-like peptide-1 (GLP-1) are peptide hormones that contribute to the regulation of appetite. Leptin...... increases with hypoxia; however, the influence of hypoxia on GLP-1 has not been studied in animals or humans to date. We sought to determine the influence of normobaric hypoxia on plasma leptin and GLP-1 levels in 25 healthy humans. Subjects ingested a control meal during normoxia and after 17 h of exposure...... to normobaric hypoxia (fraction of inspired oxygen of 12.5%, simulating approximately 4100 m). Plasma leptin was assessed before the meal, and GLP-1 was assessed premeal, at 20 min postmeal, and at 40 min postmeal. We found that hypoxia caused a significant elevation in plasma leptin levels (normoxia, 4.9 +/- 0...

  8. 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

    2008-01-01

    OBJECTIVE: Biochemical markers for bone resorption (s-CTX) are reduced by food intake, whereas markers for bone formation seem to be unaffected by meal status. Glucagon-like peptide-2 (GLP-2) is a peptide secreted from endocrine L cells in the intestinal mucosa in relation to food-intake. Subcuta...

  9. Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats

    DellaValle, Brian; Brix, Gitte S; Brock, Birgitte;

    2016-01-01

    (GLP-1) family, is also anti-diabetic and weight-reducing and is, moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing......Introduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1...... the experimental model, experimental autoimmune encephalitis (EAE). Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 μg/kg s.c.) or saline. Healthy controls were included (saline, n = 6, liraglutide, n = 7). Clinical score and weight were assessed daily...

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

    Della Valle, Brian William; 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...

  11. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes

    Nauck, M A; Vardarli, I; Deacon, C F;

    2011-01-01

    The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP......-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency...... with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual incretin secretory responses and explain some...

  12. Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin

    Bahne, Emilie; Hansen, Morten; Brønden, Andreas;

    2016-01-01

    Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously...... administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin......-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target...

  13. 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

    Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral...... 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...... 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

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

    Vilsbøll, Tina

    2009-01-01

    Type 2 diabetes is a progressive disease characterized by insulin resistance and impaired beta-cell function. Treatments that prevent further beta-cell decline are therefore essential for the management of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is known...... to stimulate glucose-dependent insulin secretion. Furthermore, GLP-1 appears to have multiple positive effects on beta cells. However, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which limits the clinical relevance of GLP-1 for the treatment of type 2 diabetes. Two main classes of GLP-1-based...... therapies have now been developed: DPP-4 inhibitors and GLP-1 receptor agonists. Liraglutide and exenatide are examples of GLP-1 receptor agonists that have been developed to mimic the insulinotropic characteristics of endogenous GLP-1. Both have demonstrated improved beta-cell function in patients...

  15. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology.

    Drucker, D J; Rosen, C F

    2011-11-01

    Type 2 diabetes mellitus is characterised by beta cell failure, which frequently develops in the setting of insulin resistance. Inflammation contributes to the pathophysiology of type 2 diabetes by impairing insulin action in peripheral tissues and via reduction of beta cell function. Inflammation may also play an important role in the development of complications that arise in patients with type 2 diabetes. Hence, the anti-inflammatory actions of commonly used glucose-lowering drugs may contribute, indirectly, to their mechanisms of action and therapeutic benefit. Herein we highlight the anti-inflammatory actions of glucagon-like peptide-1 (GLP-1), which exerts direct and indirect actions on immune function. The observations that GLP-1 receptor agonists exert anti-inflammatory actions in preclinical studies, taken together with case reports linking improvements in psoriasis with GLP-1 receptor agonist therapy, illustrates the emerging clinical implications of non-classical anti-inflammatory actions of incretin-based therapeutics.

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

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

    2012-01-01

    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...... are 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...... 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...

  17. 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

    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......). 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...

  18. Porcine glucagon-like peptide-2: structure, signaling, metabolism and effects

    Pedersen, Nis Borbye; Hjøllund, Karina Rahr; Johnsen, Anders H;

    2007-01-01

    Mass spectrometry of HPLC-purified porcine glucagon-like peptide-2 (pGLP-2)(1) revealed a 35 amino acid sequence with C-terminal Ser and Leu, in contrast to the 33 amino acids of human, cow, rat and mouse GLP-2. Synthetic pGLP-2 stimulated cAMP-production in COS-7 cells expressing human GLP-2 (h......GLP-2) receptor with the same potency and efficacy as hGLP-2. In anesthetized pigs (n=9) given intravenous pGLP-2 infusions, the half life (t1/2) of intact pGLP-2 (8.4+/-0.9 min) was shorter (p... MCR of hGLP-2 in pig. The MCR of intact pGLP-2 was reduced by valine-pyrrolidide (pinsulin or somatostatin release...

  19. 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 encapsulation...... and quality control is performed in compliance with good manufacturing practice and fulfils all regulatory requirements for human clinical use. GLP-1 CellBeads combine the neuro- and cardioprotective properties of both GLP-1 and mesenchymal stem cells. First promising results were obtained from preclinical...... method is described for the manufacturing of homogeneous CellBeads. Viability and sustained secretion was shown for the recombinant GLP-1 and the cell endogenous bioactive factors like vascular endothelial growth factor, neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor. Manufacturing...

  20. Treatment of type 2 diabetes with glucagon-like peptide-1 receptor agonists

    Hansen, K B; Knop, F K; Holst, Jens Juul;

    2009-01-01

    ongoing decline in pancreatic beta-cell function and, lastly, they have a number of side effects including hypoglycaemia and weight gain. Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of pharmacological agents, which improve glucose homeostasis in a multifaceted way. Their effects...... of hypoglycaemia with GLP-1 receptor agonists is low, the compounds have clinically relevant effects on body weight, and data are suggesting beneficial effects on cardiovascular risk factors. Exenatide was released in 2005 for the treatment of type 2 diabetes and liraglutide is expected to be approved by the Food...... and Drug Administration in US and the European Medical Agency in Europe for use in 2009. In this review, the available data on the two drugs are presented and discussed....

  1. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, secreted in response to ingestion of nutrients, and has important effects on several of the pathophysiological features of type 2 diabetes (T2D). The effects include potentiation of insulin secretion, suppression of glucagon secretion...... developed. At the moment four different compounds are available for the treatment of T2D and many more are in clinical development. These compounds, although all based on the effects of native GLP-1, differ with regards to structure, pharmacokinetics and size, which ultimately leads to different clinical...... effects. This review gives an overview of the clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds. Highlighting these similarities and differences could be beneficial for physicians in choosing the best treatment...

  2. Pharmacokinetics and pharmacodynamics of the glucagon-like peptide-1 analog liraglutide in healthy cats.

    Hall, M J; Adin, C A; Borin-Crivellenti, S; Rudinsky, A J; Rajala-Schultz, P; Lakritz, J; Gilor, C

    2015-04-01

    Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Glucagon-like peptide-1 also increases beta cell mass and satiation while decelerating gastric emptying. Liraglutide is a fatty-acid derivative of GLP-1 with a protracted pharmacokinetic profile that is used in people for treatment of type II diabetes mellitus and obesity. The aim of this study was to determine the pharmacokinetics and pharmacodynamics of liraglutide in healthy cats. Hyperglycemic clamps were performed on days 0 (HGC) and 14 (LgHGC) in 7 healthy cats. Liraglutide was administered subcutaneously (0.6 mg/cat) once daily on days 8 through 14. Compared with the HGC (mean ± standard deviation; 455.5 ± 115.8 ng/L), insulin concentrations during LgHGC were increased (760.8 ± 350.7 ng/L; P = 0.0022), glucagon concentrations decreased (0.66 ± 0.4 pmol/L during HGC vs 0.5 ± 0.4 pmol/L during LgHGC; P = 0.0089), and there was a trend toward an increased total glucose infused (median [range] = 1.61 (1.11-2.54) g/kg and 2.25 (1.64-3.10) g/kg, respectively; P = 0.087). Appetite reduction and decreased body weight (9% ± 3%; P = 0.006) were observed in all cats. Liraglutide has similar effects and pharmacokinetics profile in cats to those reported in people. With a half-life of approximately 12 h, once daily dosing might be feasible; however, significant effects on appetite and weight loss may necessitate dosage or dosing frequency reductions. Further investigation of liraglutide in diabetic cats and overweight cats is warranted.

  3. Intracerebroventricular administration of chicken glucagon-like peptide-2 potently suppresses food intake in chicks.

    Honda, Kazuhisa; Saneyasu, Takaoki; Shimatani, Tomohiko; Aoki, Koji; Yamaguchi, Takuya; Nakanishi, Kiwako; Kamisoyama, Hiroshi

    2015-03-01

    Glucagon-related peptides, such as glucagon-like peptide (GLP)-1, GLP-2 and oxyntomodulin (OXM), are processed from an identical precursor proglucagon. In mammals, all of these peptides are suggested to be involved in the central regulation of food intake. We previously showed that intracerebroventricular administration of chicken OXM and GLP-1 significantly suppressed food intake in chicks. Here, we show that central administration of chicken GLP-2 potently suppresses food intake in chicks. Male 8-day-old chicks (Gallus gallus domesticus) were used in all experiments. Intracerebroventricular administration of chicken GLP-2 significantly suppressed food intake in chicks. Plasma glucose concentration was significantly decreased by chicken GLP-2, whereas plasma nonesterified fatty acid concentration was significantly increased. Intracerebroventricular administration of chicken GLP-2 did not affect plasma corticosterone concentration. In addition, the anorexigenic effect of GLP-2 was not reversed by the corticotropin-releasing factor (CRF) receptor antagonist α-helical CRF, suggesting that CRF is not a downstream mediator of the anorexigenic pathway of GLP-2 in chicks. Intracerebroventricular administration of an equimolar amount of GLP-1 and GLP-2, but not OXM, significantly suppressed food intake in both broiler and layer chicks. All our findings suggest that GLP-2 functions as a potent anorexigenic peptide in the brain, as well as GLP-1, in chicks.

  4. 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...

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

    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 object...

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

    Green, Charlotte J; Henriksen, Tora I; Pedersen, Bente K;

    2012-01-01

    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....

  7. Glucagon-like peptide-2 increases splanchnic blood flow acutely in calves but loses effectiveness with chronic exposure

    Glucagon-like peptide-2 (GLP-2) is a 33-amino acid hormone secreted from the gastrointestinal tract that rapidly increases small intestinal blood flow. No experiments have been conducted evaluating the blood flow response to GLP-2 after extended administration, nor have investigations been performed...

  8. 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 acut...

  9. 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...

  10. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes

    Zander, M; Taskiran, M; Toft-Nielsen, M B;

    2001-01-01

    OBJECTIVE: The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted...

  11. 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 ...

  12. Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease

    Junker, Anders E; Gluud, Lise L; van Hall, Gerrit

    2016-01-01

    BACKGROUND & AIMS: We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS: On two separate days 10 non...

  13. 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

    Glucagon-like peptide 2 (GLP-2) is a gut hormone that stimulates mucosal growth in total parenteral nutrition (TPN)-fed piglets; however, the dose-dependent effects on apoptosis, cell proliferation, and protein synthesis are unknown. We studied 38 TPN-fed neonatal piglets infused iv with either s...

  14. The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes.

    Moon, Ho-Sang; Kim, Mi-Kyung; Son, Moon-Ho

    2011-07-01

    Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.

  15. Does Glucagon-Like Peptide-1 Have a Role in the Etiopathogenesis of Gestational Diabetes?

    Mustafa Demirpençe

    2016-06-01

    Full Text Available Purpose: The aim of this study was to evaluate glucagon-like peptide-1 (GLP-1 levels, lipid parameters, thyroid-stimulating hormone (TSH, c peptide and glycated hemoglobin (A1C values in pregnant women at high-risk for gestational diabetes mellitus (GDM. Material and Method: In this cross-sectional study, we included pregnant women at high-risk for GDM who attended the endocrinology and metabolic diseases outpatient clinics at İzmir Katip Çelebi University Atatürk Training and Research Hospital between January 2013 and April 2013. Twenty pregnant women with GDM and eleven without GDM participated in the study. The dependent variable in the study was GDM that was evaluated by 75 mg oral glucose tolerance test (OGTT. Independent variables were the levels of glucose, A1C, insulin, c-peptide, GLP-1, TSH, and lipid parameters, all evaluated in fasting blood samples. Besides, glucose, insulin, c-peptide, GLP-1 levels during OGTT were also evaluated in blood samples collected at 60 and 120 minutes. Results: While fasting insulin levels were statistically significantly higher among women with GDM, there was no statistically significant difference in the levels at 60 and 120 minutes between the two groups. There was no significant difference in fasting c-peptide levels and c-peptide levels at 60 minutes during OGTT between the two groups, however, c-peptide levels at 120 minutes were higher in women with GDM. The women with GDM was found to have lower fasting GLP-1 levels than women without GDM. Although it was not significant, GLP-1 levels at 60 and 120 minutes were also lower among women with GDM. Discussion: A decrease in GLP-1 levels may have a role in the etiopathogenesis of GDM and type 2 diabetes mellitus.

  16. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain-Adipocyte Axis.

    Geloneze, Bruno; de Lima-Júnior, José Carlos; Velloso, Lício A

    2017-02-23

    The complexity of neural circuits that control food intake and energy balance in the hypothalamic nuclei explains some of the constraints involved in the prevention and treatment of obesity. Two major neuronal populations present in the arcuate nucleus control caloric intake and energy expenditure: one population co-expresses orexigenic agouti-related peptide (AgRP) and neuropeptide Y and the other expresses the anorexigenic anorectic neuropeptides proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART). In addition to integrating signals from neurotransmitters and hormones, the hypothalamic systems that regulate energy homeostasis are affected by nutrients. Fat-rich diets, for instance, elicit hypothalamic inflammation (reactive activation and proliferation of microglia, a condition named gliosis). This process generates resistance to the anorexigenic hormones leptin and insulin, contributing to the genesis of obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have increasingly been used to treat type 2 diabetes mellitus. One compound (liraglutide) was recently approved for the treatment of obesity. Although most studies suggest that GLP-1RAs promote weight loss mainly due to their inhibitory effect on food intake, other central effects that have been described for native GLP-1 and some GLP-1RAs in rodents and humans encourage future clinical trials to explore additional mechanisms that potentially underlie the beneficial effects observed with this drug class. In this article we review the most relevant data exploring the mechanisms involved in the effects of GLP-1RAs in the brain-adipocyte axis.

  17. Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.

    Hennen, Stephanie; Kodra, János T; Soroka, Vladyslav; Krogh, Berit O; Wu, Xiaoai; Kaastrup, Peter; Ørskov, Cathrine; Rønn, Sif G; Schluckebier, Gerd; Barbateskovic, Silvia; Gandhi, Prafull S; Reedtz-Runge, Steffen

    2016-05-19

    The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor (GPCR) family and a well-established target for the treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD complex was reported previously. The first structure of a class B GPCR transmembrane (TM) domain was solved recently, but the full length receptor structure is still not well understood. Here we describe the molecular details of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52) blocked the GLP-1 binding site of the ECD directly and thereby acts as a competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a short peptide agonist believed to engage primarily the transmembrane and extracellular loop region of GLP-1R, whereas functionality of an allosteric small-molecule agonist was not inhibited. This study has implications for the structural understanding of the GLP-1R and related class B GPCRs, which is important for the development of new and improved therapeutics targeting these receptors.

  18. Alveolar Rhabdomyosarcoma in a 69-Year-Old Woman Receiving Glucagon-Like Peptide-2 Therapy

    Laura E. Zyczynski

    2015-01-01

    Full Text Available A 69-year-old woman was diagnosed with alveolar rhabdomyosarcoma (ARMS of the nasopharynx. She has a history of catastrophic thromboembolic event in the abdomen that caused short-gut syndrome and dependence on total parenteral nutrition (TPN twelve hours per day. She was treated for short-gut syndrome with teduglutide, a glucagon-like peptide-2 (GLP-2 analog, which led to reduction of TPN requirements. However, a few months later, she developed metastatic alveolar rhabdomyosarcoma. Though a causative relationship is unlikely between the peptide and ARMS due to the brief time course between teduglutide therapy and sarcoma diagnosis, neoplastic growth may have been accelerated by the GLP-2 analog, causing release of IGF-1. The transmembrane receptor for IGF-1 is frequently overexpressed in ARMS and is implicated in cell proliferation and metastatic behavior. This case describes a rare incidence of metastatic alveolar rhabdomyosarcoma in a sexagenarian and possibly the first case reported associated with the use of teduglutide. Teduglutide was discontinued due to a potential theoretical risk of acceleration of sarcoma growth, and the patient’s rhabdomyosarcoma is in remission following sarcoma chemotherapy.

  19. Differences in the Central Anorectic Effects of Glucagon-Like Peptide-1 and Exendin-4 in Rats

    Barrera, Jason G.; D'Alessio, David A.; Drucker, Daniel J.; Woods, Stephen C.; Seeley, Randy J

    2009-01-01

    OBJECTIVE Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting GLP-1 receptor (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of ...

  20. Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice.

    Akiko Mizokami

    Full Text Available The uncarboxylated form (ucOC, but not the γ-carboxylated form (GlaOC, of the bone-derived protein osteocalcin stimulates insulin secretion and regulates energy metabolism in insulin target tissues. Glucagon-like peptide-1 (GLP-1 is an insulin secretagogue that is released from the gut in response to food intake. We have now found that Gprc6a, a putative ucOC receptor, is expressed in epithelial cells of the mouse small intestine as well as in STC-1 enteroendocrine cells. Secretion of GLP-1 by STC-1 cells was stimulated by ucOC but not by GlaOC. The serum GLP-1 concentration in mice was increased by intraperitoneal or oral administration of ucOC, whereas GlaOC was effective in this regard only after oral application. Serum insulin levels were also increased by ucOC, and this effect was potentiated by an inhibitor of dipeptidyl peptidase IV and blocked by a GLP-1 receptor antagonist. Intravenous injection of ucOC in mice increased the serum GLP-1 concentration, and also increased the serum level of insulin. Our results suggest that ucOC acts via Gprc6a to induce GLP-1 release from the gut, and that the stimulatory effect of ucOC on insulin secretion is largely mediated by GLP-1.

  1. GLUCAGON LIKE PEPTIDE – 1: A NEW ERA IN TREATMENT OF TYPE- 2 DIABETES MELLITUS

    Singhal Manmohan

    2010-09-01

    Full Text Available Therapies based on the incretin hormone glucagon-like peptide 1 (GLP-1 are novel treatment options for type 2 diabetes that act through a variety of complementary mechanisms. GLP-1 is produced by the proglucagon gene in L-cells of the small intestine in response to nutrients. It stimulates glucose-dependent insulin release from the pancreatic islets. In addition to its insulinotropic effects, it is thought to exert ant hyperglycemic effects by slowing gastric emptying, inhibiting inappropriate glucagon release, stimulating β-cell proliferation and differentiation, and improving satiety. GLP-1 secretion is decreased in type 2 diabetes, thus making it a logical target for novel treatments of type 2 diabetes. In clinical trials, GLP-1 effects are evident regardless of the duration or severity of diabetes. Thus, modulating GLP-1 levels and GLP-1 activity through administration of the native hormone, analogs, and mimetics or by inhibiting its degradation has become a major focus of investigation for treating type 2 diabetes over the past decade.

  2. A Review on the Association between Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer

    Wei-Yih Chiu

    2012-01-01

    Full Text Available There is a concern on the risk of thyroid cancer associated with glucagon-like peptide-1 (GLP-1 analogs including liraglutide and exenatide. In this article, we review related experimental studies, clinical trials and observational human studies currently available. In rodents, liraglutide activated the GLP-1 receptors on C-cells, causing an increased incidence of C-cell neoplasia. Animal experiments with monkeys demonstrated no increase in calcitonin release and no C-cell proliferation after long-term liraglutide administration. Longitudinal 2-year data from clinical trials do not support any significant risk for the activation or growth of C-cell cancer in humans in response to liraglutide. However, an analysis of the FDA adverse event reporting system database suggested an increased risk for thyroid cancer associated with exenatide after its marketing. Noticeably, a recent study discovered that GLP-1 receptor could also be expressed in human papillary thyroid carcinomas (PTC, but the impact of GLP-1 analogs on PTC is not known. Therefore, GLP-1 analogs might increase the risk of thyroid C-cell pathology in rodents, but its risk in humans awaits confirmation. Since GLP-1 receptor is also expressed in PTC besides C-cells, it is important to investigate the actions of GLP-1 on different subtypes of thyroid cancer in the future.

  3. 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.

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

    Näslund, Erik; King, N; Mansten, S;

    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 given for 5 d by prandial subcutaneous injections (PSI) (76 nmol 30 min before meals, four times daily; a total of 302.4 nmol/24 h) or by continuous subcutaneous infusion (CSI) (12.7 nmol/h; a total of 304.8 nmol/24 h). This was performed in nineteen healthy obese subjects (mean age 44.2 (sem 2.5) years......; BMI 39.0 (sem 1.2) kg/m(2)) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15 % reduction in mean food intake per meal (P=0.02) after 5 d treatment. A weight loss of 0.55 (sem 0.2) kg (P

  5. [Glucagon-like peptide-1 (GLP-1) mimetics: a new treatment for Alzheimer's disease?].

    García-Casares, Natalia; García-Arnés, Juan Antonio; Gómez-Huelgas, Ricardo; Valdivielso-Felices, Pedro; García-Arias, Carlota; González-Santos, Pedro

    2014-12-01

    Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.

  6. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.

    Lau, Jesper; Bloch, Paw; Schäffer, Lauge; Pettersson, Ingrid; Spetzler, Jane; Kofoed, Jacob; Madsen, Kjeld; Knudsen, Lotte Bjerre; McGuire, James; Steensgaard, Dorte Bjerre; Strauss, Holger Martin; Gram, Dorte X; Knudsen, Sanne Møller; Nielsen, Flemming Seier; Thygesen, Peter; Reedtz-Runge, Steffen; Kruse, Thomas

    2015-09-24

    Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib(8), Arg(34)) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.

  7. 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.

  8. Design of Glucagon-Like Peptide-1 Receptor Agonist for Diabetes Mellitus from Traditional Chinese Medicine

    Hsin-Chieh Tang

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a promising target for diabetes mellitus (DM therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4. We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD, solvent accessible surface (SAS, mean square deviation (MSD, Gyrate, total energy, root mean square fluctuation (RMSF, matrices of smallest distance of residues, database of secondary structure assignment (DSSP, cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists.

  9. [Albiglutide (Eperzan): a new once-weekly agonist of glucagon-like peptide-1 receptors].

    Scheen, A J

    2015-04-01

    Albiglutide (Eperzan) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors that is indicated in the treatment of type 2 diabetes. Two doses are available, 30 mg and 50 mg, to be injected subcutaneously once a week. It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes, in comparison with placebo or an active comparator. The endocrine and metabolic effects of albiglutide are similar to those of other GLP-1 receptor agonists: stimulation of insulin secretion (incretin effect) and inhibition of glucagon secretion, both in a glucose-dependent manner, retardation of gastric emptying and increase of satiety. These effects lead to a reduction in glycated haemoglobin (HbA(1c)) levels, combined with a weight reduction. The overall tolerance profile is good. Albiglutide is currently reimbursed in Belgium after failure (HbA(1c) > 7.5%) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin (with or without oral antidiabetic drugs). To avoid hypoglycaemia, a reduction in the dose of sulfonylurea or insulin may be recommended. A once-weekly administration should increase patient's acceptance of injectable therapy and improve compliance.

  10. Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages

    C. Guo

    Full Text Available Glucagon-like peptide 1 (GLP-1, a kind of gut hormone, is used in the treatment of type 2 diabetes (T2D. Emerging evidence indicates that GLP-1 has anti-inflammatory activity. Chronic inflammation in the adipose tissue of obese individuals is a cause of insulin resistance and T2D. We hypothesized that GLP-1 analogue therapy in patients with T2D could suppress the inflammatory response of macrophages, and therefore inhibit insulin resistance. Our results showed that GLP-1 agonist (exendin-4 not only attenuated macrophage infiltration, but also inhibited the macrophage secretion of inflammatory cytokines including TNF-β, IL-6, and IL-1β. Furthermore, we observed that lipopolysaccharide (LPS-induced macrophage conditioned media could impair insulin-stimulated glucose uptake. This effect was compensated by treatment with the conditioned media from macrophages treated with the combination of LPS and exendin-4. It was also observed that exendin-4 directly inhibited the activation of NF-κB in macrophages. In conclusion, our results indicated that GLP-1 improved inflammatory macrophage-derived insulin resistance by inhibiting NF-κB pathway and secretion of inflammatory cytokines in macrophages. Furthermore, our observations suggested that the anti-inflammatory effect of GLP-1 on macrophages can contribute to GLP-1 analogue therapy of T2D.

  11. 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.

  12. Glucagon-like peptide-2-induced memory improvement and anxiolytic effects in mice.

    Iwai, Takashi; Jin, Kazushi; Ohnuki, Tomoko; Sasaki-Hamada, Sachie; Nakamura, Minami; Saitoh, Akiyoshi; Sugiyama, Azusa; Ikeda, Masaatsu; Tanabe, Mitsuo; Oka, Jun-Ichiro

    2015-02-01

    We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) on memory impairment in lipopolysaccharide (LPS)-treated mice, and anxiety-like behavior in adrenocorticotropic hormone (ACTH)-treated mice. In the Y-maze test, LPS (10 µg/mouse, i.c.v.) significantly decreased spontaneous alternation, which was prevented by pretreatment with GLP-2 (0.01-0.3 µg/mouse, i.c.v.). The GLP-2 treatment just before the Y-maze test also improved LPS-induced memory impairment. Continuous treatment with GLP-2 (3 µg/mouse, i.c.v.) had no effect on the open-field test in saline-treated or ACTH-treated mice. Chronic ACTH treatment did not cause anxiogenic effects in the elevated plus-maze test. GLP-2 showed weak anxiolytic-like effects in the elevated plus-maze test in ACTH-treated, but not saline-treated mice. Moreover, GLP-2 increased 5-HT, but not 5-HIAA and tryptophan hydroxylase 2 levels in the amygdala of ACTH-treated mice. Pharmacological depletion of 5-HT prevented the anxiolytic effects of GLP-2. These results suggest that GLP-2 protected and improved memory function in LPS-treated mice, and also had anxiolytic effects due to changes in the 5-HT system.

  13. Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis.

    Monami, Matteo; Dicembrini, Ilaria; Marchionni, Niccolò; Rotella, Carlo M; Mannucci, Edoardo

    2012-01-01

    Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for "exenatide," "liraglutide," "albiglutide," "semaglutide," and "lixisenatide" was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients) and 7 (2,416 patients) trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of -1.0 [-1.3; -0.6] kg/m(2). Considering the average BMI at baseline (32.4 kg/m(2)) these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction.

  14. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Body Weight: A Meta-Analysis

    Matteo Monami

    2012-01-01

    Full Text Available Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs, approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for “exenatide,” “liraglutide,” “albiglutide,” “semaglutide,” and “lixisenatide” was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients and 7 (2,416 patients trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of −1.0 [−1.3; −0.6] kg/m2. Considering the average BMI at baseline (32.4 kg/m2 these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction.

  15. Oral Delivery of Pentameric Glucagon-Like Peptide-1 by Recombinant Lactobacillus in Diabetic Rats

    Krogh-Andersen, Kasper; Pelletier, Julien; Marcotte, Harold; Östenson, Claes-Göran; Hammarström, Lennart

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by intestinal cells and stimulates insulin secretion from the pancreas in a glucose-dependent manner. Exogenously supplied GLP-1 analogues are used in the treatment of type 2 diabetes. An anti-diabetic effect of Lactobacillus in lowering plasma glucose levels and its use as a vehicle for delivery of protein and antibody fragments has been shown previously. The aim of this study was to employ lactobacilli as a vehicle for in situ production and delivery of GLP-1 analogue to normalize blood glucose level in diabetic GK (Goto-Kakizaki) rats. In this study, we designed pentameric GLP-1 (5×GLP-1) analogues which were both expressed in a secreted form and anchored to the surface of lactobacilli. Intestinal trypsin sites were introduced within 5×GLP-1, leading to digestion of the pentamer into an active monomeric form. The E. coli-produced 5×GLP-1 peptides delivered by intestinal intubation to GK rats resulted in a significant improvement of glycemic control demonstrated by an intraperitoneal glucose tolerance test. Meanwhile, the purified 5×GLP-1 (trypsin-digested) from the Lactobacillus cultures stimulated insulin secretion from HIT-T15 cells, similar to the E. coli-produced 5×GLP-1 peptides. When delivered by gavage to GK rats, non-expressor L. paracasei significantly lowered the blood glucose level but 5×GLP-1 expression did not provide an additional anti-diabetic effect, possibly due to the low levels produced. Our results indicate that lactobacilli themselves might be used as an alternative treatment method for type 2 diabetes, but further work is needed to increase the expression level of GLP-1 by lactobacilli in order to obtain a significant insulinotropic effect in vivo. PMID:27610615

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

    Wewer Albrechtsen, Nicolai J; Bak, Monika J; Hartmann, Bolette; Christensen, Louise Wulff; Kuhre, Rune E; Deacon, Carolyn F; Holst, Jens J

    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. Pooled human plasma (n=20), to which a dipeptidyl peptidase 4 (DPP4) inhibitor and aprotinin were added, was spiked with synthetic GLP-1 (intact, 7–36NH2 as well as the primary metabolite, GLP-1 9–36NH2) or glucagon. Peptide recoveries were measured in samples kept for 1 and 3 h at room temperature or on ice, treated with various enzyme inhibitors, after up to three thawing–refreezing cycles, and after storage at −20 and −80 °C for up to 1 year. Recoveries were unaffected by freezing cycles or if plasma was stored on ice for up to 3 h, but were impaired when samples stood at RT for more than 1 h. Recovery of intact GLP-1 increased by addition of a DPP4 inhibitor (no ice), but was not further improved by neutral endopeptidase 24.11 inhibitor or an inhibitor cocktail. GLP-1, but not glucagon, was stable for at least 1 year. Surprisingly, the recovery of glucagon was reduced by almost 50% by freezing compared with immediate analysis, regardless of storage time. Plasma handling procedures can significantly influence results of subsequent hormone analysis. Our data support addition of DPP4 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 and results should be interpreted with caution. PMID:25596009

  17. Glucagon-Like Peptide-1 Regulates Cholecystokinin Production in β-Cells to Protect From Apoptosis.

    Linnemann, Amelia K; Neuman, Joshua C; Battiola, Therese J; Wisinski, Jaclyn A; Kimple, Michelle E; Davis, Dawn Belt

    2015-07-01

    Cholecystokinin (CCK) is a classic gut hormone that is also expressed in the pancreatic islet, where it is highly up-regulated with obesity. Loss of CCK results in increased β-cell apoptosis in obese mice. Similarly, islet α-cells produce increased amounts of another gut peptide, glucagon-like peptide 1 (GLP-1), in response to cytokine and nutrient stimulation. GLP-1 also protects β-cells from apoptosis via cAMP-mediated mechanisms. Therefore, we hypothesized that the activation of islet-derived CCK and GLP-1 may be linked. We show here that both human and mouse islets secrete active GLP-1 as a function of body mass index/obesity. Furthermore, GLP-1 can rapidly stimulate β-cell CCK production and secretion through direct targeting by the cAMP-modulated transcription factor, cAMP response element binding protein (CREB). We find that cAMP-mediated signaling is required for Cck expression, but CCK regulation by cAMP does not require stimulatory levels of glucose or insulin secretion. We also show that CREB directly targets the Cck promoter in islets from obese (Leptin(ob/ob)) mice. Finally, we demonstrate that the ability of GLP-1 to protect β-cells from cytokine-induced apoptosis is partially dependent on CCK receptor signaling. Taken together, our work suggests that in obesity, active GLP-1 produced in the islet stimulates CCK production and secretion in a paracrine manner via cAMP and CREB. This intraislet incretin loop may be one mechanism whereby GLP-1 protects β-cells from apoptosis.

  18. 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;

    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...... intestinal adaptation in weanling pigs. During the first 6 d after weaning, piglets were intragastrically infused once daily with either deionized water (control), chenodeoxycholic acid (CDC; 60 mg/kg body weight), or β-sitoesterol (BSE; 100 mg/kg body weight). Infusing CDC increased plasma GLP-2 (P ....05) but did not affect plasma GLP-1 and feed intake. The intestinal expression of glucagon-like peptide 2 receptor, sodium-dependent bile acid transporter, farnesoid X receptor, and guanosine protein-coupled bile acid receptor genes were not affected by CDC treatment. The intragastric administration of CDC...

  19. Truncated glucagon-like peptide-1 (proglucagon 78-107 amide), an intestinal insulin-releasing peptide, has specific receptors on rat insulinoma cells (RIN 5AH)

    Orskov, C; Nielsen, Jens Høiriis

    1988-01-01

    We studied binding of 125I-labelled truncated-glucagon-like peptide-1 (proglucagon 78-107 amide) to a cloned rat insulin-producing cell line, RIN 5AH, in monolayer culture. Interaction of the peptide with pancreatic insulinoma cells was saturable and time dependent. Half-maximal binding was obtai......We studied binding of 125I-labelled truncated-glucagon-like peptide-1 (proglucagon 78-107 amide) to a cloned rat insulin-producing cell line, RIN 5AH, in monolayer culture. Interaction of the peptide with pancreatic insulinoma cells was saturable and time dependent. Half-maximal binding...

  20. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials

    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......-acting glucagon-like peptide-1 receptor agonists liraglutide and exenatide long-acting release reduce haemoglobin A1c by about 1.0-2.0% and have fewer gastrointestinal side-effects. The orally available dipeptidyl peptidase-4 inhibitors, that is sitagliptin and vildagliptin reduce haemoglobin A1c by 0...

  1. Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes:A Clinical Update of Safety and Efficacy

    Drab, Scott R.

    2016-01-01

    Abstract: Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer. Methods A MEDLINE search (2010-2015) ident...

  2. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future

    Sanjay Kalra; Baruah, Manash P.; Rakesh K Sahay; Ambika Gopalakrishnan Unnikrishnan; Shweta Uppal; Omolara Adetunji

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)–based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selec...

  3. The role of glucagon-like peptide 1 in glucose homeostasis and in other aspects of human physiology.

    Franek, Edward; Gajos, Grzegorz; Gumprecht, Janusz; Kretowski, Adam; Zahorska-Markiewicz, Barbara; Małecki, Maciej T

    2009-11-01

    This paper reviews the structure, function, and pathophysiology of glucagon-like peptide 1 (GLP-1). It describes the physiology and pathophysiology of the incretin axis, of which GLP-1 is a component, as well as the biosynthesis, secretion, activity, and degradation of this intestinal hormone. Effects of GLP-1 on the endocrine function of the pancreas, cardiovascular system, central nervous system, and on water-electrolyte balance have been also presented.

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

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

    2012-01-01

    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...... in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia....

  5. Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest

    Wiberg, Sebastian; Hassager, Christian; Schmidt, Henrik

    2016-01-01

    BACKGROUND: -In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mell...... not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791....

  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;

    2008-01-01

    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...... 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...... intolerance in patients with self-reported food hypersensitivity. Other mechanisms related to bacterial fermentation may be involved and should be investigated further....

  7. 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 islet...... cell hyperplasia and increased insulin secretion. Conventionally, the effect of gastrointestinal hormones on insulin secretion (the incretin effect) has been defined and quantified in relation to oral versus intravenous glucose loadings. Under these unphysiological conditions, the release of 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, however...

  8. Long-term management of type 2 diabetes with glucagon-like peptide-1 receptor agonists

    Courtney, Hamish; Nayar, Rahul; Rajeswaran, Chinnadorai; Jandhyala, Ravi

    2017-01-01

    Continuously reducing excess blood glucose is a primary goal for the management of type 2 diabetes (T2D). Most patients with T2D require glucose-lowering medications to achieve and maintain adequate glycemic control; however, treatment failure may occur, limiting treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an emerging therapeutic class that can be prescribed for patients instead of basal insulin after the failure of oral therapies. Recent studies have focused on the durability and tolerability of long-term GLP-1RA therapy. This review summarizes the key efficacy and safety findings from prospective phase 3 clinical studies of at least 76 weeks’ duration for the GLP-1RAs currently approved in the United States and the European Union (albiglutide, dulaglutide, exenatide twice daily [BID], exenatide once weekly [QW], liraglutide, and lixisenatide). Currently, most of the long-term data are from uncontrolled extension studies, and continuous patient benefit has been observed for up to 3 years with multiple GLP-1RAs. Four-year comparative data demonstrated a longer time to treatment failure for exenatide BID than for sulfonylurea, and 3-year comparative extension data demonstrated greater glycated hemoglobin (HbA1c) reductions and weight loss with exenatide QW than with insulin glargine. Currently, the longest extension study for a GLP-1RA is the DURATION-1 study of exenatide QW, with >7 years of clinical data available. Data from DURATION-1 demonstrated that continuous HbA1c reductions and weight loss were observed for the patients continuing on the treatment, with no unexpected adverse events. Taken together, these data support GLP-1RAs as a long-term noninsulin treatment option after the failure of oral therapies.

  9. Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats.

    DellaValle, Brian; Brix, Gitte S; Brock, Birgitte; Gejl, Michael; Landau, Anne M; Møller, Arne; Rungby, Jørgen; Larsen, Agnete

    2016-01-01

    Introduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1) family, is also anti-diabetic and weight-reducing and is, moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE). Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 μg/kg s.c.) or saline. Healthy controls were included (saline, n = 6, liraglutide, n = 7). Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11) or if exceeding humane endpoint (clinical score ≥4). Protein levels of manganese superoxide dismutase (MnSOD), amyloid precursor protein (APP), and glial fibrillary acidic protein (GFAP) were determined. Results: Liraglutide treatment delayed disease onset (group clinical score significantly >0) by 2 days and markedly reduced disease severity (median clinical score 2 vs. 5; p = 0.0003). Fourteen of 15 (93%) of vehicle-treated rats reached the humane endpoint (clinical score ≥4) by day 11 compared to 5 of 15 (33%) of liraglutide-treated rats (p = 0.0004). Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p drug treatment (p = 0.09). Conclusion: We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor agonists should be investigated further as a potential therapy for MS.

  10. Glucagon-like peptide-2 and mouse intestinal adaptation to a high-fat diet.

    Baldassano, Sara; Amato, Antonella; Cappello, Francesco; Rappa, Francesca; Mulè, Flavia

    2013-04-01

    Endogenous glucagon-like peptide-2 (GLP2) is a key mediator of refeeding-induced and resection-induced intestinal adaptive growth. This study investigated the potential role of GLP2 in mediating the mucosal responses to a chronic high-fat diet (HFD). In this view, the murine small intestine adaptive response to a HFD was analyzed and a possible involvement of endogenous GLP2 was verified using GLP2 (3-33) as GLP2 receptor (GLP2R) antagonist. In comparison with animals fed a standard diet, mice fed a HFD for 14 weeks exhibited an increase in crypt-villus mean height (duodenum, 27.5±3.0%; jejunum, 36.5±2.9%; P<0.01), in the cell number per villus (duodenum, 28.4±2.2%; jejunum, 32.0±2.9%; P<0.01), and in Ki67-positive cell number per crypt. No change in the percent of caspase-3-positive cell in the villus-crypt was observed. The chronic exposure to a HFD also caused a significant increase in GLP2 plasma levels and in GLP2R intestinal expression. Daily administration of GLP2 (3-33) (30-60  ng) for 4 weeks did not modify the crypt-villus height in control mice. In HFD-fed mice, chronic treatment with GLP2 (3-33) reduced the increase in crypt-villus height and in the cell number per villus through reduction of cell proliferation and increase in apoptosis. This study provides the first experimental evidence for a role of endogenous GLP2 in the intestinal adaptation to HFD in obese mice and for a dysregulation of the GLP2/GLP2R system after a prolonged HFD.

  11. Dietary lipids and sweeteners regulate glucagon-like peptide-2 secretion.

    Sato, Shingo; Hokari, Ryota; Kurihara, Chie; Sato, Hirokazu; Narimatsu, Kazuyuki; Hozumi, Hideaki; Ueda, Toshihide; Higashiyama, Masaaki; Okada, Yoshikiyo; Watanabe, Chikako; Komoto, Shunsuke; Tomita, Kengo; Kawaguchi, Atsushi; Nagao, Shigeaki; Miura, Soichiro

    2013-04-15

    Glucagon-like peptide-2 (GLP-2) is a potent intestinal growth factor derived from enteroendocrine L cells. Although food intake is known to increase GLP-2 secretion, its regulatory mechanisms are largely unknown as a result of its very short half-life in venules. The aims of this study were to compare the effects of luminal nutrients on the stimulation of GLP-2 secretion in vivo using lymph samples and to clarify the involvement of the sweet taste receptor in this process in vitro. Lymph samples were collected from the thoracic duct after bolus administration of dietary lipids or sweetening agents into the duodenum of rats. Human enteroendocrine NCI-H716 cells were also used to compare the effects of various nutrients on GLP-2 secretion. GLP-2 concentrations were measured by ELISA in vivo and in vitro. GLP-2 secretion was enhanced by polyunsaturated fatty acid- and monounsaturated fatty acid-rich dietary oils, dietary carbohydrates, and some kinds of sweeteners in rats; this effect was reproduced in NCI-H716 cells using α-linolenic acid (αLA), glucose, and sweeteners. GLP-2 secretion induced by sweetening agents was inhibited by lactisole, a sweetness-antagonizing inhibitor of T1R3. In contrast, lactisole was unable to inhibit GLP-2 secretion induced by αLA alone. Our results suggested that fatty acid- and sweetener-induced GLP-2 secretion may be mediated by two different pathways, with the sweet taste receptor involved in the regulation of the latter.

  12. 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.

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

    Liu, Xiaowen; Murali, Sangita G; Holst, Jens J; Ney, Denise M

    2009-11-01

    Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral 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 gain of body weight, and improved feed efficiency compared with PN+GLP-2 alone. EN induced greater ileal proglucagon expression, increased plasma concentration of bioactive GLP-2 by 35%, and reduced plasma dipeptidyl peptidase IV (DPP-IV) activity compared with PN+GLP-2 alone, P 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 whey protein to induce greater mucosal surface area was associated with decreased DPP-IV activity in ileum and colon compared with casein, soy, or PN+GLP-2 alone, P whey protein potentiates the action of GLP-2 to reverse PN-induced mucosal hypoplasia in association with decreased intestinal DPP-IV activity.

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

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

    2016-06-01

    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 of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists. Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50mM) and rebaudioside A (12.5mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release. Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155μM) further enhanced casein and safflower oil induced-serotonin release. Exposure of ileal tissue segments to serotonin (30μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process.

  15. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials

    Vilsbøll, Tina; Christensen, Mikkel; Junker, Anders E;

    2012-01-01

    To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.......To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus....

  16. Steviol glycoside rebaudioside A induces glucagon-like peptide-1 and peptide YY release in a porcine ex vivo intestinal model

    Ripken, D.; Wielen, van der N.; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F.; Hendriks, H.F.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are hormones important for satiation and are involved in the process called "ileal brake". The aim of this study was to investigate the GLP-1- and PYY-stimulating efficacy of rebaudioside A, casein, and sucrose. This was studied using tissue segme

  17. Steviol Glycoside Rebaudioside A Induces Glucagon-like Peptide-1 and Peptide YY Release in a Porcine ex Vivo Intestinal Model

    Ripken, D.; Wielen, N. van der; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F.; Hendriks, H.F.J.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are hormones important for satiation and are involved in the process called “ileal brake”. The aim of this study was to investigate the GLP-1- and PYY-stimulating efficacy of rebaudioside A, casein, and sucrose. This was studied using tissue segme

  18. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery

    Svane, M S; Jørgensen, N B; Bojsen-Møller, K N;

    2016-01-01

    BACKGROUND/OBJECTIVES: Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery...

  19. Apelin stimulates both cholecystokinin and glucagon-like peptide 1 secretions in vitro and in vivo in rodents.

    Wattez, Jean-Sébastien; Ravallec, Rozenn; Cudennec, Benoit; Knauf, Claude; Dhulster, Pascal; Valet, Philippe; Breton, Christophe; Vieau, Didier; Lesage, Jean

    2013-10-01

    Apelin is an enteric peptide that exerts several digestive functions such as stimulation of cell proliferation and cholecystokinin (CCK) secretion. We investigated using murine enteroendocrine cell line (STC-1) and rats if apelin-13 stimulates both CCK and glucagon-like peptide 1 (GLP-1) secretions. We demonstrated that, in vitro and in vivo, apelin-13 increases the release of these two hormones in a dose-dependent manner. Present data suggest that apelin may modulate digestive functions, food intake behavior and glucose homoeostasis via apelin-induced release of enteric CCK but also through a new incretin-releasing activity on enteric GLP-1.

  20. 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

    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......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...

  1. 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

    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......, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential...

  2. Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis

    Sharma Pawana

    2010-12-01

    Full Text Available Abstract Background Glucagon-like peptide (GLP-1 analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs. Methods MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events. Results Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily. Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists

  3. Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats

    DellaValle, Brian; Brix, Gitte S.; Brock, Birgitte; Gejl, Michael; Landau, Anne M.; Møller, Arne; Rungby, Jørgen; Larsen, Agnete

    2016-01-01

    Introduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1) family, is also anti-diabetic and weight-reducing and is, moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE). Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 μg/kg s.c.) or saline. Healthy controls were included (saline, n = 6, liraglutide, n = 7). Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11) or if exceeding humane endpoint (clinical score ≥4). Protein levels of manganese superoxide dismutase (MnSOD), amyloid precursor protein (APP), and glial fibrillary acidic protein (GFAP) were determined. Results: Liraglutide treatment delayed disease onset (group clinical score significantly >0) by 2 days and markedly reduced disease severity (median clinical score 2 vs. 5; p = 0.0003). Fourteen of 15 (93%) of vehicle-treated rats reached the humane endpoint (clinical score ≥4) by day 11 compared to 5 of 15 (33%) of liraglutide-treated rats (p = 0.0004). Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p < 0.01) and reduced the neurodegenerative marker APP (p = 0.036) in the brain. GFAP levels were not significantly changed with drug treatment (p = 0.09). Conclusion: We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1

  4. [Protective effects of glucagon-like peptide-1 on beta-cells: preclinical and clinical data].

    Consoli, Agostino; Di Biagio, Rosamaria

    2011-12-01

    Dipartimento di Medicina Interna e Scienze dell'Invecchiamento, Università degli Studi "G. d'Annunzio", Chieti Continuing b-cell mass and function loss represents the key mechanism for the pathogenesis and the progression of type 2 diabetes mellitus. Drugs capable of arresting b-cell loss and eventually able to bring b-cell function close to be back to normal would then be a formidable help in type 2 diabetes mellitus treatment. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide can stimulate in vitro neogenesis and prevent apoptosis in b-cell-like cell lines. Consistently, treatment with GLP-1 receptor agonists ameliorates glucose metabolism, preserves b-cell mass and improves b-cell function in several animal models of diabetes. For instance, in the db/db mice, liraglutide protects the b-cell from oxidative stress and endoplasmic reticulum stress-related damage. Data in humans, in vivo, are less definitive and often based on scarcely reliable indexes of b-cell function. However, short-term treatment (14 weeks) with liraglutide increased b-cell maximal response capacity in a dose-response fashion. A longer (1 year) exenatide treatment also was able to increase b-cell maximal response capacity, but the effect was no longer there after a 4-week washout period. However, a marginal, although significant as compared to glargine treatment, improvement in another b-cell function index (disposition index) was observed after a 4-week washout period following 3-year exenatide treatment. Finally, although no clinical trials with a long enough follow-up period are presently available, durable glucose control has been obtained during 2 years of liraglutide treatment in monotherapy. Since the durability of good control is strictly dependent upon a lack of further b-cell function deterioration, these clinical data may foster hope that GLP-1 receptor antagonist treatment might help preserving b-cell function also in individuals affected by type 2

  5. 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

    Glucagon-like peptide 2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential in the treatment of intestinal deficiencies. It has recently been approved for the treatment of short bowel syndrome. The effects of GLP-2 are mediated by specific binding of the hormone to the GLP......-2 receptor (GLP-2R) which was cloned in 1999. However, consensus about the exact receptor localization in the intestine has never been established. By physical, chemical and enzymatic tissue fragmentation, we were able to divide rat jejunum into different compartments consisting of: (1) epithelium...... compartments rich in enteric neurons and, importantly they exclude significant expression in the epithelium of rat jejunal mucosa....

  6. Increased Postprandial Response of Glucagon-Like Peptide-2 in Patients with Chronic Pancreatitis and Pancreatic Exocrine Insufficiency

    Hornum, Mads; Pedersen, Jan F; Larsen, Steen;

    2010-01-01

    Background/Aims: Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects...... to delivery of a larger nutrient load to the distal part of the small intestine, where GLP-2 secreting L-cells are abundant - and that this hypersecretion of GLP-2 is associated with a higher SMA flow. and IAP.......Background/Aims: Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects...... min, p = 0.027). No difference was observed with regard to GIP. GLP-2, but not GIP, responses correlated significantly with postprandial SMA flow. Conclusion: These results suggest that delayed assimilation of nutrients in patients with CP and PEI increases the secretion of GLP-2 - possibly due...

  7. 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.

  8. 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.

  9. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes

    Zander, M; Taskiran, M; Toft-Nielsen, M B;

    2001-01-01

    OBJECTIVE: The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted...... this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally......) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite. RESULTS: Fasting plasma glucose (day 2...

  10. 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

  11. 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;

    2012-01-01

    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...... of endogenous GLP-2 to the intestinal epithelia also might mediate growth and promote neoplasia. We investigated the intestinal growth effect of the GLP-1 receptor agonists (GLP-1 RAs) (liraglutide and exenatide) and DPP-4 inhibition (sitagliptin) in healthy mice. We also investigated the potential tumour...

  12. 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

    Glucagon-like peptide-2 (GLP-2) is a potent trophic gut hormone, yet its function in ruminants is relatively unknown. Experiment 1 was conducted as a pilot study to establish the presence of GLP-2 in ruminants and to ascertain whether it was responsive to increased nutrition, as in non-ruminants.......Glucagon-like peptide-2 (GLP-2) is a potent trophic gut hormone, yet its function in ruminants is relatively unknown. Experiment 1 was conducted as a pilot study to establish the presence of GLP-2 in ruminants and to ascertain whether it was responsive to increased nutrition, as in non...

  13. 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

    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......-1 infusion. Glucose disappearance rate (Rd) did not change significantly, but glucose clearance increased significantly compared with saline. All parameters of glucose turnover remained constant during saline infusion. We conclude that GLP-1 may potently control hepatic glucose production...... and glucose clearance through its effects on the pancreatic glucoregulatory hormones. The effect of GLP-1 on glucose production is consistent with its proposed use in the treatment of type II diabetes....

  14. 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

    The present experiments were performed in order to elucidate the acute effects of intravenous infusion of glucagon-like peptide (GLP-1) on central and renal hemodynamics in healthy men. Seven healthy middle-aged men were examined on two different occasions in random order. During a 3-hour infusion......acute intravenous administration of GLP-1 leads to an increased cardiac output due to a simultaneous increase in stroke volume and heart rate, while no effect on renal hemodynamics could be demonstrated...... of either GLP-1 (1.5 pmol kg-1 min-1) or saline, cardiac output was estimated non-invasively, and intra-arterial blood pressure and heart rate were measured continuously. Renal plasma flow, glomerular filtration rate, and uptake/release of hormones and ions were measured by Fick's Principle after...

  15. 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...... apoptosis and decreases mucosal permeability. Lack of GLP-2 may increase the risk of malabsorption and intestinal bacterial translocation. The aim of this study is to evaluate meal stimulated secretion of GLP-2 in children with cancer undergoing anti-cancer treatment. METHODS: Plasma-GLP-2 analysis after...... an overnight fast and 1 hour after intake of a mixed test meal. Data on gastrointestinal toxicity, blood neutrophile counts and food records were included in the analysis. RESULTS: Forty-four meal stimulation tests were performed in 25 children (median age, 6.0 years; range, 2.5-19) during anti-cancer...

  16. Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity.

    Linnemann, Amelia K; Davis, Dawn Belt

    2016-04-01

    Precise control of blood glucose is dependent on adequate β-cell mass and function. Thus, reductions in β-cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon-like peptide-1 regulates β-cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β-cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

  17. 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 saline (n......Exogenous glucagon-like peptide 2 (GLP-2) prevents intestinal atrophy and increases nutrient absorption in term newborn pigs receiving total parenteral nutrition (TPN). We tested the hypothesis that the immature intestine of fetuses and preterm neonates has a diminished nutrient absorption response...... 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...

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

    Thulesen, J; Hartmann, B; Kissow, Hannelouise;

    2001-01-01

    , and 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...... GLP-2 levels in the intestinal segments were unchanged. In resected rats with reduced intestinal capacity, adaptive small bowel growth was more pronounced following proximal resection than distal small bowel resection. Circulating GLP-2 levels increased threefold in proximally resected animals...

  19. Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat

    Bucinskaite, V; Tolessa, T; Pedersen, J

    2009-01-01

    The vagus nerve plays a role in mediating effects of the two glucagon-like peptides GLP-1 and GLP-2 on gastrointestinal growth, functions and eating behaviour. To obtain electrophysiological and molecular evidence for the contribution of afferent pathways in chemoreception from the gastrointestinal...... tract, afferent mass activity in the ventral gastric branch of the vagus nerve and gene expression of GLP-1 receptors and GLP-2 receptors in the nodose ganglion were examined in Sprague-Dawley rats. Intravenous administration of GLP-1 (30-1000 pmol kg(-1)), reaching high physiological plasma...... afferent nerves mediate sensory input from the gastrointestinal tract or pancreas; either directly or indirectly via the release of another mediator. GLP-2 receptors appear not be functionally expressed on vagal afferents....

  20. TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE.

    Johnson, James G; Langan, Jennifer N; Gilor, Chen

    2016-09-01

    An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

  1. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

  2. Identification of potent 11mer glucagon-like peptide-1 receptor agonist peptides with novel C-terminal amino acids: Homohomophenylalanine analogs.

    Haque, Tasir S; Lee, Ving G; Riexinger, Douglas; Lei, Ming; Malmstrom, Sarah; Xin, Li; Han, Songping; Mapelli, Claudio; Cooper, Christopher B; Zhang, Ge; Ewing, William R; Krupinski, John

    2010-05-01

    We report the identification of potent agonists of the Glucagon-Like Peptide-1 Receptor (GLP-1R). These compounds are short, 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of homohomophenylalanine (hhPhe) at the C-terminal position. Typically the functional activity of the more potent peptides in this class is in the low picomolar range in an in vitro cAMP assay, with one example demonstrating excellent in vivo activity in an ob/ob mouse model of diabetes.

  3. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively.

    Neary, Nicola M; Small, Caroline J; Druce, Maralyn R; Park, Adrian J; Ellis, Sandra M; Semjonous, Nina M; Dakin, Catherine L; Filipsson, Karin; Wang, Fang; Kent, Aysha S; Frost, Gary S; Ghatei, Mohammad A; Bloom, Stephen R

    2005-12-01

    Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

  4. No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis

    Knop, Filip K; Vilsbøll, Tina; Larsen, Steen;

    2003-01-01

    Glucagon-like peptide 1 (GLP-1) is a proglucagon derivative secreted primarily from the L-cells of the small intestinal mucosa in response to the ingestion of meals. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. It has previously been shown that intravenous or subcutaneous...

  5. No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis

    Knop, Filip K; Vilsbøll, Tina; Larsen, Steen;

    2003-01-01

    OBJECTIVE: Glucagon-like peptide 1 (GLP-1) is a proglucagon derivative secreted primarily from the L-cells of the small intestinal mucosa in response to the ingestion of meals. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. It has previously been shown that intravenous...

  6. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes

    Kumarathurai, Preman; Anholm, Christian; Nielsen, Olav W;

    2016-01-01

    BACKGROUND: Patients with type 2 diabetes (T2D) and coronary artery disease (CAD) have increased risk of cardiac dysfunction. The diabetic heart is characterized by increased fatty acid oxidation and reduced glucose uptake resulting in reduced cardiac efficiency. Glucagon-like peptide-1 (GLP-1) has...

  7. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans

    van Bloemendaal, L.; Veltman, D. J.; ten Kulve, J. S.; Groot, P. F. C.; Ruhe, H. G.; Barkhof, F.; Sloan, J. H.; Diamant, M.; Ijzerman, R. G.

    2015-01-01

    AimTo test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. MethodsAs part of a larger study, we determined the effects of GLP-1 receptor activation on brain respo

  8. 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...

  9. 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

    Luminal nutrients stimulate structural and functional regeneration in the intestine through mechanisms thought to involve insulin-like growth factor I (IGF-I) and glucagon-like peptide-2 (GLP-2). We investigated the relationship between IGF-I and GLP-2 responses and mucosal growth in rats fasted ...

  10. 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 ...

  11. Carboxypeptidase-B-like processing of the C-terminus of glucagon-like peptide-2 in pig and human small intestine

    Orskov, C; Buhl, T; Rabenhøj, L;

    1989-01-01

    no mutual cross-reactivity. By gel filtration of extracts of pig and human small intestine, the immunoreactivity eluting at the position of GLP-2 was identified by the radioimmunoassays for glucagon-like peptide-2 (PG 126-159) and for PG 151-158, whereas the assay for PG 151-160 was completely negative. We...

  12. 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;

    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 d...

  13. 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;

    2014-01-01

    Context: The affect of the kidneys in elimination and degradation of intact incretin hormones and their truncated metabolites is unclear. Objective: To evaluate elimination and degradation of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in patients with d...

  14. Glucagon-like peptide-2 intracellularly stimulates eNOS phosphorylation and specifically induces submucosal arteriole vasodilation via a sheer stress-independent, local neural mechanism

    Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive neuropeptide that exerts diverse actions in the gastrointestinal tract, including enhancing mucosal cell survival and proliferation, mucosal blood flow, luminal nutrient uptake, and suppressing gastric motility and secretion. We have shown th...

  15. 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...

  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; A. Buchman; 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. 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 he...

  18. Glucagon-Like Peptide 1 Prevents Reactive Oxygen Species-Induced Endothelial Cell Senescence Through the Activation of Protein Kinase A

    Oeseburg, Hisko; de Boer, Rudolf A.; Buikema, Hendrik; van der Harst, Pim; van Gilst, Wiek H.; Sillje, Herman H. W.

    2010-01-01

    Objective-Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells. Metho

  19. Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass

    Dirksen, Carsten; Bojsen-Møller, Kirstine N; Jørgensen, Nils Bruun;

    2013-01-01

    Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon-like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones...

  20. The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liraglutide, a glucagon-like peptide 1 receptor agonist, in mice.

    Nonogaki, Katsunori; Suzuki, Marina; Sanuki, Marin; Wakameda, Mamoru; Tamari, Tomohiro

    2011-07-29

    Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200μg/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100μg/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100μg/kg) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways.

  1. 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.

  2. Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post-Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs.

    McKnight, Leslie L; Eyre, Ryan; Gooding, Margaret A; Davenport, Gary M; Shoveller, Anna Kate

    2015-06-16

    There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 ± 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 ± 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure.

  3. REVIEW: Role of cyclic AMP signaling in the production and function of the incretin hormone glucagon-like peptide-1

    Yu, Zhiwen; Jin, Tianru

    2008-01-01

    Pancreatic cells express the proglucagon gene (gcg) and thereby produce the peptide hormone glucagon, which stimulates hepatic glucose production and thereby increases blood glucose levels. The same gcg gene is also expressed in the intestinal endocrine L cells and certain neural cells in the brain. In the gut, gcg expression leads to the production of glucagon-like peptide-1 (GLP-1). This incretin hormone stimulates insulin secretion when blood glucose level is high. In addition, GLP-1 stimulates pancreatic cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells. Today, a long-term effective GLP-1 receptor agonist has been developed as a drug in treating diabetes and potentially other metabolic disorders. Extensive investigations have shown that the expression of gcg and the production of GLP-1 can be activated by the elevation of the second messenger cyclic AMP (cAMP). Recent studies suggest that in addition to protein kinase A (PKA), exchange protein activated by cAMP (Epac), another effector of cAMP signaling, and the crosstalk between PKA and Wnt signaling pathway, are also involved in cAMP-stimulated gcg expression and GLP-1 production. Furthermore, functions of GLP-1 in pancreatic cells are mainly mediated by cAMP-PKA, cAMP-Epac and Wnt signaling pathways as well.

  4. Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats.

    Gülpinar, M A; Bozkurt, A; Coşkun, T; Ulusoy, N B; Yegen, B C

    2000-06-01

    In addition to its insulinotropic action, exogenously administered glucagon-like peptide (GLP-1) inhibits gastropancreatic motility and secretion via central pathways. The aims of the present study were to evaluate the effects of exogenous GLP-1-(7-36) amide on fecal output and to investigate the role of endogenous GLP-1 on stress-induced colonic activity. With the use of a stereotaxic instrument, adult male Sprague-Dawley rats weighing 200-250 g were fitted with stainless steel cerebroventricular guide cannulas under ketamine anesthesia. A group of rats were placed in Bollman-type cages to induce restraint stress. Fecal output monitored for 2 h was increased significantly by intracerebroventricular GLP-1 to 500, 1, 000, and 3,000 pmol/rat (P corticotropin-releasing factor receptor antagonist astressin (10 microg/rat icv). The significant increase in fecal pellet output induced by restraint stress was also decreased by both intracerebroventricular exendin (10 nmol/rat) and astressin (10 microg/rat; Pmotility via its own receptor and that GLP-1 is likely to be a candidate brain-gut peptide that acts as a physiological modulator of stress-induced colonic motility.

  5. 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...

  6. Differentiating effects of the glucagon-like peptide-1 analogue exendin-4 in a human neuronal cell model.

    Luciani, Paola; Deledda, Cristiana; Benvenuti, Susanna; Cellai, Ilaria; Squecco, Roberta; Monici, Monica; Cialdai, Francesca; Luciani, Giorgia; Danza, Giovanna; Di Stefano, Chiara; Francini, Fabio; Peri, Alessandro

    2010-11-01

    Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptide with neurotrophic properties, as assessed in animal cell models. Exendin-4, a GLP-1 analogue, has been recently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to morphologically, structurally, and functionally characterize the differentiating actions of exendin-4 using a human neuronal cell model (i.e., SH-SY5Y cells). We found that exendin-4 increased the number of neurites paralleled by dramatic changes in intracellular actin and tubulin distribution. Electrophysiological analyses showed an increase in cell membrane surface and in stretch-activated-channels sensitivity, an increased conductance of Na(+) channels and amplitude of Ca(++) currents (T- and L-type), typical of a more mature neuronal phenotype. To our knowledge, this is the first demonstration that exendin-4 promotes neuronal differentiation in human cells. Noteworthy, our data support the claimed favorable role of exendin-4 against diabetic neuropathy as well as against different neurodegenerative diseases.

  7. Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus.

    Holz, George G; Chepurny, Oleg G

    2003-11-01

    Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic beta-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing beta-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate beta-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.

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

    Knop, Filip K; Lund, Asger; Madsbad, Sten

    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 test: 3...... insulin and C-peptide responses were observed during meal test (peak concentrations: 300 and 3,278 pM) and glucagon test (peak concentrations: 250 and 2,483 pM). During the hyperglycaemic clamp with continuous intravenous infusion of GLP-1 the subject exhibited plasma insulin and C-peptide concentrations...

  9. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut

    Holst, J J; Orskov, C; Nielsen, O V;

    1987-01-01

    By hydrophobic gel permeation and high pressure liquid chromatography we isolated from pig intestinal mucosa a peptide which corresponds to proglucagon 78-107 as suggested by chromatography and determination of its N-terminal sequence. Natural and synthetic proglucagon 78-107 dose dependently...

  10. 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;

    2004-01-01

    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...... the effect of proglucagon products, glucagon (10 nM), GLP-1 and GLP-2 (0.1, 1, and 10 nM) on GLP-1 and SS secretion, as well as on glucagon-like peptide-2 (GLP-2), peptide YY (PYY) and GIP secretion, all possible product of L-cells or neighbour cells. Perfusate glucose concentration dose......-dependently stimulated GLP-1 secretion (p=0.011). Insulin had no effect. Glucagon weakly stimulated GIP secretion. GLP-1 stimulated SS secretion and motor activity, but inhibited GLP-2, GIP and PYY secretion and perfusion pressure. GLP-2 weakly stimulated SS secretion. We conclude (a) that GLP-1 secretion is influenced...

  11. Effects of glucagon-like peptide-1 and feeding on gastric volumes in diabetes mellitus with cardio-vagal dysfunction.

    Delgado-Aros, S; Vella, A; Camilleri, M; Low, P A; Burton, D D; Thomforde, G M; Stephens, D

    2003-08-01

    Glucagon-like peptide-1 (GLP-1) increases gastric volume in humans possibly through the vagus nerve. Gastric volume response to feeding is preserved after vagal denervation in animals. We evaluated gastric volume responses to GLP-1 and placebo in seven diabetic patients with vagal neuropathy in a crossover study. We also compared gastric volume response to feeding in diabetes with that in healthy controls. We measured gastric volume using SPECT imaging. Data are median (interquartile range). In diabetic patients, GLP-1 did not increase gastric volume during fasting [5 mL (-3; 30)] relative to placebo [4 mL (-14; 50) P = 0.5], or postprandially [Delta postprandial minus fasting volume 469 mL (383; 563) with GLP-1 and 452 mL (400; 493) with placebo P = 0.3]. Change in gastric volume over fasting in diabetic patients on placebo was comparable to that of healthy controls [452 mL (400; 493)], P = 0.5. In contrast to effects in health, GLP-1 did not increase gastric volume in diabetics with vagal neuropathy, suggesting GLP-1's effects on stomach volume are vagally mediated. Normal gastric volume response to feeding in diabetics with vagal neuropathy suggests that other mechanisms compensate for vagal denervation.

  12. Glucagon-like Peptide-1 Protects Pancreatic Beta-cells from Death by Increasing Autophagic Flux and Restoring Lysosomal Function.

    Zummo, Francesco P; Cullen, Kirsty S; Honkanen-Scott, Minna; Shaw, James Am; Lovat, Penny E; Arden, Catherine

    2017-02-23

    Studies in animal models of type 2 diabetes have shown that glucagon-like peptide-1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown.Here we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5mmol/l palmitate, 25mmol/l glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilisation (LMP) and release of Cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Co-treatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. siRNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4.Collectively, our data highlights lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy / lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signalling pathway as a potential focus.

  13. The influence of restricted feeding on glucagon-like peptide-1 (GLP-1)-containing cells in the chicken small intestine.

    Monir, M M; Hiramatsu, K; Yamasaki, A; Nishimura, K; Watanabe, T

    2014-04-01

    The influence of restricted feeding on the distribution of glucagon-like peptide-1 (GLP-1)-containing endocrine cells in the chicken small intestine was investigated using immunohistochemical and morphometrical techniques. This study demonstrated that the restricted feeding had an influence on the activity of GLP-1-immunoreactive cells in the chicken small intestine. There were differences in the localization and the frequency of occurrence of GLP-1-immunoreactive cells in the small intestine between control and restricted groups, especially 25% feed supply group provided with 25% of the intake during the adapting period. GLP-1-immunoreactive cells in the control chickens were mainly located in epithelium from crypts to the lower part of intestinal villi. Those in restricted groups, however, tended to be located from crypts to the middle part of intestinal villi. The frequency of occurrence of GLP-1-immunoreactive cells was lowest in the control group, medium in 50% feed supply group and highest in 25% feed supply group at each intestinal region examined in this study, that is, increased with the advancement of restricting the amount of feed supply. These data show that the quantity of food intake is one of signals that have an influence on the secretion of GLP-1 from L cells in the chicken small intestine.

  14. 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.

  15. Serum levels of glucagon-like peptide (GLP-1 and GLP-2 in patients with Hashimoto′s thyroiditis

    Yue Jin

    2015-01-01

    Full Text Available Background: The influence of Hashimoto′s thyroiditis (HT with subclinical hypothyroidism or euthyroid status on the alteration of glucagon-like peptide (GLP-1 and GLP-2 levels remains uncertain. Materials and Methods: Twenty-four untreated HT patients with subclinical hypothyroidism, 24 euthyroid HT patients, and 24 age- and gender-matched controls were enrolled in the study. The levels of GLP-1, GLP-2, glucose, glycated albumin, insulin, thyroid hormone, and thyroid autoantibodies were measured and evaluated. Results: The levels of GLP-1, blood glucose, and triglyceride were higher in HT patients with subclinical hypothyroidism than in controls (all P < 0.05, respectively. However, the above variables, including GLP-2, were similar in euthyroid patients and controls. Neither GLP-1 nor GLP-2 was correlated with thyroid hormone, thyroid autoantibodies or metabolic parameters. Conclusion: The serum levels of GLP-1, not GLP-2, were increased in patients with subclinical hypothyroidism. Our data suggest that subclinical hypothyroidism affects circulating GLP-1 levels.

  16. 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.

  17. Spergularia marina induces glucagon-like peptide-1 secretion in NCI-H716 cells through bile acid receptor activation.

    Kim, Kyong; Lee, Yu Mi; Rhyu, Mee-Ra; Kim, Hye Young

    2014-11-01

    Spergularia marina Griseb. (SM) is a halophyte that grows in mud flats. The aerial portions of SM have been eaten as vegetables and traditionally used to prevent chronic diseases in Korea. However, there has been no scientific report that demonstrates the pharmacological effects of SM. Glucagon-like peptide-1 (GLP-1) is important for the maintenance of glucose and energy homeostasis through acting as a signal in peripheral and neural systems. To discover a functional food for regulating glucose and energy homeostasis, we evaluated the effect of an aqueous ethanolic extract (AEE) of SM on GLP-1 release from enteroendocrine NCI-H716 cells. In addition, we explored the Takeda G-protein-coupled receptor 5 (TGR5) agonist activity of AEE-SM in Chinese hamster ovary (CHO)-K1 cells transiently transfected with human TGR5. As a result, treatment of NCI-H716 cells with AEE-SM increased GLP-1 secretion and intracellular Ca(2+) and cyclic AMP (cAMP) levels in a dose-dependent manner. Transfection of NCI-H716 cells with TGR5-specific small interference RNA inhibited AEE-SM-induced GLP-1 secretion and the increase in Ca(2+) and cAMP levels. Moreover, AEE-SM showed that the TGR5 agonist activity in CHO-K1 cells transiently transfected with TGR5. The results suggest that AEE-SM might be a candidate for a functional food to regulate glucose and energy homeostasis.

  18. Diuretic and Natriuretic Effects of Dipeptidyl Peptidase-4 Inhibitor Teneligliptin: The Contribution of Glucagon-like Peptide-1.

    Moroi, Masao; Kubota, Tetsuya

    2015-08-01

    Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents; however, their mechanisms of action are different. GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they regulate Na reabsorption. We investigated whether the DPP-4 inhibitor, teneligliptin, has diuretic and natriuretic effects and whether these are associated with the stimulation of the GLP-1R in rats. Oral administration of teneligliptin resulted in a reduction of plasma DPP-4 activity over 6 hours, as well as an induction of diuresis and natriuresis. Although teneligliptin did not change the increase in blood glucose levels by glucose loading, percentage of urine volume and Na/K ratio with teneligliptin to vehicle were augmented by glucose loading. Peak levels of plasma GLP-1 did not change after oral administration of teneligliptin when glucose was not loaded but increased at least 2-fold with glucose loading. Furthermore, the natriuretic effect of teneligliptin was inhibited by the GLP-1R antagonist, exendin9-39, whereas the diuresis was not affected. These results suggest that the mechanism of natriuresis was different from that of diuresis, and the natriuresis is associated with the stimulation of GLP-1R. There may be mechanistic differences in DPP-4 inhibition between diuresis and natriuresis.

  19. 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.

  20. Cholecystokinin-Induced Gallbladder Emptying and Single-Dose Metformin Elicit Additive Glucagon-Like Peptide-1 Responses

    Rohde, Ulrich; Sonne, David Peick; Christensen, Mikkel;

    2016-01-01

    CONTEXT: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion via activation of the bile acid receptor TGR5 on enteroendocrine L cells. Metformin too has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin or a combination has however...... never been studied. OBJECTIVE: We hypothesized that cholecystokinin-8 (CCK)-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. DESIGN: A double-blinded, randomized study. SETTING: The study was conducted at a specialized research unit....... 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...

  1. Glucagon-like peptide-2 but not imipramine exhibits antidepressant-like effects in ACTH-treated mice.

    Iwai, Takashi; Ohnuki, Tomoko; Sasaki-Hamada, Sachie; Saitoh, Akiyoshi; Sugiyama, Azusa; Oka, Jun-Ichiro

    2013-04-15

    We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) against refractory depression in adrenocorticotropic hormone (ACTH)-treated mice as a model of tricyclic antidepressant (TCA)-resistant depression. Chronic ACTH treatment (0.45 mg/kg, s.c., 14 days) weakened the antidepressant-like effects of imipramine (20 mg/kg, i.p., 6 days) in the forced-swim test (FST). Conversely, GLP-2 (3 μg/mice, i.c.v., 6 days) induced antidepressant-like effects in the ACTH-treated mice in the FST. ACTH-treatment increased basal serum corticosterone levels, with an additional increase induced by the FST. Imipramine or GLP-2 had no effect on the basal corticosterone level, but GLP-2 attenuated the additional increase caused by the FST. Moreover, GLP-2 increased 5-HT levels, but not 5-HIAA. These results suggest that GLP-2 induced antidepressant-like effects under imipramine-resistant conditions through increase in 5-HT levels.

  2. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.

    Knauf, Claude; Cani, Patrice D; Perrin, Christophe; Iglesias, Miguel A; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J; Kahn, C Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M; Postic, Catherine; Burcelin, Rémy

    2005-12-01

    Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

  3. 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.

  4. Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation.

    Shiraishi, Daisuke; Fujiwara, Yukio; Komohara, Yoshihiro; Mizuta, Hiroshi; Takeya, Motohiro

    2012-08-24

    It is known that glucagon-like peptide-1 (GLP-1) is a hormone secreted postprandially from the L-cells of the small intestine and regulates glucose homeostasis. GLP-1 is now used for the treatment of diabetes because of its beneficial role against insulin resistance. The GLP-1 receptor (GLP-1R) is expressed on many cell types, including macrophages, and GLP-1 suppresses the development of atherosclerosis by inhibiting macrophage function. However, there have so far been few studies that have investigated the significance of GLP-1/GLP-1R signaling in macrophage activation. In the present study, we examined the effect of GLP-1 and exenatide, a GLP-1R agonist, on human monocyte-derived macrophage (HMDM) activation. We found that GLP-1 induced signal transducer and activator of transcription 3 (STAT3) activation. Silencing of GLP-1R suppressed the GLP-1-induced STAT3 activation. In addition, alternatively activated (M2) macrophage-related molecules, such as IL-10, CD163, and CD204 in HMDM, were significantly upregulated by GLP-1. Furthermore, the co-culture of 3T3-L1 adipocytes with GLP-1-treated RAW 264.7 macrophages increased the secretion of adiponectin compared to co-culture of the 3T3-L1 adipocytes with untreated RAW 264.7 macrophages. Our results demonstrate that GLP-1 induces macrophage polarization toward the M2 phenotype, which may contribute to the protective effects of GLP-1 against diabetes and cardiovascular diseases.

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

    Sørensen, Gunnar; Reddy, India A; Weikop, Pia; Graham, Devon L; Stanwood, Gregg D; Wortwein, Gitta; Galli, Aurelio; Fink-Jensen, Anders

    2015-10-01

    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 reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.

  6. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia.

    Teramoto, Shinichiro; Miyamoto, Nobukazu; Yatomi, Kenji; Tanaka, Yasutaka; Oishi, Hidenori; Arai, Hajime; Hattori, Nobutaka; Urabe, Takao

    2011-08-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion. The GLP-1 receptor agonist, exendin-4, has similar properties to GLP-1 and is currently in clinical use for type 2 diabetes mellitus. As GLP-1 and exendin-4 confer cardioprotection after myocardial infarction, this study was designed to assess the neuroprotective effects of exendin-4 against cerebral ischemia-reperfusion injury. Mice received a transvenous injection of exendin-4, after a 60-minute focal cerebral ischemia. Exendin-4-treated vehicle and sham groups were evaluated for infarct volume, neurologic deficit score, various physiologic parameters, and immunohistochemical analyses at several time points after ischemia. Exendin-4 treatment significantly reduced infarct volume and improved functional deficit. It also significantly suppressed oxidative stress, inflammatory response, and cell death after reperfusion. Furthermore, intracellular cyclic AMP (cAMP) levels were slightly higher in the exendin-4 group than in the vehicle group. No serial changes were noted in insulin and glucose levels in both groups. This study suggested that exendin-4 provides neuroprotection against ischemic injury and that this action is probably mediated through increased intracellular cAMP levels. Exendin-4 is potentially useful in the treatment of acute ischemic stroke.

  7. Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation.

    Chen, S; An, F-M; Yin, L; Liu, A-R; Yin, D-K; Yao, W-B; Gao, X-D

    2014-01-03

    We have previously demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonist ameliorated neurodegenerative changes in rat models of diabetes-related Alzheimer's disease (AD), and protected neurons from glucose toxicity in vitro. Herein, we investigated the effects of GLP-1 receptor mediates on cell toxicity and tau hyperphosphorylation induced by advanced glycation end products (AGEs), which are associated with glucose toxicity, and the molecular mechanism in PC12 cells and the primary hippocampal neurons. Our study demonstrated that the similar protection effects of GLP-1 existed in PC12 cells treated with glucose-bovine serum albumin (BSA) in hyperglycemic conditions or with glycoaldehyde-BSA alone. Additionally, glucose-BSA alone did not induce significant cytotoxicity in PC12 cells, but resulted in tau hyperphosphorylation in primary hippocampal neurons in 24h. And we found that GLP-1 could reduce cell tau phosphorylation induced by high glucose or glucose-BSA. Furthermore, our data in the present study suggested that GLP-1 regulated tau phosphorylation induced by AGEs through a signaling pathway involving glycogen synthase kinase 3β (GSK-3β), similarly to the GSK-3β inhibitor, lithium chloride. Our findings suggest that GLP-1 can protect neurons from diabetes-associated AGE insults in vitro, and provide new evidence for a potential therapeutic value of GLP-1 receptor agonist in the treatment of AD especially diabetes-related AD.

  8. 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.

  9. 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.

  10. A critical appraisal of antihyperglycemic and cardioprotective activities of liraglutide: A glucagon-like peptide-1 analog

    Sayed Aliul Hasan Abdi

    2014-04-01

    Full Text Available Diabetes is leading cause for cardiovascular complication, drugs having cardioprotective and antihyperglycemic actions are constantly in search. Oral glucose elicits a three to four times higher peak insulin response compared with an equivalent dose of glucose, if infused intravenously. This is due to the reasons behind, the oral glucose causes a secretion of gut hormones, mainly the glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP which enhance the glucose-induced insulin release. In patients with type 2 diabetes mellitus (type 2 DM, glucose-induced insulin release is unsatisfactory or absent. Because of this type 2 DM patients are unable to adjust their insulin secretion as per the need exist. GLP-1 secretion (but not GIP secretion is diminished in patients with type 2 diabetes. However, when the GLP-1 and GIP agonist are administered in patients with type 2 diabetes, they elicit insulin secretion resulting in lowering of blood glucose level. In addition to its insulin stimulatory effect, GLP-1 agonist also induces cardioprotective effects. It increases nuclear respiratory factor-2 (Nrf2 and heamoxigenase-1(Ho-1 in cell which have antioxidant and cardioprotective property. GLP-1 maintains islets integrity and reduces apoptotic cell death of human islet cells in culture. Improved understanding of the mechanism of action and clinical effects of incretin-based therapies would be useful in advancement of its appropriate use in clinical practices.

  11. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future

    Sanjay Kalra

    2016-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1–based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD statement on pancreatic safety.

  12. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future.

    Kalra, Sanjay; Baruah, Manash P; Sahay, Rakesh K; Unnikrishnan, Ambika Gopalakrishnan; Uppal, Shweta; Adetunji, Omolara

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD) statement on pancreatic safety.

  13. 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 short bowel syndrome.

  14. Potential roles of glucagon-like peptide-1-based therapies in treating non-alcoholic fatty liver disease.

    Liu, Ye; Wei, Rui; Hong, Tian-Pei

    2014-07-21

    Glucagon-like peptide-1 (GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease (NAFLD). Recent studies showed that glucose-induced GLP-1 secretion was decreased in patients with NAFLD and that the level of dipeptidyl peptidase-4, which inactivates intact GLP-1, was upregulated. Moreover, the expression of the GLP-1 receptor was downregulated in livers from patients with NAFLD, indicating an association of defective GLP-1 signalling with NAFLD. Notably, GLP-1-based therapies are reported to be effective in improving hepatic endpoints in patients with NAFLD, such as reducing hepatic fat content, hepatic steatosis and plasma transaminase levels, and preventing fibrosis. GLP-1-based therapies are beneficial for body weight control and glycaemic normalisation, which are important for the management of NAFLD. Moreover, clinical and preclinical studies showed that GLP-1-based agents might directly exert their actions on the liver through activation of functional GLP-1 receptors in hepatocytes. The possible mechanisms involve regulating gene expression that is associated with insulin resistance and lipid metabolism, and suppressing oxidative stress in the liver cells, thus preventing the development and progression of NAFLD. Based on these promising data, large-scale randomised controlled trials are warranted to assess the efficacy and safety of GLP-1-based therapies in treating NAFLD.

  15. Preliminary Examination of Glucagon-Like Peptide-1 Levels in Women with Purging Disorder and Bulimia Nervosa

    Dossat, Amanda M.; Bodell, Lindsay P.; Williams, Diana L.; Eckel, Lisa A.; Keel, Pamela K.

    2014-01-01

    Objective This study examined pre- and post-prandial glucagon-like peptide 1 (GLP-1) levels in women with bulimia nervosa (BN), purging disorder (PD), and non-eating disorder control women to better understand whether alterations in satiation-related hormones in BN may be linked to binge-eating episodes or other altered ingestive behaviors. Method Participants included women with BN (n = 19), PD (n = 14), or controls (n = 14). Participants provided subjective ratings for hunger and fullness and plasma samples before and after consumption of a standardized test meal. Results As expected, GLP-1 levels increased significantly following test meal consumption; however, participants with BN displayed significantly lower GLP-1 levels compared to PD and control participants both before and after consumption of the test meal. There were no significant differences between PD and control participants in GLP-1 levels, but individuals with PD displayed significantly higher levels of fullness throughout the test meal as compared to both control and BN participants. Discussion Our findings provide preliminary evidence that reduced GLP-1 levels in individuals with BN may be associated with binge-eating episodes. Additionally, increased fullness in individuals with PD does not appear to be accounted for by exaggerated post-prandial GLP-1 release. PMID:24590464

  16. 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.

  17. 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

  18. 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.

  19. A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities.

    He, Min; Guan, Ni; Gao, Wei-wei; Liu, Qing; Wu, Xiao-yan; Ma, Da-wei; Zhong, Da-fang; Ge, Guang-bo; Li, Chuan; Chen, Xiao-yan; Yang, Ling; Liao, Jia-yu; Wang, Ming-wei

    2012-02-01

    Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4-24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

  20. A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities

    Min HE; Xiao-yan CHEN; Ling YANG; Jia-yu LIAO; Ming-wei WANG; Ni GUAN; Wei-wei GAO; Qing LIU; Xiao-yan WU; Da-wei MA; Da-fang ZHONG; Guang-bo GE; Chuan LI

    2012-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes.However,there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development.This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R).Here,we briefly review the discovery,characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R,including Boc5 and its newly discovered analogue WB4-24.Although the oral bioavailability of such compounds still poses great challenges,the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

  1. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1.

    Holst, Jens Juul

    2002-01-01

    GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake, that is, inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety and promotes tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it is an essential incretin hormone. In addition, the hormone has been demonstrated to promote insulin biosynthesis and insulin gene expression and to have trophic effects on the beta cells. The trophic effects include proliferation of existing beta cells, maturation of new cells from duct progenitor cells and inhibition of apoptosis. Furthermore, glucagon secretion is inhibited. Because of these effects, the hormone effectively improves metabolism in patients with type 2 diabetes mellitus. Thus, continuous subcutaneous administration of the peptide for six weeks in patients with rather advanced disease greatly improved glucose profiles and lowered body weight, haemoglobin A(1C), and free fatty acids (FFA). In addition, insulin sensitivity doubled and insulin responses to glucose were greatly improved. There were no side effects. Continuous administration is necessary because of rapid degradation by the enzyme dipeptidyl peptidase-IV. Alternative approaches include the use of analogues that are resistant to the actions of the enzyme, as well as inhibitors of the enzyme. Both approaches have shown remarkable efficacy in both experimental and clinical studies. The GLP-1-based therapy of type 2 diabetes, therefore, represents a new and attractive alternative.

  2. Metabolism of glucagon-like peptide-2 in pigs: role of dipeptidyl peptidase IV

    Hansen, Lene; Hare, Kristine J; Hartmann, Bolette;

    2006-01-01

    -33). During infusion of GLP-2 alone, 30.9+/-1.7% of the infused peptide was degraded to GLP-2 (3-33). After valine-pyrrolidide, there was no significant formation of the metabolite. Significant extraction of intact GLP-2 was observed across the kidneys, the extremities (represented by a leg......), and the splanchnic bed, resulting in a metabolic clearance rate (MCR) of 6.80+/-0.47 ml/kg/min and a plasma half-life of 6.8+/-0.8 min. Hepatic extraction was not detected. Valine-pyrrolidide addition did not affect extraction ratios significantly, but decreased (p=0.003) MCR to 4.18+/-0.27 ml/kg/min and increased...

  3. 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.

  4. Prediction of the effect on antihyperglycaemic action of sitagliptin by plasma active form glucagon-like peptide-1

    Akifumi; Kushiyama; Takako; Kikuchi; Kentaro; Tanaka; Tazu; Tahara; Toshiko; Takao; Yukiko; Onishi; Yoko; Yoshida; Shoji; Kawazu; Yasuhiko; Iwamoto

    2016-01-01

    AIM: To investigate whether active glucagon-like peptide-1(GLP-1) is a prediction Factor of Effect of sitagliptin on patients with type 2 diabetes mellitus(GLP-1 FEST:UMIN000010645). METHODS: Seventy-six patients with type 2 diabetes, who had insufficient glycemic control [Hemoglobin A1c(Hb A1c) ≥ 7%] in spite of treatment with metformin and/or sulfonylurea, were included in the investigation. Patients were divided into three groups by tertiles of fasting plasma active GLP-1 level, before the administration of 50 mg sitagliptin. RESULTS: At baseline, body mass index, serum UA, insulin and HOMA-IR were higher in the high active GLP-1 group than in the other two groups. The high active GLP-1 group did not show any decline of Hb A1c(7.6% ± 1.4% to 7.5% ± 1.5%), whereas the middle and low groups indicated significant decline of Hb A1c(7.4 ± 0.7 to 6.8 ± 0.6 and 7.4 ± 1.2 to 6.9 ± 1.3, respectively) during six months. Only the low and middle groups showed a significant increment of active GLP-1, C-peptide level, a decreased log and proinsulin/insulin ratio after administration. In logistic analysis, the low or middle group is a significantexplanatory variable for an Hb A1 c decrease of ≥ 0.5%, and its odds ratio is 4.5(1.40-17.6)(P = 0.01) against the high active GLP-1 group. This remains independent when adjusted for Hb A1 c level before administration, patients’ medical history, medications, insulin secretion and insulin resistance.CONCLUSION: Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin.

  5. 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.

  6. The effect of Glucagon-Like Peptide-2 on mesenteric blood flow and cardiac parameters in end-jejunostomy short bowel patients

    Bremholm, Lasse; Hornum, Mads; Andersen, Ulrik B;

    2011-01-01

    Exogenous Glucagon-Like Peptide-2 (GLP-2) treatment improves intestinal wet weight absorption in short bowel syndrome (SBS) patients. In healthy subjects, administration of GLP-2 increases small intestinal blood flow. The aim of the study was to evaluate the effect of GLP-2 on mesenteric blood flow...... and dynamic changes in cardiac parameters in SBS patients with jejunostomy and varying length of remnant small intestine....

  7. 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...... augments adaptive growth and digestive capacity of the residual small intestine in a rat model of mid-small bowel resection by increasing plasma GLP-2 concentrations and GLP-2 receptor expression without diminishing endogenous proglucagon expression....

  8. The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

    2011-01-01

    The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason...

  9. Solid phase synthesis of fatty acid modified glucagon-like peptide-1(7-36) amide under thermal and controlled microwave irradiation

    2010-01-01

    Fatty acid modified glucagon-like peptide-1(7-36) amide was synthesized efficiently on Rink-Amide-MBHA resin by microwave-assisted solid phase method.The method of thermal and controlled microwave irradiation provided impressive enhancements in product yield,selectivity,and reaction rate.The coupling time was dramatically decreased to 6 min,and the desired products were obtained in high yield and purity.

  10. 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

    BACKGROUND/AIMS: Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hy...... of glibenclamide is not accentuated by the coadministration of vildagliptin. This may be explained by a negative feedback regulation of GLP-1 and GIP secretion that limits the degree to which the active incretin levels are enhanced....

  11. Role of cholinergic neurons in the motor effects of glucagon-like peptide-2 in mouse colon.

    Amato, Antonella; Rotondo, Alessandra; Cinci, Lorenzo; Baldassano, Sara; Vannucchi, Maria Giuliana; Mulè, Flavia

    2010-11-01

    Glucagon-like peptide-2 (GLP-2) reduces mouse gastric tone and small intestine transit, but its action on large intestine motility is still unknown. The purposes of the present study were 1) to examine the influence of GLP-2 on spontaneous mechanical activity and on neurally evoked responses, by recording intraluminal pressure from mouse isolated colonic segments; 2) to characterize GLP-2 mechanism of action; and 3) to determine the distribution of GLP-2 receptor (GLP-2R) in the mouse colonic muscle coat by immunohistochemistry. Exogenous GLP-2 (0.1-300 nM) induced a concentration-dependent reduction of the spontaneous mechanical activity, which was abolished by the desensitization of GLP-2 receptor or by tetrodotoxin, a voltage-dependent Na(+)-channel blocker. GLP-2 inhibitory effect was not affected by N(ω)-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor), apamin (a blocker of small conductance Ca(2+)-dependent K(+) channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP(7-28) (a VIP receptor antagonist), but it was prevented by atropine or pertussis toxin (PTX), a G(i/o) protein inhibitor. Proximal colon responses to electrical field stimulation were characterized by nitrergic relaxation, which was followed by cholinergic contraction. GLP-2 reduced only the cholinergic evoked contractions. This effect was almost abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed to affect the contractile responses to exogenous carbachol. GLP-2R immunoreactivity (IR) was detected only in the neuronal cells of both plexuses of the colonic muscle coat. More than 50% of myenteric GLP-2R-IR neurons shared the choline acetyltransferase IR. In conclusion, the activation of GLP-2R located on cholinergic neurons may modulate negatively the colonic spontaneous and electrically evoked contractions through inhibition of acetylcholine release. The effect is mediated by G(i) protein.

  12. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice.

    Valdecantos, M Pilar; Pardo, Virginia; Ruiz, Laura; Castro-Sánchez, Luis; Lanzón, Borja; Fernández-Millán, Elisa; García-Monzón, Carmelo; Arroba, Ana I; González-Rodríguez, Águeda; Escrivá, Fernando; Álvarez, Carmen; Rupérez, Francisco J; Barbas, Coral; Konkar, Anish; Naylor, Jacqui; Hornigold, David; Santos, Ana Dos; Bednarek, Maria; Grimsby, Joseph; Rondinone, Cristina M; Valverde, Ángela M

    2017-03-01

    Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49.

  13. 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.

  14. Resistant maltodextrin promotes fasting glucagon-like peptide-1 secretion and production together with glucose tolerance in rats.

    Hira, Tohru; Ikee, Asuka; Kishimoto, Yuka; Kanahori, Sumiko; Hara, Hiroshi

    2015-07-14

    Glucagon-like peptide-1 (GLP-1), which is produced and released from enteroendocrine L cells, plays pivotal roles in postprandial glycaemia. The ingestion of resistant maltodextrin (RMD), a water-soluble non-digestible saccharide, improves the glycaemic response. In the present study, we examined whether the continuous feeding of RMD to rats affected GLP-1 levels and glycaemic control. Male Sprague-Dawley rats (6 weeks of age) were fed an American Institute of Nutrition (AIN)-93G-based diet containing either cellulose (5 %) as a control, RMD (2.5 or 5 %), or fructo-oligosaccharides (FOS, 2.5 or 5 %) for 7 weeks. During the test period, an intraperitoneal glucose tolerance test (IPGTT) was performed after 6 weeks. Fasting GLP-1 levels were significantly higher in the 5 % RMD group than in the control group after 6 weeks. The IPGTT results showed that the glycaemic response was lower in the 5 % RMD group than in the control group. Lower caecal pH, higher caecal tissue and content weights were observed in the RMD and FOS groups. Proglucagon mRNA levels were increased in the caecum and colon of both RMD and FOS groups, whereas caecal GLP-1 content was increased in the 5 % RMD group. In addition, a 1 h RMD exposure induced GLP-1 secretion in an enteroendocrine L-cell model, and single oral administration of RMD increased plasma GLP-1 levels in conscious rats. The present study demonstrates that continuous ingestion of RMD increased GLP-1 secretion and production in normal rats, which could be stimulated by its direct and indirect (enhanced gut fermentation) effects on GLP-1-producing cells, and contribute to improving glucose tolerance.

  15. Indirect effects of glucagon-like peptide-1 receptor agonist exendin-4 on the peripheral circadian clocks in mice.

    Ando, Hitoshi; Ushijima, Kentarou; Fujimura, Akio

    2013-01-01

    Circadian clocks in peripheral tissues are powerfully entrained by feeding. The mechanisms underlying this food entrainment remain unclear, although various humoral and neural factors have been reported to affect peripheral clocks. Because glucagon-like peptide-1 (GLP-1), which is rapidly secreted in response to food ingestion, influences multiple humoral and neural signaling pathways, we suggest that GLP-1 plays a role in the food entrainment of peripheral clocks. To test this, we compared the effects of exendin-4, a GLP-1 receptor agonist, on mRNA expression of the clock genes (Clock, Bmal1, Nr1d1, Per1, Per2, and Cry1) with those of refeeding. In addition, we investigated whether exendin-4 could affect the rhythms of the peripheral clocks. In male C57BL/6J mice, although refeeding rapidly (within 2 h) altered mRNA levels of Per1 and Per2 in the liver and that of Per1 in adipose tissue, a single i.p. injection of exendin-4 did not cause such changes. However, unlike the GLP-1 receptor antagonist exendin-(9-39), exendin-4 significantly influenced Per1 mRNA levels in the liver at 12 h after injection. Moreover, pretreatment with exendin-4 affected the rapid-feeding-induced change in Per1 not only in the liver, but also in adipose tissue, without effect on food intake. Furthermore, during light-phase restricted feeding, repeated dosing of exendin-4 at the beginning of the dark phase profoundly influenced both the food intake and daily rhythms of clock gene expression in peripheral tissues. Thus, these results suggest that exendin-4 modulates peripheral clocks via multiple mechanisms different from those of refeeding.

  16. 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.

  17. Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: yes.

    Scheen, André J

    2012-03-01

    The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especially regarding easiness of use, tolerance profile and cost. However, because they can only increase endogenous GLP-1 concentrations to physiological (rather than pharmacological) levels, they are less potent to improve glucose control, promote weight reduction ("weight neutrality") and reduce blood pressure compared to GLP-1 receptor agonists. Of note, none of the two classes have proven long-term safety and positive impact on diabetic complications yet. The role of DPP-4 inhibitors and GLP-1 receptor agonists in the therapeutic armamentarium of T2DM is rapidly evolving, but their respective potential strengths and weaknesses should be better defined in long-term head-to-head comparative controlled trials. Instead of trying to answer the question whether DPP-4 inhibitors are favourable to GLP-1 receptor agonists (or vice versa), it is probably more clinically relevant to look at which T2DM patient will benefit more from one or the other therapy considering all his/her individual clinical characteristics ("personalized medicine").

  18. Distinct effects of dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 receptor agonist on islet morphology and function.

    Morita, Asuka; Mukai, Eri; Hiratsuka, Ayano; Takatani, Tomozumi; Iwanaga, Toshihiko; Lee, Eun Young; Miki, Takashi

    2016-03-01

    Although the two anti-diabetic drugs, dipeptidyl peptidase-4 inhibitors (DPP4is) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1RAs), have distinct effects on the dynamics of circulating incretins, little is known of the difference in their consequences on morphology and function of pancreatic islets. We examined these in a mouse model of β cell injury/regeneration. The model mice were generated so as to express diphtheria toxin (DT) receptor and a fluorescent protein (Tomato) specifically in β cells. The mice were treated with a DPP4i (MK-0626) and a GLP1RA (liraglutide), singly or doubly, and the morphology and function of the islets were compared. Prior administration of MK-0626 and/or liraglutide similarly protected β cells from DT-induced cell death, indicating that enhanced GLP-1 signaling can account for the cytoprotection. However, 2-week intervention of MK-0626 and/or liraglutide in DT-injected mice resulted in different islet morphology and function: β cell proliferation and glucose-stimulated insulin secretion (GSIS) were increased by MK-0626 but not by liraglutide; α cell mass was decreased by liraglutide but not by MK-0626. Although liraglutide administration nullified MK-0626-induced β cell proliferation, their co-administration resulted in increased GSIS, decreased α cell mass, and improved glucose tolerance. The pro-proliferative effect of MK-0626 was lost by co-administration of the GLP-1 receptor antagonist exendin-(9-39), indicating that GLP-1 signaling is required for this effect. Comparison of the effects of DPP4is and/or GLP1RAs treatment in a single mouse model shows that the two anti-diabetic drugs have distinct consequences on islet morphology and function.

  19. Indirect effects of glucagon-like peptide-1 receptor agonist exendin-4 on the peripheral circadian clocks in mice.

    Hitoshi Ando

    Full Text Available Circadian clocks in peripheral tissues are powerfully entrained by feeding. The mechanisms underlying this food entrainment remain unclear, although various humoral and neural factors have been reported to affect peripheral clocks. Because glucagon-like peptide-1 (GLP-1, which is rapidly secreted in response to food ingestion, influences multiple humoral and neural signaling pathways, we suggest that GLP-1 plays a role in the food entrainment of peripheral clocks. To test this, we compared the effects of exendin-4, a GLP-1 receptor agonist, on mRNA expression of the clock genes (Clock, Bmal1, Nr1d1, Per1, Per2, and Cry1 with those of refeeding. In addition, we investigated whether exendin-4 could affect the rhythms of the peripheral clocks. In male C57BL/6J mice, although refeeding rapidly (within 2 h altered mRNA levels of Per1 and Per2 in the liver and that of Per1 in adipose tissue, a single i.p. injection of exendin-4 did not cause such changes. However, unlike the GLP-1 receptor antagonist exendin-(9-39, exendin-4 significantly influenced Per1 mRNA levels in the liver at 12 h after injection. Moreover, pretreatment with exendin-4 affected the rapid-feeding-induced change in Per1 not only in the liver, but also in adipose tissue, without effect on food intake. Furthermore, during light-phase restricted feeding, repeated dosing of exendin-4 at the beginning of the dark phase profoundly influenced both the food intake and daily rhythms of clock gene expression in peripheral tissues. Thus, these results suggest that exendin-4 modulates peripheral clocks via multiple mechanisms different from those of refeeding.

  20. Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway.

    Thompson, Aiysha; Kanamarlapudi, Venkateswarlu

    2015-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Gαs and Gαq coupled pathways to stimulate insulin secretion. The agonist-induced GLP-1R internalisation has recently been shown to be important for insulin secretion. However, the molecular mechanisms underlying GLP-1R internalisation remain unknown. The aim of this study was to determine the role of GLP-1R downstream signalling pathways in its internalisation. Agonist-induced human GLP-1R (hGLP-1R) internalisation and activity were examined using a number of techniques including immunoblotting, ELISA, immunofluorescence and luciferase assays to determine cAMP production, intracellular Ca(2+) accumulation and ERK phosphorylation. Agonist-induced hGLP-1R internalisation is dependent on caveolin-1 and dynamin. Inhibition of the Gαq pathway but not the Gαs pathway affected hGLP-1R internalisation. Consistent with this, hGLP-1R mutant T149M and small-molecule agonists (compound 2 and compound B), which activate only the Gαs pathway, failed to induce internalisation of the receptor. Chemical inhibitors of the Gαq pathway, PKC and ERK phosphorylation significantly reduced agonist-induced hGLP-1R internalisation. These inhibitors also suppressed agonist-induced ERK1/2 phosphorylation demonstrating that the phosphorylated ERK acts downstream of the Gαq pathway in the hGLP-1R internalisation. In summary, agonist-induced hGLP-1R internalisation is mediated by the Gαq pathway. The internalised hGLP-1R stimulates insulin secretion from pancreatic β-cells, indicating the importance of GLP-1 internalisation for insulin secretion.

  1. Chronic liraglutide therapy induces an enhanced endogenous glucagon-like peptide-1 secretory response in early type 2 diabetes.

    Kramer, Caroline K; Zinman, Bernard; Choi, Haysook; Connelly, Philip W; Retnakaran, Ravi

    2017-02-09

    Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUCGIP between the groups. By contrast, although fasting GLP-1 was unaffected, the liraglutide arm had ~2-fold higher AUCGLP-1 at 12 weeks ( P  < .001), 24 weeks ( P  < .001), 36 weeks ( P  = .03) and 48 weeks ( P  = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP-1 response, highlighting the need for further study of the long-term effects of incretin mimetics on L-cell physiology.

  2. Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes:A Clinical Update of Safety and Efficacy

    Drab, Scott R.

    2016-01-01

    Abstract: Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer. Methods A MEDLINE search (2010-2015) identified publications that discussed longer-acting GLP-1 RAs. Search terms included GLP-1 receptor agonists, liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide, albiglutide, efficacy, safety, pancreatitis, pancreatic cancer, and thyroid cancer. Abstracts from the American Diabetes Association, European Association for the Study of Diabetes, and American Association of Clinical Endocrinologists from 2010 to 2015 were also searched. Efficacy and safety studies, pooled analyses, and meta-analyses were prioritized. Results Research has confirmed that GLP-1 RAs provide robust glycemic control, weight loss, and blood pressure re-duction. Current studies do not prove increased risk of pancreatitis, pancreatic cancer, or thyroid cancer but more trials are needed since publications that indicate safety or suggest increased risk have methodological flaws that prevent firm conclusions to be drawn about these rare, long-term events. Conclusion GLP-1 RA therapy in the context of individualized, patient-centered care continues to be supported by current literature. GLP-1 RA therapy provides robust glycemic control, blood pressure reduction, and weight loss, but studies are still needed to address concerns about tolerability and safety, including pancreatitis and cancer. PMID:26694823

  3. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats.

    Darsalia, Vladimer; Mansouri, Shiva; Ortsäter, Henrik; Olverling, Anna; Nozadze, Nino; Kappe, Camilla; Iverfeldt, Kerstin; Tracy, Linda M; Grankvist, Nina; Sjöholm, Åke; Patrone, Cesare

    2012-05-01

    Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.

  4. The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes.

    Ali, Eunüs S; Hua, Jin; Wilson, Claire H; Tallis, George A; Zhou, Fiona H; Rychkov, Grigori Y; Barritt, Greg J

    2016-09-01

    The release of Ca(2+) from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca(2+) by Ca(2+) entry through store-operated Ca(2+) channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca(2+) release and Ca(2+) entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood. The aim of this study was to determine whether exendin-4 alters intracellular Ca(2+) homeostasis in steatotic hepatocytes, and to evaluate the mechanisms involved. Exendin-4 completely reversed lipid-induced inhibition of SOCE in steatotic liver cells, but did not reverse lipid-induced inhibition of ER Ca(2+) release. The action of exendin-4 on Ca(2+) entry was rapid in onset and was mimicked by GLP-1 or dibutyryl cyclic AMP. In steatotic liver cells, exendin-4 caused a rapid decrease in lipid (half time 6.5min), inhibited the accumulation of lipid in liver cells incubated in the presence of palmitate plus the SOCE inhibitor BTP-2, and enhanced the formation of cyclic AMP. Hormone-stimulated accumulation of extracellular glucose in glycogen replete steatotic liver cells was inhibited compared to that in non-steatotic cells, and this effect of lipid was reversed by exendin-4. It is concluded that, in steatotic hepatocytes, exendin-4 reverses the lipid-induced inhibition of SOCE leading to restoration of hormone-regulated cytoplasmic Ca(2+) signalling. The mechanism may involve GLP-1 receptors, cyclic AMP, lipolysis, decreased diacylglycerol and decreased activity of protein kinase C.

  5. 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

  6. 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...... but not by staurosporine. These results indicate that glucose does not directly stimulate canine L-cells. It is more probable that glucose releases GIP from the upper intestine that in turn stimulates GLP-1 secretion. The ability of GIP to stimulate GLP-1 secretion is probably mediated through activation of protein kinase...... dependently stimulated the release of GLP-1 and resulted in a 2-fold increase at 100 nM GIP. This effect was fully inhibited by 10 nM somatostatin. However, neither basal or GIP stimulated GLP-1 secretion were affected by ambient glucose concentrations from 5-25 mM. The receptor-independent secretagogues beta...

  7. 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

    INTRODUCTION: Intestinal lipase inhibition using tetrahydrolipstatin (Orlistat) has been widely used in the pharmacotherapy of morbid obesity. However, the effects of Orlistat on the secretion of appetite regulating gastrointestinal hormones and appetite sensations are still debated. We addressed...... 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...... 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

  8. Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

    Torekov, S S; Ma, L; Grarup, N;

    2011-01-01

    The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.......The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits....

  9. 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.)

  10. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

    Kingsbury Ann E

    2008-05-01

    Full Text Available Abstract Background It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD. This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R agonist exendin-4 (EX-4, which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. Methods Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA and lipopolysaccaride (LPS, were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. Results EX-4 (0.1 and 0.5 μg/kg was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. Conclusion The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models

  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...... 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. 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

  13. Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice.

    Selwyn, Felcy Pavithra; Csanaky, Iván L; Zhang, Youcai; Klaassen, Curtis D

    2015-10-01

    It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein-coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2- to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non-12α-OH BAs, namely, β-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid-binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter α, and organic solute transporter β) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non-12α-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.

  14. Glucagon-like peptide-1 analogue, liraglutide, delays onset and reduces severity of experimental autoimmune encephalitis in Lewis rats

    Brian DellaValle

    2016-11-01

    Full Text Available AbstractIntroduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS pathology and influence the susceptibility to treatment, directing attention towards anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1 family, is also anti-diabetic and weight-reducing and is moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE.Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 µg/kg s.c. or saline. Healthy controls were included (saline, n=6, liraglutide, n=7. Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11 or if exceeding humane endpoint (clinical score ≥4. Protein levels of manganese superoxide dismutase (MnSOD, amyloid precursor protein (APP, and glial fibrillary acidic protein (GFAP were determined.Results: Liraglutide treatment delayed disease onset (group clinical score significantly >0 by two days and markedly reduced disease severity (median clinical score 2 vs. 5; p=0.0003. Fourteen of 15 (93% of vehicle-treated rats reached the humane endpoint (clinical score ≥4 by day 11 compared to 5 of 15 (33% of liraglutide-treated rats (p=0.0004. Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p<0.01 and reduced the neurodegenerative marker APP (p=0.036 in the brain. GFAP levels were not significantly changed with drug treatment (p=0.09Conclusion: We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor

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

    Taing, Meng-Wong; Rose, Felicity J; Whitehead, Jonathan P

    2014-01-01

    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(28-36) amide, 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 effects of GLP-1 receptor analogs may be mediated by the nonapeptide. However, the concentrations required to elicit some of these effects are in the micromolar range, leading to reservations about potentially related therapeutic benefits. Moreover, although controversial, concerns have been raised about the potential for incretin

  16. 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

  17. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level.

    Ishibashi, Yuji; Nishino, Yuri; Matsui, Takanori; Takeuchi, Masayoshi; Yamagishi, Sho-ichi

    2011-09-01

    Advanced glycation end products (AGE) and receptor for AGE (RAGE) interaction elicits reactive oxygen species (ROS) generation and inflammatory reactions, thereby being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, found that glucagon-like peptide-1 (GLP-1), one of the incretins and a gut hormone secreted from L cells in the intestine in response to food intake, could have anti-inflammatory and antithrombogenic properties in cultured endothelial cells. However, the effects of GLP-1 on renal mesangial cells are largely unknown. Therefore, to elucidate the role of GLP-1 in diabetic nephropathy, this study investigated whether and how GLP-1 blocked AGE-induced monocyte chemoattractant protein-1 expression in human cultured mesangial cells. Gene and protein expression was analyzed by quantitative real-time reverse transcription polymerase chain reactions, Western blots, and enzyme-linked immunosorbent assay. The ROS generation was measured with dihydroethidium staining. Glucagon-like peptide-1 receptor (GLP-1R) was expressed in mesangial cells. Glucagon-like peptide-1 inhibited RAGE gene expression in mesangial cells, which was blocked by small interfering RNAs raised against GLP-1R. Furthermore, GLP-1 decreased ROS generation and subsequently reduced monocyte chemoattractant protein-1 gene and protein expression in AGE-exposed mesangial cells. An analogue of cyclic adenosine monophosphate mimicked the effects of GLP-1 on mesangial cells. Our present study suggests that GLP-1 may directly act on mesangial cells via GLP-1R and that it could work as an anti-inflammatory agent against AGE by reducing RAGE expression via activation of cyclic adenosine monophosphate pathway.

  18. 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 to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy....

  19. Allosteric Modulation of the Activity of the Glucagon-like Peptide-1 (GLP-1) Metabolite GLP-1 9–36 Amide at the GLP-1 Receptor

    Naichang Li; Jing Lu; Willars, Gary B

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compo...

  20. 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.

  1. Expression and Distribution of Glucagon-Like Peptide-1 Receptor mRNA, Protein and Binding in the Male Nonhuman Primate (Macaca mulatta) Brain

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract, where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been...

  2. GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects.

    Lin, J; Hodge, R J; O'Connor-Semmes, R L; Nunez, D J

    2015-10-01

    We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides.

  3. The peptide agonist-binding site of the glucagon-like peptide-1 (GLP-1) receptor based on site-directed mutagenesis and knowledge-based modelling.

    Dods, Rachel L; Donnelly, Dan

    2015-11-23

    Glucagon-like peptide-1 (7-36)amide (GLP-1) plays a central role in regulating blood sugar levels and its receptor, GLP-1R, is a target for anti-diabetic agents such as the peptide agonist drugs exenatide and liraglutide. In order to understand the molecular nature of the peptide-receptor interaction, we used site-directed mutagenesis and pharmacological profiling to highlight nine sites as being important for peptide agonist binding and/or activation. Using a knowledge-based approach, we constructed a 3D model of agonist-bound GLP-1R, basing the conformation of the N-terminal region on that of the receptor-bound NMR structure of the related peptide pituitary adenylate cyclase-activating protein (PACAP21). The relative position of the extracellular to the transmembrane (TM) domain, as well as the molecular details of the agonist-binding site itself, were found to be different from the model that was published alongside the crystal structure of the TM domain of the glucagon receptor, but were nevertheless more compatible with published mutagenesis data. Furthermore, the NMR-determined structure of a high-potency cyclic conformationally-constrained 11-residue analogue of GLP-1 was also docked into the receptor-binding site. Despite having a different main chain conformation to that seen in the PACAP21 structure, four conserved residues (equivalent to His-7, Glu-9, Ser-14 and Asp-15 in GLP-1) could be structurally aligned and made similar interactions with the receptor as their equivalents in the GLP-1-docked model, suggesting the basis of a pharmacophore for GLP-1R peptide agonists. In this way, the model not only explains current mutagenesis and molecular pharmacological data but also provides a basis for further experimental design.

  4. Effects of treatment with glucagon-like peptide-2 on bone resorption in colectomized patients with distal ileostomy or jejunostomy and short-bowel syndrome

    Gottschalck, I.B.; Jeppesen, Palle Bekker; Hartmann, B.;

    2008-01-01

    OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome (...... and therefore precludes treatment of their osteopenia with GLP-2. The anti-resorptive response to GLP-2 seems to require an intact small intestine and may involve suppression of PTH secretion Udgivelsesdato: 2008......OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome...... (SBS) and they have reduced bone mineral density (BMD). The aim of the study was to investigate the anti-resorptive effect (assessed by s-CTX) of 14 days of GLP-2 treatment in these patients and to determine whether 56 days of treatment would improve BMD. PTH secretion in response to GLP-2 was also...

  5. Effects of treatment with glucagon-like peptide-2 on bone resorption in colectomized patients with distal ileostomy or jejunostomy and short-bowel syndrome

    Gottschalck, Ida B; Jeppesen, Palle B; Hartmann, Bolette;

    2008-01-01

    OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome (...... and therefore precludes treatment of their osteopenia with GLP-2. The anti-resorptive response to GLP-2 seems to require an intact small intestine and may involve suppression of PTH secretion.......OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome...... (SBS) and they have reduced bone mineral density (BMD). The aim of the study was to investigate the anti-resorptive effect (assessed by s-CTX) of 14 days of GLP-2 treatment in these patients and to determine whether 56 days of treatment would improve BMD. PTH secretion in response to GLP-2 was also...

  6. Immunohistochemical study on the ontogenetic development of the regional distribution of peptide YY, pancreatic polypeptide, and glucagon-like peptide 1 endocrine cells in bovine gastrointestinal tract.

    Pyarokhil, Asadullah Hamid; Ishihara, Miyuki; Sasaki, Motoki; Kitamura, Nobuo

    2012-04-10

    The regional distribution and relative frequency of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and glucagon-like peptide 1 (GLP-1)-immunoreactive (IR) cells were determined immunohistochemically in the gastrointestinal tract at seven ontogenetic stages in pre- and postnatal cattle. Different frequencies of PYY-, PP-, and GLP-1-IR cells were found in the intestines at all stages; they were not found in the esophagus and stomach. The frequencies varied depending on the intestinal segment and the developmental stage. The frequencies of PYY- and PP-IR cells were lower in the small intestine and increased from ileum to rectum, whereas GLP-1-IR cells were more numerous in duodenum and jejunum, decreased in ileum and cecum, and increased again in colon and rectum. The frequencies also varied according to pre- and postnatal stages. All three cell types were most numerous in fetus, and decreased in calf and adult groups, indicating that the frequencies of these three types of endocrine cells decrease with postnatal development. The results suggest that these changes vary depending on feeding habits and adaptation of growth, secretion, and motility of intestine at different ontogenetic stages of cattle.

  7. Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation.

    Koole, Cassandra; Wootten, Denise; Simms, John; Miller, Laurence J; Christopoulos, Arthur; Sexton, Patrick M

    2012-02-03

    The glucagon-like peptide-1 receptor (GLP-1R) is a therapeutically important family B G protein-coupled receptor (GPCR) that is pleiotropically coupled to multiple signaling effectors and, with actions including regulation of insulin biosynthesis and secretion, is one of the key targets in the management of type II diabetes mellitus. However, there is limited understanding of the role of the receptor core in orthosteric ligand binding and biological activity. To assess involvement of the extracellular loop (ECL) 2 in ligand-receptor interactions and receptor activation, we performed alanine scanning mutagenesis of loop residues and assessed the impact on receptor expression and GLP-1(1-36)-NH(2) or GLP-1(7-36)-NH(2) binding and activation of three physiologically relevant signaling pathways as follows: cAMP formation, intracellular Ca(2+) (Ca(2+)(i)) mobilization, and phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2). Although antagonist peptide binding was unaltered, almost all mutations affected GLP-1 peptide agonist binding and/or coupling efficacy, indicating an important role in receptor activation. However, mutation of several residues displayed distinct pathway responses with respect to wild type receptor, including Arg-299 and Tyr-305, where mutation significantly enhanced both GLP-1(1-36)-NH(2)- and GLP-1(7-36)-NH(2)-mediated signaling bias for pERK1/2. In addition, mutation of Cys-296, Trp-297, Asn-300, Asn-302, and Leu-307 significantly increased GLP-1(7-36)-NH(2)-mediated signaling bias toward pERK1/2. Of all mutants studied, only mutation of Trp-306 to alanine abolished all biological activity. These data suggest a critical role of ECL2 of the GLP-1R in the activation transition(s) of the receptor and the importance of this region in the determination of both GLP-1 peptide- and pathway-specific effects.

  8. No increased risk of hypoglycaemic episodes during 48 h of subcutaneous glucagon-like-peptide-1 administration in fasting healthy subjects

    Lerche, Susanne; Soendergaard, Liselotte; Rungby, Joergen

    2008-01-01

    OBJECTIVE: It is uncertain whether the ability to avoid hypoglycaemia during fasting is preserved, and the risk of reactive hypoglycaemia after an oral glucose stimulus following a prolonged fasting period is increased at augmented glucagon-like peptide-1 (GLP-1) levels. DESIGN: A randomized...... of insulin and C-peptide were higher with GLP-1 infusion. However, PG was similar during GLP-1 vs. placebo infusions. GLP-1 infusion increased norepinephrine and cortisol levels during OGTT. CONCLUSION: The counter-regulatory response during 48 h of subcutaneous GLP-1 infusion was preserved despite long......-term fasting with no apparent increased risk of hypoglycaemic episodes. No reactive hypoglycaemia was observed when the fast was followed by an OGTT. Thus use of long-acting GLP-1 analogues may not increase the risk of hypoglycaemia....

  9. Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers.

    Bremholm, Lasse; Andersen, Ulrik B; Hornum, Mads; Hilsted, Linda; Veedfald, Simon; Hartmann, Bolette; Holst, Jens Juul

    2017-02-01

    Glucagon-like peptide-1 (GLP-1, GLP-17-36amide) and its sister peptide glucagon-like peptide 2 (GLP-2) influence numerous intestinal functions and GLP-2 greatly increases intestinal blood flow. We hypothesized that GLP-1 also stimulates intestinal blood flow and that this would impact on the overall digestive and cardiovascular effects of the hormone. To investigate the influence of GLP-1 receptor agonism on mesenteric and renal blood flow and cardiovascular parameters, we carried out a double-blinded randomized clinical trial. A total of eight healthy volunteers received high physiological subcutaneous injections of GLP-1, GLP-19-36 amide (bioactive metabolite), exenatide (stable GLP-1 agonist), or saline on four separate days. Blood flow in mesenteric, celiac, and renal arteries was measured by Doppler ultrasound. Blood pressure, heart rate, cardiac output, and stroke volume were measured continuously using an integrated system. Plasma was analyzed for glucose, GLP-1 (intact and total), exenatide and Pancreatic polypeptide (PP), and serum for insulin and C-peptide. Neither GLP-1, GLP-19-36 amide, exenatide nor saline elicited any changes in blood flow parameters in the mesenteric or renal arteries. GLP-1 significantly increased heart rate (two-way ANOVA, injection [P = 0.0162], time [P = 0.0038], and injection × time [P = 0.082]; Tukey post hoc GLP-1 vs. saline and GLP-19-36amide [P < 0.011]), and tended to increase cardiac output and decrease stroke volume compared to GLP-19-36 amide and saline. Blood pressures were not affected. As expected, glucose levels fell and insulin secretion increased after infusion of both GLP-1 and exenatide.

  10. The noncaloric sweetener rebaudioside a stimulates glucagon-like peptide 1 release and increases enteroendocrine cell numbers in 2-dimensional mouse organoids derived from different locations of the intestine

    Wielen, van der Nikkie; Klooster, ten Jean Paul; Muckenschnabl, Susanne; Pieters, Raymond; Hendriks, Henk F.J.; Witkamp, Renger F.; Meijerink, Jocelijn

    2016-01-01

    Background: Glucagon-like peptide 1 (GLP-1) contributes to satiety and plays a pivotal role in insulin secretion and glucose homeostasis. Similar to GLP-1, peptide YY (PYY) and cholecystokinin also influence food intake. The secretion of these hormones by enteroendocrine cells along the intestine

  11. The Noncaloric Sweetener Rebaudioside A Stimulates Glucagon-Like Peptide 1 Release and Increases Enteroendocrine Cell Numbers in 2-Dimensional Mouse Organoids Derived from Different Locations of the Intestine

    van der Wielen, Nikkie; Ten Klooster, Jean Paul; Muckenschnabl, Susanne; Pieters, Raymond; Hendriks, Henk Fj; Witkamp, Renger F; Meijerink, Jocelijn

    2016-01-01

    BACKGROUND: Glucagon-like peptide 1 (GLP-1) contributes to satiety and plays a pivotal role in insulin secretion and glucose homeostasis. Similar to GLP-1, peptide YY (PYY) and cholecystokinin also influence food intake. The secretion of these hormones by enteroendocrine cells along the intestine is

  12. 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.

  13. Synthesis and Evaluation of a Series of Long-Acting Glucagon-Like Peptide-1 (GLP-1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes.

    Irwin, Nigel; Patterson, Steven; de Kort, Martin; Moffett, R Charlotte; Wisse, Jeffry A J; Dokter, Wim H A; Bos, Ebo S; Miltenburg, André M M; Flatt, Peter R

    2015-08-01

    The present study details the development of a family of novel D-Ala(8) glucagon-like peptide-1 (GLP-1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin-releasing activity. Peptides with short linkers (GLP-1 receptor (GLP-1-R) binding affinity. All D-Ala(8) GLP-1 conjugates exhibited prominent glucose-lowering action. Biological activity of the Lys(37) short-linker peptide was evident up to 72 h post-injection. In agreement, the pharmacokinetic profile of this conjugate (t1/2 , 11 h) was superior to that of the GLP-1-R agonist, exenatide. Once-daily injection of the Lys(37) short-linker peptide in ob/ob mice for 21 days significantly decreased food intake and improved HbA1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys(37) short-linker peptide were similar to or better than either exenatide or liraglutide, another GLP-1-R agonist. In conclusion, GLP-1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once-weekly treatment of type 2 diabetes in humans.

  14. 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.

  15. Steviol glycoside rebaudioside A induces glucagon-like peptide-1 and peptide YY release in a porcine ex vivo intestinal model.

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

    2014-08-20

    Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are hormones important for satiation and are involved in the process called "ileal brake". The aim of this study was to investigate the GLP-1- and PYY-stimulating efficacy of rebaudioside A, casein, and sucrose. This was studied using tissue segments collected from various regions of the pig small intestine. GLP-1 release was strongest from the distal ileum. There, control release was 0.06 ± 0.01 (GLP-1) and 0.07 ± 0.01 (PYY) pmol/cm(2) of tissue. Rebaudioside A (2.5, 12.5, and 25 mM) stimulated GLP-1 release (0.14 ± 0.02, 0.16 ± 0.02, and 0.13 ± 0.02 pmol/cm(2) of tissue, p < 0.001) and PYY release (0.19 ± 0.02, 0.42 ± 0.06, and 0.27 ± 0.03 pmol/cm(2) of tissue, p < 0.001). Sucrose stimulated GLP-1 release (0.08 ± 0.01 pmol/cm(2) of tissue, p < 0.05) only at 10 mM. Casein (0.5%, 1%, and 2.5%, w/v) stimulated GLP-1 release (0.15 ± 0.03, 0.13 ± 0.02, and 0.14 ± 0.01 pmol/cm(2) of tissue, p < 0.001) and PYY release (0.13 ± 0.02, 0.20 ± 0.03, and 0.27 ± 0.03 pmol/cm(2) of tissue, p < 0.01). These findings may help in developing dietary approaches for weight management.

  16. 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...... 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....... 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...

  17. 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....... The aim of study was to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy. SUBJECTS AND METHODS: The study group (GDM) consisted of 13...... 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...

  18. [Dulaglutide (Trulicity®), a new once-weekly agonist of glucagon-like peptide-1 receptors for type 2 diabetes].

    Scheen, A J

    2016-03-01

    Dulaglutide (Trulicity®) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors indicated in the treatment of type 2 diabetes. Phase III clinical trials in AWARD programme demonstrated the efficacy and safety of dulaglutide in patients with type 2 diabetes treated by diet and exercise, metformin, a combination of metformin and a sulfonylurea or metformin and pioglitazone or even by supplements of prandial insulin. In the AWARD programme, dulaglutide (subcutaneous 0.75 or 1.5 mg once weekly) exerted a greater glucose-lowering activity than metformin, sitagliptin, exenatide or insulin glargine, and was non-inferior to liraglutide 1.8 mg once daily. Dulaglutide is currently reimbursed in Belgium after failure of and in combination with a dual oral therapy with metformin and a sulfonylurea or metformin and pioglitazone.

  19. 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

    ). 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...... (GLP-1R) agonist, liraglutide, may modify their risk of developing T2D. METHODS AND ANALYSES: 100 women with previous GDM will be randomised to either liraglutide or placebo treatment for 1 year (blinded) with an open-label extension for another 4 years. Additionally, 15 women without previous GDM...... will constitute a baseline control group. Women will be tested with an oral glucose tolerance test (primary endpoint: area under the curve for plasma glucose) and an isoglycaemic intravenous glucose infusion at baseline, after 1 year and after 5 years. Additional evaluations include a glucagon test, dual-energy X...

  20. Near-normalization of glycaemic control with glucagon-like peptide-1 receptor agonist treatment combined with exercise in patients with type 2 diabetes

    Mensberg, Pernille; Nyby, Signe; Jørgensen, Peter Godsk;

    2016-01-01

    .002)). Greater reductions in fasting plasma glucose (-3.4 ± 2.3 vs -0.3 ± 2.6 mM, p quality of life during......AIMS: Exercise as well as glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment improves glycaemic control in patients with type 2 diabetes. We investigated the effects of exercise in combination with a GLP-1RA (liraglutide) or placebo for the treatment of type 2 diabetes. METHODS: Thirty......-three overweight, dysregulated and sedentary patients with type 2 diabetes were randomly allocated to 16 weeks of exercise and liraglutide or exercise and placebo. Both groups had three supervised 60-minute training sessions per week including spinning and resistance training. RESULTS: HbA1c levels dropped by 2...

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

    Ohara-Imaizumi, Mica; Aoyagi, Kyota [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Akimoto, Yoshihiro [Department of Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Nakamichi, Yoko; Nishiwaki, Chiyono [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Kawakami, Hayato [Department of Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Nagamatsu, Shinya, E-mail: shinya@ks.kyorin-u.ac.jp [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan)

    2009-12-04

    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 {beta} cells, the regulated biphasic exocytosis from two types of granules may be a common mechanism in glucose-evoked hormone release from endocrine cells.

  2. An adaptive, dose-finding, seamless phase 2/3 study of a long-acting glucagon-like peptide-1 analog (dulaglutide): trial design and baseline characteristics.

    Geiger, Mary Jane; Skrivanek, Zachary; Gaydos, Brenda; Chien, Jenny; Berry, Scott; Berry, Donald

    2012-11-01

    Dulaglutide (dula, LY2189265) is a once-weekly glucagon-like peptide-1 analog in development for the treatment of type 2 diabetes mellitus. An adaptive, dose-finding, inferentially seamless phase 2/3 study was designed to support the development of this novel diabetes therapeutic. The study is divided into two stages based on two randomization schemes: a Bayesian adaptive scheme (stage 1) and a fixed scheme (stage 2). Stage 1 of the trial employs an adaptive, dose-finding design to lead to a dula dose-selection decision or early study termination due to futility. If dose selection occurs, the study proceeds to stage 2 to allow continued evaluation of the selected dula doses. At completion, the entire study will serve as a confirmatory phase 3 trial. The final study design is discussed, along with specifics pertaining to the actual execution of this study and selected baseline characteristics of the participants.

  3. Near-normalization of glycaemic control with glucagon-like peptide-1 receptor agonist treatment combined with exercise in patients with type 2 diabetes

    Mensberg, Pernille; Nyby, Signe; Jørgensen, Peter Godsk

    2017-01-01

    AIMS: Exercise as well as glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment improves glycaemic control in patients with type 2 diabetes. We investigated the effects of exercise in combination with a GLP-1RA (liraglutide) or placebo for the treatment of type 2 diabetes. METHODS: Thirty......-three overweight, dysregulated and sedentary patients with type 2 diabetes were randomly allocated to 16 weeks of exercise and liraglutide or exercise and placebo. Both groups had three supervised 60-minute training sessions per week including spinning and resistance training. RESULTS: HbA1c levels dropped by 2...... the intervention. CONCLUSIONS: In obese patients with type 2 diabetes, exercise combined with GLP-1RA treatment near-normalised HbA1c levels and caused a robust weight loss when compared to placebo. These results suggest that a combination of exercise and GLP-1RA treatment is effective in type 2 diabetes....

  4. 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;

    2016-01-01

    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...... 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....... 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...

  5. 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;

    2011-01-01

    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...... 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...... with exenatide BID and liraglutide. In humans, no signal has been found indicating an association between the once-weekly agonists and C-cell cancer. The cardiovascular safety, durability of glucose control and effect on weight will emerge from several ongoing major long-term trials. The once-weekly GLP-1...

  6. 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...... normalized with disease remission. The change in the lactulose⁄mannitol ratio was due to both reduced lactulose and increased mannitol absorption. CONCLUSIONS: These findings suggest that pediatric patients with acute ileal CD have decreased postprandial GLP-2 release, reduced glucose absorption...

  7. Exendin-4, a glucagon-like peptide 1 receptor agonist, protects against amyloid-β peptide-induced impairment of spatial learning and memory in rats.

    Jia, Xiao-Tao; Ye-Tian; Yuan-Li; Zhang, Ge-Juan; Liu, Zhi-Qin; Di, Zheng-Li; Ying, Xiao-Ping; Fang, Yan; Song, Er-Fei; Qi, Jin-Shun; Pan, Yan-Fang

    2016-05-15

    Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Aβ) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Aβ1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Aβ1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Aβ1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Aβ1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD.

  8. 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

  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;

    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 en...

  10. [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma.

    Wicki, A.; Wild, D.; Storch, D.; Seemayer, C.; Gotthardt, M.; Behe, M.; Kneifel, S.; Mihatsch, M.J.; Reubi, J.C.; Macke, H.R.; Christofori, G.

    2007-01-01

    PURPOSE: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in

  11. 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....

  12. 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;

    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% wh...

  13. 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

  14. Exaggerated Glucagon-Like Peptide 1 Response Is Important for Improved β-Cell Function and Glucose Tolerance After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes

    Jørgensen, Nils B; Dirksen, Carsten; Bojsen-Møller, Kirstine N;

    2013-01-01

    β-cell function is improved in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to an exaggerated glucagon-like peptide 1 (GLP-1) secretion, but causality has not been established. The aim of this study...

  15. Effect of surface chemistry of porous silicon microparticles on glucagon-like peptide-1 (GLP-1) loading, release and biological activity.

    Huotari, Anne; Xu, Wujun; Mönkäre, Juha; Kovalainen, Miia; Herzig, Karl-Heinz; Lehto, Vesa-Pekka; Järvinen, Kristiina

    2013-09-15

    Recently, mesoporous silicon (PSi) microparticles have been shown to extend the duration of action of peptides, reducing the need for frequent injections. Glucagon-like peptide 1 (GLP-1) is a potential novel treatment for type 2 diabetes. The aim of this study was to evaluate whether GLP-1 loading into PSi microparticles reduce blood glucose levels over an extended period. GLP-1 (pI 5.4) was loaded and released from the negatively charged thermally oxidized (TOPSi, pI 1.8) and thermally carbonized (TCPSi, pI 2.6) PSi microparticles and from the novel positively charged amine modified microparticles, designated as TOPSi-NH2-D (pI 8.8) and TCPSi-NH2-D (pI 8.8), respectively. The adsorption of GLP-1 onto the PSi microparticles could be increased 3-4-fold by changing the PSi surface charge from negative to positive, indicating that the positive surface charge of PSi promoted an electrostatic interaction between the negatively charged peptide. All the GLP-1 loaded PSi microparticles lowered the blood glucose levels after a single s.c. injection but surprisingly, TOPSi-NH2-D and TCPSi-NH2-D were not able to prolong the effect when compared to TOPSi, TCPSi or GLP-1 solution. However, TOPSi-NH2-D and TCPSi-NH2-D microparticles were able to carry improved payloads of active GLP-1 encouraging continuing further attempts to achieve sustained release.

  16. Therapeutic concentrations of glucagon-like peptide-1 in cerebrospinal fluid following cell-based delivery into the cerebral ventricles of cats

    Glage Silke

    2011-05-01

    Full Text Available Abstract Background Neuropeptides may have considerable potential in the treatment of acute and chronic neurological diseases. Encapsulated genetically engineered cells have been suggested as a means for sustained local delivery of such peptides to the brain. In our experiments, we studied human mesenchymal stem cells which were transfected to produce glucagon-like peptide-1 (GLP-1. Methods Cells were packed in a water-permeable mesh bag containing 400 polymeric microcapsules, each containing 3000 cells. The mesh bags were either transplanted into the subdural space, into the brain parenchyma or into the cerebral ventricles of the cat brain. Mesh bags were explanted after two weeks, and cell viability, as well as GLP-1 concentration in the cerebrospinal fluid (CSF, was measured. Results Viability of cells did not significantly differ between the three implantation sites. However, CSF concentration of GLP-1 was significantly elevated only after ventricular transplantation with a maximum concentration of 73 pM (binding constant = 70 pM. Conclusions This study showed that ventricular cell-based delivery of soluble factors has the capability to achieve concentrations in the CSF which may become pharmacologically active. Despite the controversy about the pharmacokinetic limitations of ventricular drug delivery, there might be a niche in this for encapsulated cell biodelivery of soluble, highly biologically-effective neuropeptides of low molecular weight like GLP-1.

  17. Normal secretion and action of the gut incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in young men with low birth weight

    Schou, Jakob Hagen; Pilgaard, Kasper; Vilsbøll, Tina

    2005-01-01

    CONTEXT: Low birth weight (LBW) is associated with increased risk of type 2 diabetes mellitus. An impaired incretin effect was reported previously in type 2 diabetic patients. OBJECTIVE: We studied the secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic po...... or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young LBW men....... polypeptide (GIP) in young LBW men (n = 24) and matched normal birth weight controls (NBW) (n = 25). RESULTS: LBW subjects were 5 cm shorter but had a body mass index similar to NBW. LBW subjects had significantly elevated fasting and postprandial plasma glucose, as well as postprandial (standard meal test......) plasma insulin and C-peptide concentrations, suggestive of insulin resistance. Insulin secretion in response to changes in glucose concentration ("beta-cell responsiveness") during the meal test was similar in LBW and NBW but inappropriate in LBW relative to insulin sensitivity. Fasting and postprandial...

  18. Glucagon-like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling.

    Ronveaux, Charlotte C; Tomé, Daniel; Raybould, Helen E

    2015-04-01

    Emerging evidence has suggested a possible physiologic role for peripheral glucagon-like peptide 1 (GLP-1) in regulating glucose metabolism and food intake. The likely site of action of GLP-1 is on vagal afferent neurons (VANs). The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the central nervous system and influences feeding behavior. Peripheral GLP-1 acts on VANs to inhibit food intake. The mechanism of the GLP-1 receptor (GLP-1R) is unlike other gut-derived receptors; GLP-1Rs change their cellular localization according to feeding status rather than their protein concentrations. It is possible that several gut peptides are involved in mediating GLP-1R translocation. The mechanism of peripheral GLP-1R translocation still needs to be elucidated. We review data supporting the role of peripheral GLP-1 acting on VANs in influencing glucose homeostasis and feeding behavior. We highlight evidence demonstrating that GLP-1 interacts with ghrelin and leptin to induce satiation. Our aim was to understand the mechanism of peripheral GLP-1 in the development of noninvasive antiobesity treatments.

  19. Inulin-enriched pasta improves intestinal permeability and modifies the circulating levels of zonulin and glucagon-like peptide 2 in healthy young volunteers.

    Russo, Francesco; Linsalata, Michele; Clemente, Caterina; Chiloiro, Marisa; Orlando, Antonella; Marconi, Emanuele; Chimienti, Guglielmina; Riezzo, Giuseppe

    2012-12-01

    Apart from the intestinal environment, inulin induces physiological effects, which includes a reduction in glucose and lipid concentrations and modulation of gastrointestinal motility through the release of different peptides. We hypothesized that inulin-enriched pasta may also improve small intestine permeability in relation to zonulin and glucagon-like peptide 2 (GLP-2) levels in healthy young subjects. Twenty healthy, young male volunteers completed a randomized, double-blind crossover study consisting of a 2-week run-in period and two 5-week study periods (11% inulin-enriched or control pasta), with an 8-week washout period in between. The intestinal barrier function was assessed by lactulose-mannitol excretion in urine. Zonulin values and GLP-2 release were evaluated by enzyme-linked immunosorbent assay. In the inulin group, the urinary lactulose recovery was significantly lower than the other 2 groups. There were no significant differences in urinary mannitol levels between groups. Accordingly, the lactulose-mannitol excretion ratio was significantly decreased in the inulin-enriched pasta group compared with the other 2 groups. The inulin-enriched pasta group had significantly lower zonulin serum values and significantly higher GLP-2 basal values when compared with the baseline and control pasta groups. The dietary use of inulin-enriched pasta preserves intestinal mucosal barrier functioning and modulates circulating levels of zonulin and GLP-2, suggesting that prebiotics could be used in the prevention of gastrointestinal diseases and metabolic disorders.

  20. Dietary unsaturated fatty acids increase plasma glucagon-like peptide-1 and cholecystokinin and may decrease premeal ghrelin in lactating dairy cows.

    Bradford, B J; Harvatine, K J; Allen, M S

    2008-04-01

    Previous reports have indicated that dietary unsaturated fat can decrease energy intake of lactating dairy cattle. However, the mechanism for this response is unclear. To evaluate the potential role of gut peptides, periprandial concentrations of cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and ghrelin were measured. From a replicated 4 x 4 Latin square experiment, 4 cows from a single square were selected for analysis of responses to 3 treatments: a control diet (5.5% total fatty acids, 65% unsaturated), a diet with added saturated fat (SAT, 8.3% fatty acids, 47% unsaturated), and a diet with added unsaturated fat (UNS, 7.8% fatty acids, 63% unsaturated). The SAT treatment increased duodenal flow of saturated fatty acids compared with UNS and control and, despite the fact that ruminal biohydrogenation altered fatty acid profiles of digesta, UNS increased duodenal flow of unsaturated fatty acids compared with SAT and control. Blood samples were collected at 8-min intervals through the first 2 meals of the day and analyzed by commercial radioimmunoassays. The UNS treatment increased plasma CCK concentration relative to SAT and control, and increased plasma GLP-1 concentration compared with control. Furthermore, fat treatments tended to suppress the prandial ghrelin surge that was evident for control. Suppression of feed intake by unsaturated fats is likely mediated in part by increased secretion of CCK and GLP-1, and dietary fat may also inhibit ghrelin release before conditioned meals.

  1. [Construction of yeast strains expressing long-acting glucagon-like peptide-1 (GLP-1) and their therapeutic effects on type 2 diabetes mellitus mouse model].

    Ri, Wu; Chao, Ma; Xiaodan, Li; Huikun, Duan; Yanli, Ji; Yu, Wang; Pingzhe, Jiang; Haisong, Wang; Peipei, Tu; Miao, Li; Ganggang, Ni; Baicheng, Ma; Minggang, Li

    2015-02-01

    Probiotics, i.e., bacteria expressing therapeutic peptides (protein), are used as a new type of orally administrated biologic drugs to treat diseases. To develop yeast strains which could effectively prevent and treat type 2 diabetes mellitus, we firstly constructed the yeast integrating plasmid pNK1-PGK which could successfully express green fluorescent protein (GFP) in Saccharomyces cerevisiae. The gene encoding ten tandem repeats of glucagon-like peptide-1(10 × GLP-1) was cloned into the vector pNK1-PGK and the resulting plasmids were then transformed into the S. cerevisiae INVSc1. The long-acting GLP-1 hypoglycemic yeast (LHY) which grows rapidly and expresses 10 × GLP-1 stably was selected by nutrition screening and Western blotting. The amount of 10 × GLP-1 produced by LHY reached 1.56 mg per gram of wet cells. Moreover, the oral administration of LHY significantly reduced blood glucose level in type 2 diabetic mice induced by streptozotocin plus high fat and high sugar diet.

  2. Glucagon-like peptide-2, but not glucose-dependent insulinotropic polypeptide, stimulates glucagon release in patients with type 1 diabetes

    Christensen, Mikkel; Knop, Filip K; Vilsbøll, Tina;

    2010-01-01

    This study investigated the glucagon-releasing properties of the hormones glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) in 8 patients with type 1 diabetes mellitus (T1DM) without paracrine intraislet influence of insulin (C-peptide negative following a 5 g...... intravenous arginine stimulation; on study days only treated with basal insulin substitution). On 3 study days, 180-minute two-step glucose clamps were performed. Plasma glucose (PG) was clamped at fasting values, with a mean of 7.4+/-0.5 mM in the first 90 min (period 1) and raised 1.5 times the fasting...... values to a mean of 11.1+/-0.1 mM in the last 90 min (period 2). In randomised order either GIP, GLP-2, or saline were infused intravenously during first 50 min in both periods at rates designed to mimic postprandial hormone responses. The resulting incremental area under curve values of glucagon were...

  3. Glucagon-like peptide-1 (GLP-1) increases in plasma and colon tissue prior to estrus and circulating levels change with increasing age in reproductively competent Wistar rats.

    Johnson, Michelle L; Saffrey, M Jill; Taylor, Victoria J

    2017-02-22

    There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females.

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

    Gelhorn HL

    2016-07-01

    Full Text Available Heather L Gelhorn,1 Elizabeth D Bacci,2 Jiat Ling Poon,1 Kristina S Boye,3 Shuichi Suzuki,4 Steven M Babineaux3 1Outcomes Research, Evidera, Bethesda, MD, 2Evidera, Seattle, WA, 3Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, IN, USA; 4Medicines Development Unit Japan, Eli Lilly Japan, Kobe, Japan 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%; P<0.0001.Conclusion: This study elicited the preferences of Japanese T2DM patients for attributes and levels

  5. 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...

  6. A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1

    Qu, Wei; Li, Yong; Hovgaard, Lars; Li, Song; Dai, Wenbin; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2012-01-01

    Background Glucagon-like peptide-1 (GLP-1) (7–36) is a peptide incretin hormone released from the endocrine L-cells of the intestinal mucosa with unique antidiabetic potential. Due to low absorption efficiency and instability in the gastrointestinal tract, the introduction of orally active GLP-1 is a large challenge. Here we developed a novel silica-based pH-sensitive nanomatrix of GLP-1 (SPN-GLP-1) in order to provide a strategy for oral peptide delivery. Methods SPN-GLP-1 composed of silica nanoparticles and pH-sensitive Eudragit® was prepared and characterized by dynamic light scattering, scanning electron microscope, transmission electron microscope, high-performance liquid chromatography, surface analysis, drug release, and so on. Its permeability across the Caco-2 cell monolayer and intestinal mucosa, proteolytic stability against the intestinal enzymes, pharmacokinetics, hypoglycemic effect in the intraperitoneal glucose tolerance test (IPGTT), and primary toxicity were then evaluated. Results It was indicated that the nanomatrix system obtained had a unique nanoscale structure and pH-sensitivity in drug release. It displayed a five-fold intestinal mucosa permeability and significantly higher proteolytic stability compared to native GLP-1 (P < 0.001). A longer half-life was observed after oral administration of SPN-GLP-1, and its relative bioavailability was 35.67% in comparison to intraperitoneal GLP-1. Oral delivery of SPN-GLP-1 significantly reduced the blood glucose level and its hypoglycemic effect over intraperitoneal GLP-1 reached 77%. There was no evident toxicity of SPN-GLP-1 found from both animal status and histochemical analysis of gastrointestinal tissues. Conclusion The silica-based pH-sensitive nanomatrix designed and prepared here might be considered as a potential oral delivery system not only for GLP-1, but also for other peptide or macromolecular drugs. PMID:23028226

  7. 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.

  8. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test.

    Isacson, Ruben; Nielsen, Elisabet; Dannaeus, Karin; Bertilsson, Göran; Patrone, Cesare; Zachrisson, Olof; Wikström, Lilian

    2011-01-10

    We have earlier shown that the glucagon-like peptide 1 receptor agonist exendin-4 stimulates neurogenesis in the subventricular zone and excerts anti-parkinsonian behavior. The aim of this study was to assess the effects of exendin-4 treatment on hippocampus-associated cognitive and mood-related behavior in adult rodents. To investigate potential effects of exendin-4 on hippocampal function, radial maze and forced swim test were employed. The time necessary to solve a radial maze task and the duration of immobility in the forced swim test were significantly reduced compared to respective vehicle groups if the animals had received exendin-4 during 1-2weeks before testing. In contrast to the positive control imipramine, single administration of exendin-4 1h before the challenge in the forced swim test had no effect. Immunohistochemical analysis showed that the incorporation of bromodeoxyuridine, a marker for DNA synthesis, as well as doublecortin expression was increased in the hippocampal dentate gyrus following chronic treatment with exendin-4 compared to vehicle-treated controls. The neurogenic effect of exendin-4 on hippocampus was confirmed by quantitative PCR showing an upregulation of mRNA expression for Ki-67, doublecortin and Mash-1. Since exendin-4 significantly improves hippocampus-associated behavior in adult rodents, it may be a candidate for alleviation of mood and cognitive disorders.

  9. Effect of Glucagon-like peptide 1 on Lipid Metabolism%胰升糖素样肽1对脂代谢的影响

    姚月; 李强

    2015-01-01

    [Summary] Glucagon-like peptide-1 ( GLP-1 ) as a new treatment of type 2 diabetes, not only has hypoglycemic effect, but also plays an important role in the regulation of lipid metabolism. GLP-1 plays a unique role in regulating lipid metabolism via lipid absorption and transport, fat formation and decomposition, hepatic lipid metabolism, and cholesterol transport.%胰升糖素样肽1(GLP-1)作为治疗2型糖尿病的新型药物,不仅具有降糖作用,而且在调节脂类物质代谢方面也发挥了重要作用。 GLP-1可影响脂类物质吸收与转运、脂肪形成与分解、肝脂代谢、胆固醇转运,在调节脂代谢方面具有独特的作用机制。

  10. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice.

    Viby, Niels-Erik; Isidor, Marie S; Buggeskov, Katrine B; Poulsen, Steen S; Hansen, Jacob B; Kissow, Hannelouise

    2013-12-01

    The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P agonist-treated mice (P agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression.

  11. Self-inducible secretion of glucagon-like peptide-1 (GLP-1) that allows MIN6 cells to maintain insulin secretion and insure cell survival.

    Nakashima, Koji; Shimoda, Masashi; Hamamoto, Sumiko; Tatsumi, Fuminori; Hirukawa, Hidenori; Tawaramoto, Kazuhito; Kanda, Yukiko; Kaku, Kohei

    2012-02-26

    Based on the hypothesis that MIN6 cells could produce glucagon-like peptide-1 (GLP-1) to maintain cell survival, we analyzed the effects of GLP-1 receptor agonist, exendin-4 (Ex4), and antagonist, exendin-(9-39) (Ex9) on cell function and cell differentiation. MIN6 cells expressed proglucagon mRNAs and produced GLP-1, which was accelerated by Ex4 and suppressed by Ex9. Moreover, Ex4 further enhanced glucose-stimulated GLP-1 secretion, suggesting autocrine loop-contributed amplification of the GLP-1 signal. Ex4 up-regulated cell differentiation- and cell function-related CREBBP, Pdx-1, Pax6, proglucagon, and PC1/3 gene expressions. The confocal laser scanning images revealed that GLP-1 positive cells were dominant in the early stage of cells, but positive for insulin were more prominent in the mature stage of cells. Ex4 accelerated cell viability, while Ex9 and anti-GLP-1 receptor antibody enhanced cell apoptosis. MIN6 cells possess a mechanism of GLP-1 signal amplification in an autocrine fashion, by which the cells maintained insulin production and cell survival.

  12. New insights into the role of cAMP in the production and function of the incretin hormone glucagon-like peptide-1 (GLP-1).

    Yu, Zhiwen; Jin, Tianru

    2010-01-01

    The proglucagon gene (gcg) encodes both glucagon and glucagon-like peptide-1 (GLP-1), produced in pancreatic alpha cells and intestinal endocrine L cells, respectively. The incretin hormone GLP-1 stimulates insulin secretion and pro-insulin gene transcription. GLP-1 also enhances pancreatic beta-cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells. A long-term effective GLP-1 receptor agonist, Byetta, has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders. The expression of gcg and the production of GLP-1 can be activated by the elevation of the second messenger cyclic AMP (cAMP). Recent studies suggest that in addition to protein kinase A (PKA), exchange protein activated by cAMP (Epac), another effector of cAMP, and the crosstalk between PKA and the Wnt signaling pathway, are involved in cAMP-stimulated gcg transcription and GLP-1 production as well. Finally, functions of GLP-1 in pancreatic beta cells are also mediated by PKA, Epac, as well as the effector of the Wnt signaling pathway. Together, these novel findings bring us a new insight into the role of cAMP in the production and function of the incretin hormone GLP-1.

  13. Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes

    Preiss, David; Dawed, Adem; Pearson, Ewan R.

    2017-01-01

    AIMS: To investigate, in the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) trial (NCT00723307), whether the influence of metformin on the glucagon-like peptide (GLP)-1 axis in individuals with and without type 2 diabetes (T2DM) is sustained and related to changes in glycaemia...... treated with metformin or diet, using Student's t-tests and linear regression. RESULTS: In CAMERA, metformin increased total GLP-1 at 6 (+20.7%, 95% confidence interval [CI] 4.7-39.0), 12 (+26.7%, 95% CI 10.3-45.6) and 18 months (+18.7%, 95% CI 3.8-35.7), an overall increase of 23.4% (95% CI 11.2-36.9; P....... These changes were independent of potential confounders including age, sex, adiposity and glycated haemoglobin. CONCLUSIONS: In people without diabetes, metformin increases total GLP-1 in a sustained manner and independently of changes in weight or glycaemia. Metformin-treated patients with T2DM also have...

  14. 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.

  15. Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer's Disease and Other Neurodegenerative Diseases.

    Calsolaro, Valeria; Edison, Paul

    2015-12-01

    The link between diabetes mellitus and Alzheimer's disease (AD) has been known for the last few decades. Since insulin and insulin receptors are known to be present in the brain, the downstream signalling as well as the effect of hyperinsulinemia have been extensively studied in both AD and Parkinson's disease. Glucagon-like peptide-1 (GLP-1) is a hormone belonging to the incretin family, and its receptors (GLP-1Rs) can be found in pancreatic cells and in vascular endothelium. Interestingly, GLP-1Rs are found in the neuronal cell body and dendrites in the central nervous system (CNS), in particular in the hypothalamus, hippocampus, cerebral cortex and olfactory bulb. Several studies have shown the importance of both insulin and GLP-1 signalling on cognitive function, and many preclinical studies have been performed to evaluate the potential protective role of GLP-1 on the brain. Here we review the underlying mechanism of insulin and GLP-1 signalling in the CNS, as well as the preclinical data for the use of GLP-1 analogues such as liraglutide, exenatide and lixisenatide in neurodegenerative diseases.

  16. 胰高血糖素样肽-1与下丘脑食欲调节%Glucagon-like peptide-1 and appetite regulation in the hypothalamus

    陈瑶; 郗光霞

    2012-01-01

    Hypothalamus is the center of neuroendocrine and appetite-regulation.Glucagons-like peptide-1 (GLP-1) is an incretin which is expressed in the hypothalamus,and regulates the appetite center.GLP-1 is considered as an anorexia-peptide and reduces food intake via negative feedback signal within the hypothalamus.The important pathways of controlling appetite are corticotrophin-releasing hormone ( CRH ),histamine,neuropeptide Y/agouti-related protein ( NPY/AgRP),pro-opiomelanocortin/cocaine and amphetamine regulated transcript (POMC/CART) and AMP-activated protein kinase (AMPK).Research on the mechanism of GLP-1 appetite-regulation may provide evidences on the treatment and prevention of obesity,insulin resistance and type 2 diabetes mellitus.%下丘脑是神经内分泌中枢,也是食欲调节中枢.胰高血糖素样肽-1(GLP-1)是一种胃肠道激素,能够在下丘脑表达并对食欲中枢有调节作用.GLP-1作为一种厌食信号肽,通过促肾上腺皮质激素释放激素(CRH)通路、组胺神经元通路、神经肽和刺鼠相关蛋白(NPY/AgRP)以及前阿片黑皮质素原和可卡因-苯丙胺调节转录肽(POMC/CART)通路及AMP活化蛋白激酶(AMPK)介导的摄食负反馈信号通路参与调节摄食活动.针对GLP-1调节摄食作用机制的研究对肥胖、胰岛素抵抗和2型糖尿病的防治有重要的理论意义.

  17. Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1 metabolite GLP-1 9-36 amide at the GLP-1 receptor.

    Naichang Li

    Full Text Available Glucagon-like peptide-1 (GLP-1 released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R. GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compound 2' has been described as both an agonist and positive allosteric modulator of GLP-1 7-36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9-39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa at the GLP-1R. Given that GLP-1 9-36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9-36 amide for key cellular responses including AMP generation, Ca(2+ signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy.

  18. Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1) metabolite GLP-1 9-36 amide at the GLP-1 receptor.

    Li, Naichang; Lu, Jing; Willars, Gary B

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compound 2' has been described as both an agonist and positive allosteric modulator of GLP-1 7-36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9-39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa) at the GLP-1R. Given that GLP-1 9-36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9-36 amide for key cellular responses including AMP generation, Ca(2+) signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy.

  19. 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.; Albrechtsen, Nicolai J. Wewer; Holst, Jens J.;

    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...... 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...

  20. A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1

    Qu W

    2012-09-01

    Full Text Available Wei Qu,1,2 Yong Li,2,* Lars Hovgaard,3 Song Li,1 Wenbin Dai,1 Jiancheng Wang,1 Xuan Zhang,1 Qiang Zhang1,*1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China; 2Department of Nutrition and Food Hygiene, Peking University Health Science Center, Beijing 100191, PR China; 3Oral Formulation Development, Novo Nordisk A/S, Maalov, Denmark*Both authors contributed equally to this workBackground: Glucagon-like peptide-1 (GLP-1 (7–36 is a peptide incretin hormone released from the endocrine L-cells of the intestinal mucosa with unique antidiabetic potential. Due to low absorption efficiency and instability in the gastrointestinal tract, the introduction of orally active GLP-1 is a large challenge. Here we developed a novel silica-based pH-sensitive nanomatrix of GLP-1 (SPN-GLP-1 in order to provide a strategy for oral peptide delivery.Methods: SPN-GLP-1 composed of silica nanoparticles and pH-sensitive Eudragit® was prepared and characterized by dynamic light scattering, scanning electron microscope, transmission electron microscope, high-performance liquid chromatography, surface analysis, drug release, and so on. Its permeability across the Caco-2 cell monolayer and intestinal mucosa, proteolytic stability against the intestinal enzymes, pharmacokinetics, hypoglycemic effect in the intraperitoneal glucose tolerance test (IPGTT, and primary toxicity were then evaluated.Results: It was indicated that the nanomatrix system obtained had a unique nanoscale structure and pH-sensitivity in drug release. It displayed a five-fold intestinal mucosa permeability and significantly higher proteolytic stability compared to native GLP-1 (P < 0.001. A longer half-life was observed after oral administration of SPN-GLP-1, and its relative bioavailability was 35.67% in comparison to intraperitoneal GLP-1. Oral delivery of SPN-GLP-1 significantly reduced the blood glucose level and its

  1. 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.

  2. 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.

  3. Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure

    Polizzi Clara

    2010-11-01

    Full Text Available Abstract Background Accumulating evidence suggests glucagon-like peptide-1 (GLP-1 exerts cardioprotective effects in animal models of myocardial infarction (MI. We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC in rats with MI-induced chronic heart failure (CHF caused by coronary artery ligation. Methods Two weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min, AC3174 (1.7 or 5 pmol/kg/min or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end. Results Compared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression. Conclusions Chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes.

  4. The Role of the Pharmacist in Managing Type 2 Diabetes with Glucagon-Like Peptide-1 Receptor Agonists as Add-On Therapy.

    Meece, Jerry

    2017-02-16

    The prevalence and associated clinical burden of type 2 diabetes (T2D) is increasing in the USA and other countries. As a consequence, the role of the pharmacist in managing T2D is expanding, and it is becoming increasingly important for pharmacists to have a complete understanding of the disease course and treatment options. Pharmacists have a key role in the use of injectable therapies, including incretin-based treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This article discusses the role of the pharmacist in the management of patients with T2D, particularly with respect to the use of GLP-1RAs to achieve glycemic control. GLP-1RAs are a class of injectable agents used as an adjunct to diet and exercise to improve glycemic control in adults with T2D. GLP-1RAs have been shown to lower glucose levels, slow gastric emptying, enhance satiety, and reduce body weight without increasing the risk of hypoglycemia. GLP-1RAs currently approved in the USA include exenatide twice daily, liraglutide once daily, and albiglutide, dulaglutide, and exenatide once weekly. Pharmacists can work with physicians to help identify patients for whom GLP-1RA therapy is appropriate. In addition, pharmacists can educate patients regarding medication storage, preparation, and injection techniques, glycated hemoglobin (HbA1c) targets, pre- and post-meal blood glucose goals, adverse events and management strategies, and the long-term benefits of reducing HbA1c. As members of the diabetes care team, pharmacists play an important role in improving patient outcomes.

  5. Correlation of Glypican-4 Level with Basal Active Glucagon-Like Peptide 1 Level in Patients with Type 2 Diabetes Mellitus

    Koh, Gwanpyo; Cho, Suk Ju; Yoo, So-Yeon; Chin, Sang Ouk

    2016-01-01

    Background Previous studies have reported that glypican-4 (GPC4) regulates insulin signaling by interacting with insulin receptor and through adipocyte differentiation. However, GPC4 has not been studied with regard to its effects on clinical factors in patients with type 2 diabetes mellitus (T2DM). We aimed to identify factors associated with GPC4 level in T2DM. Methods Between January 2010 and December 2013, we selected 152 subjects with T2DM and collected serum and plasma into tubes pretreated with aprotinin and dipeptidyl peptidase-4 inhibitor to preserve active gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). GPC4, active GLP-1, active GIP, and other factors were measured in these plasma samples. We performed a linear regression analysis to identify factors associated with GPC4 level. Results The subjects had a mean age of 58.1 years, were mildly obese (mean body mass index [BMI], 26.1 kg/m2), had T2DM of long-duration (mean, 101.3 months), glycated hemoglobin 7.5%, low insulin secretion, and low insulin resistance (mean homeostatic model assessment of insulin resistance [HOMA-IR], 1.2). Their mean GPC4 was 2.0±0.2 ng/mL. In multivariate analysis, GPC4 was independently associated with age (β=0.224, P=0.009), and levels of active GLP-1 (β=0.171, P=0.049) and aspartate aminotransferase (AST; β=–0.176, P=0.043) after being adjusted for other clinical factors. Conclusion GPC4 was independently associated with age, active GLP-1, and AST in T2DM patients, but was not associated with HOMA-IR and BMI, which are well known factors related to GPC4. Further study is needed to identify the mechanisms of the association between GPC4 and basal active GLP-1 levels. PMID:27704740

  6. 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.

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

    Yu, Yunli, E-mail: chrisyu1255@yahoo.com.cn [Department of Pharmaceutics, The Second Affiliated Hospital of Soochow University, Suzhou 215004 (China); Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Wang, Xinting, E-mail: wxinting1986@yahoo.com.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Can, E-mail: ltsan@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Yao, Dan, E-mail: erinyao@126.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Shanghai Institute of Materia Medica, Shanghai 201203 (China); Hu, Mengyue, E-mail: juliahmy@126.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Li, Jia, E-mail: ljbzd@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Hu, Nan, E-mail: hn_324@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Li, E-mail: liulee@cpu.edu.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Xiaodong, E-mail: xdliu@cpu.edu.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China)

    2013-02-01

    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 K{sub ATP} 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

  8. Natural sweetener agave inhibits gastric emptying in rats by a cholecystokinin-2- and glucagon like peptide-1 receptor-dependent mechanism.

    Bihter Gürler, E; Özbeyli, Dilek; Buzcu, Hülya; Bayraktar, Sezin; Carus, İrem; Dağ, Beyza; Geriş, Yasemin; Jeral, Seda; Yeğen, Berrak Ç

    2017-02-22

    Low-calorie sweeteners are considered to be beneficial in calorie control, but the impact of these sweeteners on gastric emptying is not well described. The purpose of this study was to compare the gastric emptying rate of agave nectar with those of glucose and fructose, and to evaluate the interaction of cholecystokinin (CCK)-1, CCK-2 and glucagon-like peptide-1 (GLP-1) receptors in agave-induced alterations in gastric emptying. Female Sprague-Dawley rats were fitted with gastric cannulas. Following the recovery, the gastric emptying rates of glucose, fructose and agave at 12.5%, 15% or 50% concentrations were measured and compared with that of saline. GLP-1 receptor antagonist exendin fragment 9-39 (30 μg kg(-1)), CCK-1 receptor antagonist devazepide (1 mg kg(-1)) or gastrin/CCK-2 receptor antagonist YM022 (1 mg kg(-1)) was injected subcutaneously 1 min before the emptying of glucose, fructose or agave at their 50% concentrations. When compared with saline emptying, gastric emptying of glucose was significantly delayed at its 25% and 50% concentrations, but the emptying of 12.5% glucose was not different from that of saline. Agave emptying, which was delayed with respect to saline emptying, was not altered by CCK-1 receptor blockade; but agave emptied from the stomach as rapidly as saline following the blockade of either CCK-2 or GLP-1 receptors. The findings demonstrate that the inhibitory effect of agave on gastric emptying is mediated by both CCK-2 and GLP-1 receptors, suggesting that natural sweeteners including agave may have satiating effects through the inhibition of gastric motility via enteroendocrine mechanisms.

  9. 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

  10. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways.

  11. 人胰高血糖素样肽-1类似物的合理应用%Application of Glucagon-like Peptide-1 Analogue

    朱大龙; 杨文英

    2013-01-01

    Conventional treatment of type 2 diabetes is to use multiple oral anti-hyperglycemic drugs and/or insulin based on the control of diet and physical activity. We emphasize the efficacy and safety of the new drug—Glucagon-like peptide-1 analogue (Liraglutide) in clinical trials of treating patients with type 2 diabetes. The results of large scale of LEAD series study, clinical study in Asian especial y Chinese patients approve liraglutide’s multiple beneficial. Liraglutide decreases blood glucose in glucose-dependent manner, protectsβcel function, decreases body weight as wel as reduces systolic blood pressure. Besides, the rates of hypoglycemic and other side ef ects are low, thus providing a better way to treat type 2 diabetes.%  传统2型糖尿病的治疗是在饮食、运动控制的基础上,使用多种口服药或者联合胰岛素治疗,本文着重介绍治疗成人2型糖尿病的新药人胰高血糖素样肽-1类似物利拉鲁肽在临床应用中的疗效及不良反应。大型LEAD系列研究以及在亚洲尤其是中国患者中展开的临床研究结果证实了利拉鲁肽具有葡萄糖依赖性降糖的特点,兼具有保护β细胞、降低体重、血压以及低血糖发生率低的优势,同时不良反应发生率低,为临床治疗2型糖尿病提供了新的治疗选择。

  12. Glucagon-like peptide-1 induced signaling and insulin secretion do not drive fuel and energy metabolism in primary rodent pancreatic beta-cells.

    Marie-Line Peyot

    Full Text Available BACKGROUND: Glucagon like peptide-1 (GLP-1 and its analogue exendin-4 (Ex-4 enhance glucose stimulated insulin secretion (GSIS and activate various signaling pathways in pancreatic beta-cells, in particular cAMP, Ca(2+ and protein kinase-B (PKB/Akt. In many cells these signals activate intermediary metabolism. However, it is not clear whether the acute amplification of GSIS by GLP-1 involves in part metabolic alterations and the production of metabolic coupling factors. METHODOLOGY/PRINICIPAL FINDINGS: GLP-1 or Ex-4 at high glucose caused release (approximately 20% of the total rat islet insulin content over 1 h. While both GLP-1 and Ex-4 markedly potentiated GSIS in isolated rat and mouse islets, neither had an effect on beta-cell fuel and energy metabolism over a 5 min to 3 h time period. GLP-1 activated PKB without changing glucose usage and oxidation, fatty acid oxidation, lipolysis or esterification into various lipids in rat islets. Ex-4 caused a rise in [Ca(2+](i and cAMP but did not enhance energy utilization, as neither oxygen consumption nor mitochondrial ATP levels were altered. CONCLUSIONS/SIGNIFICANCE: The results indicate that GLP-1 barely affects beta-cell intermediary metabolism and that metabolic signaling does not significantly contribute to GLP-1 potentiation of GSIS. The data also indicate that insulin secretion is a minor energy consuming process in the beta-cell, and that the beta-cell is different from most cell types in that its metabolic activation appears to be primarily governed by a "push" (fuel substrate driven process, rather than a "pull" mechanism secondary to enhanced insulin release as well as to Ca(2+, cAMP and PKB signaling.

  13. A Novel Long-Acting Glucagon-Like Peptide-1 Agonist with Improved Efficacy in Insulin Secretion and β-Cell Growth

    Hee Young Kim

    2014-09-01

    Full Text Available BackgroundGlucagon-like peptide-1 (GLP-1 is an incretin hormone produced by cleavage of proglucagon in intestinal L-cells. In the pancreas, GLP-1 stimulates post-prandial insulin secretion, promotes insulin biosynthesis, and improves insulin sensitivity. Because of its insulinotropic activity, GLP-1 has been considered a good candidate drug for treatment of diabetes mellitus. However, clinical use of GLP-1 has been limited by its short half-life, as a result of rapid degradation by dipeptidyl peptidase-IV (DPP-IV.MethodsWe designed a novel GLP-1 analog, Xenopus GLP-1 (xGLP-E4. The Ala residue in the second position of xGLP was replaced with a Ser residue to increase the half-life in the body. The C-terminal tail of exendin-4 was added to enhance the binding affinity for the GLP-1 receptor (GLP1R. The potency of GLP-1 and its analogs was determined by luciferase assay. The stability of GLP1R agonists was evaluated by determining the activity of agonists that had been preincubated in the presence of fetal bovine serum, which contains innate DPP-IV activity. The effects of xGLP-E4 on insulin secretion and β-cell growth were investigated using insulin enzyme-linked immunosorbent assay and cell counting.ResultsxGLP-E4 exhibited improved stability against DPP-IV activity and increased potency to GLP1R, compared with GLP-1. An increase in glucose-dependent insulin secretion was observed in xGLP-E4-treated pancreatic β-cells. The effect of xGLP-E4 on β-cell growth was greater than that of GLP-1.ConclusionWe developed a novel GLP-1 analog, xGLP-E4, that shows prolonged longevity and improved efficacy. This analog is a potential candidate for treatment of type 2 diabetes.

  14. The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors.

    Dickson, Suzanne L; Shirazi, Rozita H; Hansson, Caroline; Bergquist, Filip; Nissbrandt, Hans; Skibicka, Karolina P

    2012-04-04

    The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.

  15. 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.

  16. Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment.

    Cao, Yang; Cao, Xun; Liu, Xiao-Min

    2015-03-01

    Gastrin is a gastrointestinal hormone secreted by G cells. Hypergastrinemia can improve blood glucose and glycosylated hemoglobin levels. These positive effects are primarily due to the trophic effects of gastrin on β-cells. In recent years, many receptors that regulate secretion of glucagon-like peptide 1 (GLP-1) have been identified in enteroendocrine L cell lines. This led us to hypothesize that, in addition to the trophic effects of gastrin on β-cells, L cells also express cholecystokinin2-receptor (CCK2R), which may regulate GLP-1 secretion and have synergistic effects on glucose homeostasis. Our research provides a preliminary analysis of CCK2R expression and the stimulating effect of gastrin treatment on GLP-1 secretion in a human endocrine L cell line, using RT-PCR, Western blot, immunocytochemistry, and ELISA analyses. The expression of proglucagon and prohormone convertase 3, which regulate GLP-1 biosynthesis, were also analyzed by real-time PCR. Double immunofluorescence labeling was utilized to assess the intracellular localization of CCK2R and GLP-1 in L cells harvested from rat colon tissue. Our results showed that CCK2R was expressed in both the human L cell line and the rat L cells. We also showed that treatment with gastrin, a CCK2R agonist, stimulated the secretion of GLP-1, and that this effect was likely due to increased expression of proglucagon and PCSK1 (also known as prohormone convertase 3 (PC3 gene)). These results not only provide a basis for the role gastrin may play in intestinal L cells, and may also provide the basis for the development of a method of gastrin-mediated glycemic regulation.

  17. 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.

  18. A novel dual-glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist is neuroprotective in transient focal cerebral ischemia in the rat.

    Han, Ling; Hölscher, Christian; Xue, Guo-Fang; Li, Guanglai; Li, Dongfang

    2016-01-06

    Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer's or Parkinson's disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.

  19. New screening strategy and analysis for identification of allosteric modulators for glucagon-like peptide-1 receptor using GLP-1 (9-36) amide.

    Nakane, Atsushi; Gotoh, Yusuke; Ichihara, Junji; Nagata, Hidetaka

    2015-12-15

    The glucagon-like peptide-1 receptor (GLP-1R) is an important physiologic regulator of insulin secretion and a major therapeutic target for diabetes mellitus. GLP-1 (7-36) amide (active form of GLP-1) is truncated to GLP-1 (9-36) amide, which has been described as a weak agonist of GLP-1R and the major form of GLP-1 in the circulation. New classes of positive allosteric modulators (PAMs) for GLP-1R may offer improved therapeutic profiles. To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide. Screening enabled identification of two compounds, HIT-465 and HIT-736, which possessed new patterns of modulation of GLP-1R. We investigated the ability of these compounds to modify GLP-1R signaling enhanced GLP-1 (9-36) amide- and/or GLP-1 (7-36) amide-mediated cyclic adenosine monophosphate (cAMP) accumulation. These compounds also had unique profiles with regard to allosteric modulation of multiple downstream signaling (PathHunter β-arrestin signaling, PathHunter internalization signaling, microscopy-based internalization assay). We found allosteric modulation patterns to be obviously different among HIT-465, HIT-736, and Novo Nordisk compound 2. This work may enable the design of new classes of drug candidates by targeting modulation of GLP-1 (7-36) amide and GLP-1 (9-36) amide.

  20. Progesterone receptor membrane component 1 is a functional part of the glucagon-like peptide-1 (GLP-1) receptor complex in pancreatic β cells.

    Zhang, Ming; Robitaille, Mélanie; Showalter, Aaron D; Huang, Xinyi; Liu, Ying; Bhattacharjee, Alpana; Willard, Francis S; Han, Junfeng; Froese, Sean; Wei, Li; Gaisano, Herbert Y; Angers, Stéphane; Sloop, Kyle W; Dai, Feihan F; Wheeler, Michael B

    2014-11-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis. Because of their direct stimulation of insulin secretion from pancreatic β cells, GLP-1 receptor (GLP-1R) agonists are now important therapeutic options for the treatment of type 2 diabetes. To better understand the mechanisms that control the insulinotropic actions of GLP-1, affinity purification and mass spectrometry (AP-MS) were employed to uncover potential proteins that functionally interact with the GLP-1R. AP-MS performed on Chinese hamster ovary cells or MIN6 β cells, both expressing the human GLP-1R, revealed 99 proteins potentially associated with the GLP-1R. Three novel GLP-1R interactors (PGRMC1, Rab5b, and Rab5c) were further validated through co-immunoprecipitation/immunoblotting, fluorescence resonance energy transfer, and immunofluorescence. Functional studies revealed that overexpression of PGRMC1, a novel cell surface receptor that associated with liganded GLP-1R, enhanced GLP-1-induced insulin secretion (GIIS) with the most robust effect. Knockdown of PGRMC1 in β cells decreased GIIS, indicative of positive interaction with GLP-1R. To gain insight mechanistically, we demonstrated that the cell surface PGRMC1 ligand P4-BSA increased GIIS, whereas its antagonist AG-205 decreased GIIS. It was then found that PGRMC1 increased GLP-1-induced cAMP accumulation. PGRMC1 activation and GIIS induced by P4-BSA could be blocked by inhibition of adenylyl cyclase/EPAC signaling or the EGF receptor-PI3K signal transduction pathway. These data reveal a dual mechanism for PGRMC1-increased GIIS mediated through cAMP and EGF receptor signaling. In conclusion, we identified several novel GLP-1R interacting proteins. PGRMC1 expressed on the cell surface of β cells was shown to interact with the activated GLP-1R to enhance the insulinotropic actions of GLP-1.

  1. Ingestion of coffee polyphenols increases postprandial release of the active glucagon-like peptide-1 (GLP-1(7-36)) amide in C57BL/6J mice.

    Fujii, Yoshie; Osaki, Noriko; Hase, Tadashi; Shimotoyodome, Akira

    2015-01-01

    The widespread prevalence of diabetes, caused by impaired insulin secretion and insulin resistance, is now a worldwide health problem. Glucagon-like peptide 1 (GLP-1) is a major intestinal hormone that stimulates glucose-induced insulin secretion from β cells. Prolonged activation of the GLP-1 signal has been shown to attenuate diabetes in animals and human subjects. Therefore, GLP-1 secretagogues are attractive targets for the treatment of diabetes. Recent epidemiological studies have reported that an increase in daily coffee consumption lowers diabetes risk. The present study examined the hypothesis that the reduction in diabetes risk associated with coffee consumption may be mediated by the stimulation of GLP-1 release by coffee polyphenol extract (CPE). GLP-1 secretion by human enteroendocrine NCI-H716 cells was augmented in a dose-dependent manner by the addition of CPE, and was compatible with the increase in observed active GLP-1(7-36) amide levels in the portal blood after administration with CPE alone in mice. CPE increased intracellular cyclic AMP (cAMP) levels in a dose-dependent manner, but this was not mediated by G protein-coupled receptor 119 (GPR119). The oral administration of CPE increased diet (starch and glyceryl trioleate)-induced active GLP-1 secretion and decreased glucose-dependent insulinotropic polypeptide release. Although CPE administration did not affect diet-induced insulin secretion, it decreased postprandial hyperglycaemia, which indicates that higher GLP-1 levels after the ingestion of CPE may improve insulin sensitivity. We conclude that dietary coffee polyphenols augment gut-derived active GLP-1 secretion via the cAMP-dependent pathway, which may contribute to the reduced risk of type 2 diabetes associated with daily coffee consumption.

  2. Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: A randomised double-blinded placebo-controlled clinical trial.

    Jørgensen, Peter G; Jensen, Magnus T; Mensberg, Pernille; Storgaard, Heidi; Nyby, Signe; Jensen, Jan S; Knop, Filip K; Vilsbøll, Tina

    2017-02-11

    In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP-1RA liraglutide or placebo combined with supervised exercise in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (-7.1 ± 1.6 cm/s (mean ± standard deviation) to -7.7 ± 1.8 cm/s, p = 0.01), but not in the liraglutide group (-7.1 ± 1.4 to -7.0 ± 1.4 cm/s, p = 0.60; between groups: p = 0.02). Similarly, the ratio of early and atrial mitral annular tissue velocities improved in the placebo group (1.0 ± 0.4 to 1.2 ± 0.4, p = 0.003), but not in the liraglutide group (1.0 ± 0.3 to 1.0 ± 0.3, p = 0.87; between groups: p = 0.03). We found no significant differences in heart rate, left ventricular structure or function within or between the groups. In conclusion, addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect of exercise on left ventricular diastolic function.

  3. 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, <.01, the overall SIP score (10.3±8.9% versus 6.2±9.5%, <.001, the mental component of the SF-36 (45±13% versus 53±11%, <.05, and the overall IBDQ score (5.1±0.9 versus 5.4±0.9, <.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.

  4. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.

    Nauck, M

    2016-03-01

    Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

  5. Engineering an L-cell line that expresses insulin under the control of the glucagon-like peptide-1 promoter for diabetes treatment

    Rasouli Mina

    2011-11-01

    Full Text Available Abstract Background Diabetes mellitus is a complicated disease with a pathophysiology that includes hyperinsulinemia, hyperglycemia and other metabolic impairments leading to many clinical complications. It is necessary to develop appropriate treatments to manage the disease and reduce possible acute and chronic side effects. The advent of gene therapy has generated excitement in the medical world for the possible application of gene therapy in the treatment of diabetes. The glucagon-like peptide-1 (GLP-1 promoter, which is recognised by gut L-cells, is an appealing candidate for gene therapy purposes. The specific properties of L-cells suggest that L-cells and the GLP-1 promoter would be useful for diabetes therapy approaches. Results In this study, L-cells were isolated from a primary intestinal cell line to create suitable target cells for insulin expression studies. The isolated cells displayed L-cell properties and were therefore used as an L-cell surrogate. Next, the isolated L-cells were transfected with the recombinant plasmid consisting of an insulin gene located downstream of the GLP-1 promoter. The secretion tests revealed that an increase in glucose concentration from 5 mM to 25 mM induced insulin gene expression in the L-cells by 2.7-fold. Furthermore, L-cells quickly responded to the glucose stimulation; the amount of insulin protein increased 2-fold in the first 30 minutes and then reached a plateau after 90 minutes. Conclusion Our data showed that L-cells efficiently produced the mature insulin protein. In addition, the insulin protein secretion was positively regulated with glucose induction. In conclusion, GLP-1 promoter and L-cell could be potential candidates for diabetes gene therapy agents.

  6. The pivotal role of high glucose-induced overexpression of PKCβ in the appearance of glucagon-like peptide-1 resistance in endothelial cells.

    Pujadas, Gemma; De Nigris, Valeria; La Sala, Lucia; Testa, Roberto; Genovese, Stefano; Ceriello, Antonio

    2016-11-01

    Recently, it has been demonstrated that Glucagon-like peptide-1 (GLP-1) has a protective effect on endothelial cells. Our hypothesis is that this GLP-1 protective effect is partly lost when the cells are exposed to sustained high glucose concentrations. Human umbilical vein endothelial cells (HUVECs) were cultured for 21 days in normal glucose (5 mmol/L, NG) or high glucose (25 mmol/L glucose, HG). GLP-1 (7-37) and Ruboxistaurin were added at 50 and 500 nM, respectively, alone or in combination, 1 h before cell harvesting. Analysis of GLP-1 receptor protein levels, as well as of the gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes, and PKA subunits, was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations but was partially restored by a chemical PKCβ-specific inhibitor. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of Nrf2-detoxifying enzyme targets, to increase transcription levels of scavenger genes, to attenuate the expression of high glucose-induced PKA subunits, ER stress and also the apoptotic phenotype of HUVECs; these effects occured only when high glucose-induced PKCβ overexpression was reduced by Ruboxistaurin. In a similar manner, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCβ inhibitor. This study suggests that an increase in PKCβ, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting the GLP-1 canonical pathway.

  7. 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.

  8. Incretin hormone glucagon-like peptide 1 and gut microbiota%胰高血糖素样肽1和肠道菌群

    金天如

    2016-01-01

    胃肠道生产20多种肽类激素。其中,胰高血糖素样肽1(GLP-1)在过去的30年里受到最多关注。人们对GLP-1以及另一肠道激素葡萄糖依赖性促胰岛素肽(GIP)功能的研究已导致了两类新的糖尿病治疗药物的开发,分别称为GLP-1R激动剂和DPP-Ⅳ抑制剂。肠道的这些内分泌细胞不是聚集在内分泌腺体中,而是广泛分布在整个胃肠道中,从而与“外部”环境包括食物以及肠道菌群充分接触。本文简要介绍了GLP-1以及营养成分如何调节其分泌,并重点讨论了肠道环境如何影响GLP-1的产生和分泌,包括肠道菌群的贡献。%There are more than two dozens of peptide hormones that are produced and released from the gastrointestinal (GI) tract. Among them, the incretin hormone glucagon-like peptide 1 (GLP-1) has received the most intensive attention for the past 30 years. Functional studies on GLP-1 and anoth⁃er gut incretin hormone glucose-dependent insulinotropic peptide (GIP) have led to the development of novel diabetes therapeutic agents known as GLP-1 receptor agonists and DPP-Ⅵinhibitors. Instead of forming endocrine glands, the gut hormone producing endocrine cells are widely spread throughout the entire GI tract, permitting vital interactions with the″external″environment. Here a brief introduction on GLP-1 and how nutritional components regulate its secretion were made, followed by reviewing some key development on how gut environment affects the production and secretion of GLP-1, including the contribution of gut microbiota.

  9. 胰高血糖素样肽2作用机制研究进展%Research Advance in Mechanism of Glucagon-like Peptide-2

    仇黎鹏

    2013-01-01

    Glucagon-like peptide-2( GLP-2 )is a peptide hormone secreted from enteroendocrine L-cells,which can promote the growth of intestinal mucosa, enhance intestinal mucosal barrier, upregulate nutrient absorption, stimulate intestinal blood flow, inhibit gastrointestinal motility and acid secretion. Recently,the widespread use of GLP-2 in clinical trials necessitate elucidation of the mechanism of GLP-2. GLP-2 acts through a specific G protein-coupled receptor( GLP-2R ), which is expressed in various intestinal cells,so it's inferred that GLP-2 plays its biological role through multiple downstream mediators. The intestinotropic actions of GLP-2 on the colon are mediated through the keratinocyte growth factor and insulin-like growth factor( IGF )-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands. The anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal poly-peptide released from submucosal enteric neurons and nitric oxide,respectively.%胰高血糖素样肽2(GLP-2)是一种肠道多肽类激素,具有多种肠道效应,包括刺激肠黏膜生长、促进营养物的消化和吸收、提高肠屏障功能、抑制胃能动性和胃酸分泌等.近年来GLP-2已经用于多种临床肠道疾病的治疗,因此阐明其作用机制显得尤为重要.GLP-2通过G蛋白耦联受体GLP-2R来发挥作用.GLP-2R在多种肠细胞中均有表达,故推测GLP-2通过多种下游介质来间接发挥其生物学功能.GLP-2对结肠的肠营养作用被角质化细胞生长因子和胰岛素样生长因子2(IGF-2)调节,而小肠生长除了与IGF-1R和表皮生长因子受体之一ErbB相关外,还与IGF-1、IGF-2和ErbB配体相关.GLP-2的抗炎和血流效应分别依赖于由黏膜下层神经元释放的血管活性肠肽和一氧化氮.

  10. Preserved glucagon-like peptide-1 responses to oral glucose, but reduced incretin effect, insulin secretion and sensitivity in young Asians with type 2 diabetes mellitus

    Yeow, Toh Peng; Pacini, Giovanni; Tura, Andrea; Lim, Shueh Lin; Tan, Florence Hui Sieng; Tong, Chin Voon; Hong, Janet Yeow Hua; Md Zain, Fuziah; Holst, Jens Juul; Wan Mohamud, Wan Nazaimoon

    2017-01-01

    Objective Youth onset type 2 diabetes mellitus (YT2DM) is a globally rising phenomenon with substantial Asians representation. The understanding of its pathophysiology is derived largely from studies in the obese African-American and Caucasian populations, while studies on incretin effect are scarce. We examined the insulin resistance, β-cell function (BC), glucagon-like peptide (GLP)-1 hormone and incretin effect in Asian YT2DM. Research design and methods This case–control study recruited 25 Asian YT2DM and 15 healthy controls, matched for gender, ethnicity and body mass index. Serum glucose, insulin, C peptide and GLP-1 were sampled during 2-hour oral glucose tolerance tests (OGTTs) and 1-hour intravenous glucose tolerance tests (IVGTTs). Insulin sensitivity was derived from the Quantitative Insulin Sensitivity Check Index (QUICKI), Oral Glucose Insulin Sensitivity Index (OGIS) in OGTT and surrogate index of SI from the minimal model (calculated SI, CSI). Acute insulin response (AIR) was obtained from IVGTT. Total BC was computed as incremental area under the curve of insulin/incremental area under the curve of glucose, during OGTT (BCOG) and IVGTT (BCIV), respectively. Disposition index (DI) was calculated using the product of insulin sensitivity and insulin secretion. GLP-1 response to oral glucose was calculated as incremental area under the curve of GLP-1 (ΔAUCGLP-1). Per cent incretin effect was estimated as 100×(BCOG−BCIV)/BCOG). Results The YT2DM had marked impairment in BC (>80% reduction in AIR and BCOG, p<0.001) and lower QUICKI (p<0.001), OGIS (p<0.001) and CSI (p=0.015) compared with controls. There was no difference in GLP-1 at all time points and ΔAUCGLP-1 but the per cent incretin effect was reduced in the YT2DM compared with controls (12.1±8.93 vs 70.0±4.03, p<0.001). Conclusions Asian YT2DM showed similar GLP-1 response to oral glucose as controls but reduced incretin effect, BC and insulin sensitivity. The lack of compensatory

  11. Pharmacokinetics and metabolism studies on the glucagon-like peptide-1 (GLP-1)-derived metabolite GLP-1(9-36)amide in male Beagle dogs.

    Eng, Heather; Sharma, Raman; McDonald, Thomas S; Landis, Margaret S; Stevens, Benjamin D; Kalgutkar, Amit S

    2014-09-01

    Glucagon-like peptide-1 (GLP-1)(7-36)amide is a 30-amino acid peptide hormone that is secreted from intestinal enteroendocrine L-cells in response to nutrients. GLP-1(7-36)amide possesses potent insulinotropic actions in the augmentation of glucose-dependent insulin secretion. GLP-1(7-36)amide is rapidly metabolized by dipeptidyl peptidase-IV to yield GLP-1(9-36)amide as the principal metabolite. Contrary to the earlier notion that peptide cleavage products of native GLP-1(7-36)amide [including GLP-1(9-36)amide] are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with GLP-1(9-36)amide in mice, dogs and humans. In the present work, in vitro metabolism and pharmacokinetic properties of GLP-1(9-36)amide have been characterized in dogs, since this preclinical species has been used as an animal model to demonstrate the in vivo vasodilatory and cardioprotective effects of GLP-1(9-36)amide. A liquid chromatography tandem mass spectrometry assay was developed for the quantitation of the intact peptide in hepatocyte incubations as opposed to a previously reported enzyme-linked immunosorbent assay. Although GLP-1(9-36)amide was resistant to proteolytic cleavage in dog plasma and bovine serum albumin (t1/2>240 min), the peptide was rapidly metabolized in dog hepatocytes with a t1/2 of 110 min. Metabolite identification studies in dog hepatocytes revealed a variety of N-terminus cleavage products, most of which, have also been observed in human and mouse hepatocytes. Proteolysis at the C-terminus was not observed in GLP-1(9-36)amide. Following the administration of a single intravenous bolus dose (20 µg/kg) to male Beagle dogs, GLP-1(9-36)amide exhibited a mean plasma clearance of 15 ml/min/kg and a low steady state distribution volume of 0.05 l/kg, which translated into a short elimination half life of 0.05 h. Following subcutaneous administration of GLP-1(9-36)amide at 50 µg/kg, systemic exposure of

  12. Plasma Free Amino Acid Responses to Intraduodenal Whey Protein, and Relationships with Insulin, Glucagon-Like Peptide-1 and Energy Intake in Lean Healthy Men

    Natalie D. Luscombe-Marsh

    2016-01-01

    Full Text Available This study determined the effects of increasing loads of intraduodenal (ID dairy protein on plasma amino acid (AA concentrations, and their relationships with serum insulin, plasma glucagon-like peptide-1 (GLP-1 and energy intake. Sixteen healthy men had concentrations of AAs, GLP-1 and insulin measured in response to 60-min ID infusions of hydrolysed whey protein administered, in double-blinded and randomised order, at 2.1 (P2.1, 6.3 (P6.3 or 12.5 (P12.5 kJ/min (encompassing the range of nutrient emptying from the stomach, or saline control (C. Energy intake was quantified immediately afterwards. Compared with C, the concentrations of 19/20 AAs, the exception being cysteine, were increased, and this was dependent on the protein load. The relationship between AA concentrations in the infusions and the area under the curve from 0 to 60 min (AUC0–60 min of each AA profile was strong for essential AAs (R2 range, 0.61–0.67, but more variable for non-essential (0.02–0.54 and conditional (0.006–0.64 AAs. The AUC0–60 min for each AA was correlated directly with the AUC0–60 min of insulin (R2 range 0.3–0.6, GLP-1 (0.2–0.6 and energy intake (0.09–0.3 (p < 0.05, for all, with the strongest correlations being for branched-chain AAs, lysine, methionine and tyrosine. These findings indicate that ID whey protein infused at loads encompassing the normal range of gastric emptying increases plasma concentrations of 19/20 AAs in a load-dependent manner, and provide novel information on the close relationships between the essential AAs, leucine, valine, isoleucine, lysine, methionine, and the conditionally-essential AA, tyrosine, with energy intake, insulin and GLP-1.

  13. The glucagon-like peptide-1 receptor agonist, liraglutide, attenuates the progression of overt diabetic nephropathy in type 2 diabetic patients.

    Imamura, Shigeki; Hirai, Keiji; Hirai, Aizan

    2013-01-01

    Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m² to 26.5 ± 0.8 kg/m² after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m²/year to 0.3 ± 1.9 mL/min/1.73 m²/year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.

  14. Effects of exendin-4, a glucagon like peptide-1 receptor agonist, on neutrophil count and inflammatory cytokines in a rat model of endotoxemia

    Yanay O

    2015-07-01

    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. Keywords: glucagon like peptide-1, exendin-4, sepsis, endotoxemia, inflammation, neutrophils

  15. The Impact of Pancreatic Enzyme Supplementation on Postprandial Responses of Glucagon-Like Peptide-2 in Patients with Chronic Pancreatitis and Pancreatic Exocrine Insufficiency

    Filip K Knop

    2010-09-01

    Full Text Available Dear Sir, We have recently shown that patients with chronic pancreatitis and pancreatic exocrine insufficiency exhibit greater postprandial responses of the intestinal hormone glucagon-like peptide-2 (GLP-2 as compared to healthy control subjects [1]. GLP-2 is a 33-amino acid peptide hormone secreted by the endocrine L cells of the intestinal mucosa following meal ingestion [2]. It acts as a growth factor in the small intestine [3] and, in patients with functional short-bowel syndrome, GLP-2 has been shown to improve intestinal absorption [4]. Furthermore, GLP-2 seems to increase intestinal blood flow [5], including blood flow in the superior mesenteric artery of pigs [6] and humans [7]. Interestingly, our recent observation of increased postprandial GLP-2 responses in patients with chronic pancreatitis and pancreatic exocrine insufficiency correlated with increased postprandial blood flow in the superior mesenteric arteries of these patients [1]. However, the mechanisms behind the increased postprandial GLP-2 response in chronic pancreatitis patients with pancreatic exocrine insufficiency could only be speculated upon, with one explanation being that reduced assimilation of nutrients in the proximal part of the small intestine results in delivery of a larger nutrient load to the distal L cell-rich part of the small intestine. Reduced assimilation of nutrients in chronic pancreatitis patients with pancreatic exocrine insufficiency can be clinically modulated by the administration of pancreatic enzyme supplementation. In 2007, we reported that pancreatic enzyme supplementation in these patients resulted in increased postprandial secretion of GLP-2’s sister peptide, GLP-1, also released from intestinal L cells [8]. In order to investigate potential mechanisms behind exaggerated GLP-2 levels in chronic pancreatitis we evaluated the impact of pancreatic enzyme supplementation on postprandial GLP-2 responses in the chronic pancreatitis patients

  16. A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice.

    Gault, Victor A; Bhat, Vikas K; Irwin, Nigel; Flatt, Peter R

    2013-12-06

    Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA(2)]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA(2)]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA(2)]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA(2)]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA(2)]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA(2)]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes.

  17. JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, suppresses food intake and gastric emptying with the elevation of plasma peptide YY and glucagon-like peptide-1 in a dietary fat-dependent manner.

    Hata, Takahiro; Mera, Yasuko; Ishii, Yukihito; Tadaki, Hironobu; Tomimoto, Daisuke; Kuroki, Yukiharu; Kawai, Takashi; Ohta, Takeshi; Kakutani, Makoto

    2011-03-01

    The microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. In this study, we investigated the effects of diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), a novel intestine-specific MTP inhibitor, on food intake, gastric emptying, and gut peptides using Sprague-Dawley rats fed 3.1% fat, 13% fat, or 35% fat diets. JTT-130 treatment suppressed cumulative food intake and gastric emptying in rats fed a 35% fat diet, but not a 3.1% fat diet. In rats fed a 13% fat diet, JTT-130 treatment decreased cumulative food intake but not gastric emptying. In addition, treatment with orlistat, a lipase inhibitor, completely abolished the reduction of food intake and gastric emptying by JTT-130 in rats fed a 35% fat diet. On the other hand, JTT-130 treatment increased the plasma concentrations of gut peptides, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) but not cholecystokinin, in the portal vein in rats fed a 35% fat diet. These elevations in PYY and GLP-1 were also abolished by treatment with orlistat. Furthermore, JTT-130 treatment in rats fed a 35% fat diet increased the contents of triglycerides and free fatty acids in the intestinal lumen, which might contribute to the elevation of PYY and GLP-1 levels. The present findings indicate that JTT-130 causes satiety responses, decreased food intake, and gastric emptying in a dietary fat-dependent manner, with enhanced production of gut peptides such as PYY and GLP-1 from the intestine.

  18. 胰高血糖素样肽-1对糖尿病周围神经病变的影响%Effect of glucagon-like peptide-1 on diabetic peripheral neuropathy

    万丽娟; 陈明卫

    2016-01-01

    Glucagon-like peptide-1 is a kind of insulin secreting peptide secreted by intestine L cells during eating,which plays a role for the nervous system mainly acting on GLP-1 receptor to activate multiple signaling pathways.It mainly includes such roles as speeding up the nerve conduction velocity,increasing the number of nerve axons,providing nutritional factor directly to neurons,inhibiting neuron apop-tosis,and resisting oxidative stress.Glucose-like peptide-1 and glucagon-like peptide-1 receptor agonist can improve the symptoms of dia-betic peripheral neuropathy through several different ways,which provides a new method for the therapy of diabetic peripheral neuropathy.%胰高血糖素样肽-1(GLP-1)是肠道因进食而分泌的一类促胰岛素分泌肽,主要通过作用于 GLP-1受体,激活多种信号通路而对神经系统发挥影响,主要包括加快神经传导速度,增加神经轴突的数量,为神经细胞直接提供营养因子,抑制神经细胞凋亡,拮抗氧化应激等作用。GLP-1及其受体激动剂可通过多种不同的途径改善糖尿病周围神经病变的症状,为糖尿病周围神经病变的治疗提供新的方法。

  19. GLP-1受体激动剂心血管保护机制研究进展%Update on the cardiovascular protective effects of glucagon-like peptide-1 receptor agonists

    郑仁东; 刘超; 王昆

    2012-01-01

    Along with the wide use of glucagon-like peptide-1 ( GLP-1 ) receptor agonists,evidence has been accumulated that GLP-1 receptor agonists could lead to myocardial protection,improvement of myocardial infarction and heart failure by ways of regulating blood glucose,lipid and blood pressure,anti-inflammation and anti-oxidative stress,etc.%随着胰高血糖素样肽-1( GLP-1)受体激动剂的广泛应用,越来越多的研究表明,此类药物能够通过调节血糖、血脂、血压,并通过抗炎、抗氧化应激等机制,发挥保护心肌、改善心肌梗死和心力衰竭等方面的效应.

  20. 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...... glucose, plasma concentrations of insulin and incretin hormones [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)], the ghrelin response, and satiety in healthy subjects. DESIGN: GER was measured by using real-time ultrasonography after ingestion of rice pudding...... with 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...

  1. Advances in the research of the drugs targeting glucagon-like peptide-1 receptor%胰高血糖素样肽-1受体靶向药物研究进展

    李彩娜; 申竹芳

    2009-01-01

    Glucagon-like peptide-1 (GLP-1) ,a 30 amino-acid peptide,is an incretin secreted from the in-testinal L cells. It can bind to the GLP-1 receptor to exert a variety of anti-diabetic activity. However,its half-life is only about 2 min in vivo,which may limit its application in clinic. Even though,GLP-1 receptor remains to be a new target for the research and development of anti-diabetic drugs. The aim is to discover long-term peptidic or non-pep-tidic glucagon-like peptide-1 receptor agonists,which could also resist the degradation by dipeptidyl peptidase IV (DPP IV).Up to date,besides of exenatide that has been approved by US Food Drug Administration ( FDA ) ,there are some peptides,such as liraglutide,in clinic study state and many other peptidic or non-peptidic compounds in pre-clinic study state. In this article,we reviewed the recent achievements regarding drugs targeting GLP-1 receptor.%胰高血糖素样肽-1(Ghcagon-like peptide-1,GLP-1)是一种肠道L细胞分泌的肠降糖素,由30个氨基酸组成.GLP-1与受体结合后具有一定的抗糖尿病作用,但其体内半衰期短(约2 min),临床应用受限.GLP-1受体是目前开发抗糖尿病药物的新靶点之一,旨在寻找可以同时激动GLP-1受体和耐受二肽基肽酶IV降解的长效肽类或非肽类化合物.目前该类多肽中exenatide已被美国食品药品管理局批准上市,liraglutide等处于临床研究阶段,尚有很多肽类或非肽类化合物处于临床前研究阶段.文中将近几年来靶向GLP-1受体的研究成果综述如下.

  2. 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

    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 correlated...... at 30 minutes only in the RYGB group (r = .66; P = .013). The glucose-dependent insulinotropic peptide levels at 30 minutes were lower in the RYGB group (20 pmol/L) than in the BND group (31 pmol/L) or overweight control group (33 pmol/L). The peak glucagon levels were similar among the 3 groups...... 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 minutes was significantly...

  3. Effects of calcium salts of long-chain fatty acids and rumen-protected methionine on plasma concentrations of ghrelin, glucagon-like peptide-1 (7 to 36) amide and pancreatic hormones in lactating cows.

    Fukumori, R; Sugino, T; Shingu, H; Moriya, N; Hasegawa, Y; Kojima, M; Kangawa, K; Obitsu, T; Kushibiki, S; Taniguchi, K

    2012-02-01

    Our objective was to determine the effects of calcium salts of long-chain fatty acids (CLFAs) and rumen-protected methionine (RPM) on plasma concentrations of ghrelin, glucagon-like peptide-1 (7 to 36) amide, and pancreatic hormones in lactating cows. Four Holstein cows in midlactation were used in a 4 by 4 Latin square experiment in each 2-wk period. Cows were fed corn silage-based diets with supplements of CLFAs (1.5% added on dry matter basis), RPM (20 g/d), CLFAs plus RPM, and without supplement. Jugular blood samples were taken from 1 h before to 2 h after morning feeding at 10-min intervals on day 12 of each period. CLFAs decreased dry matter intake, but RPM did not affect dry matter intake. Both supplements of CLFAs and RPM did not affect metabolizable energy intake and milk yield and composition. Plasma concentrations of NEFAs, triglyceride (TG), and total cholesterol (T-Cho) were increased with CLFAs alone, but increases of plasma concentrations of TG and T-Cho were moderated by CLFAs plus RPM. Calcium salts of long-chain fatty acids increased plasma ghrelin concentration, and the ghrelin concentration with CLFAs plus RPM was the highest among the treatments. Plasma concentrations of glucagon-like peptide-1, glucagon, and insulin were decreased with CLFAs, whereas adding RPM moderated the decrease of plasma glucagon concentration by CLFAs. These results indicate that the addition of methionine to cows given CLFAs increases plasma concentrations of ghrelin and glucagon associated with the decrease in plasma concentrations of TG and T-Cho.

  4. Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

    Reidelberger, Roger; Haver, Alvin; Anders, Krista; Apenteng, Bettye

    2014-10-15

    Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

  5. Mycoprotein reduces energy intake and postprandial insulin release without altering glucagon-like peptide-1 and peptide tyrosine-tyrosine concentrations in healthy overweight and obese adults: a randomised-controlled trial.

    Bottin, Jeanne H; Swann, Jonathan R; Cropp, Eleanor; Chambers, Edward S; Ford, Heather E; Ghatei, Mohammed A; Frost, Gary S

    2016-07-01

    Dietary mycoprotein decreases energy intake in lean individuals. The effects in overweight individuals are unclear, and the mechanisms remain to be elucidated. This study aimed to investigate the effect of mycoprotein on energy intake, appetite regulation, and the metabolic phenotype in overweight and obese volunteers. In two randomised-controlled trials, fifty-five volunteers (age: 31 (95 % CI 27, 35) years), BMI: 28·0 (95 % CI 27·3, 28·7) kg/m2) consumed a test meal containing low (44 g), medium (88 g) or high (132 g) mycoprotein or isoenergetic chicken meals. Visual analogue scales and blood samples were collected to measure appetite, glucose, insulin, peptide tyrosine-tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Ad libitum energy intake was assessed after 3 h in part A (n 36). Gastric emptying by the paracetamol method, resting energy expenditure and substrate oxidation were recorded in part B (n 14). Metabonomics was used to compare plasma and urine samples in response to the test meals. Mycoprotein reduced energy intake by 10 % (280 kJ (67 kcal)) compared with chicken at the high content (P=0·009). All mycoprotein meals reduced insulin concentrations compared with chicken (incremental AUClow (IAUClow): -8 %, IAUCmedium: -12 %, IAUChigh: -21 %, P=0·004). There was no significant difference in glucose, PYY, GLP-1, gastric emptying rate and energy expenditure. Following chicken intake, paracetamol-glucuronide was positively associated with fullness. After mycoprotein, creatinine and the deamination product of isoleucine, α-keto-β-methyl-N-valerate, were inversely related to fullness, whereas the ketone body, β-hydroxybutyrate, was positively associated. In conclusion, mycoprotein reduces energy intake and insulin release in overweight volunteers. The mechanism does not involve changes in PYY and GLP-1. The metabonomics analysis may bring new understanding to the appetite regulatory properties of food.

  6. 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 glucos...

  7. Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core.

    Nance, Kellie D; Days, Emily L; Weaver, C David; Coldren, Anastasia; Farmer, Tiffany D; Cho, Hyekyung P; Niswender, Colleen M; Blobaum, Anna L; Niswender, Kevin D; Lindsley, Craig W

    2017-02-23

    A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.

  8. 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

    OBJECTIVE: Liraglutide is a long-acting glucagon-like peptide 1 analog designed for once daily injection. This study assessed the efficacy and safety of liraglutide after 12 weeks of treatment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind, randomized, parallel...

  9. 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.

  10. Genetically-Encoded Photocrosslinkers Determine the Biological Binding Site of Exendin-4 in the N-Terminal Domain of the Intact Human Glucagon-Like Peptide-1 Receptor (GLP-1R).

    Koole, Cassandra; Reynolds, Christopher A; Mobarec, Juan C; Hick, Caroline; Sexton, Patrick M; Sakmar, Thomas P

    2017-03-10

    The glucagon-like peptide-1 receptor (GLP-1R) is a key therapeutic target in the management of type II diabetes mellitus, with actions including regulation of insulin biosynthesis and secretion, promotion of satiety and preservation of β-cell mass. Like most class B G protein-coupled receptors (GPCRs), there is limited knowledge linking biological activity of the GLP-1R with the molecular structure of an intact, full-length, functional receptor-ligand complex. In this study, we have utilized genetic code expansion to site-specifically incorporate the photoactive amino acid p-azido-L-phenylalanine (azF) into N-terminal residues of a full-length, functional human GLP-1R in mammalian cells. UV-mediated photolysis of azF was then carried out to induce targeted photocrosslinking to determine the proximity of the azido group in the mutant receptor with the peptide exendin-4. Crosslinking data were compared directly to the crystal structure of the isolated N-terminal extracellular domain (ECD) of the GLP-1R in complex with exendin(9-39), revealing both similarities as well as distinct differences in the mode of interaction. Generation of a molecular model to accommodate the photocrosslinking constraints highlights the potential influence of environmental conditions on the conformation of the receptor-peptide complex, including folding dynamics of the peptide and formation of dimeric and higher order oligomeric receptor multimers. These data demonstrate that crystal structures of isolated receptor regions may not give a complete reflection of peptide-receptor interactions, and should be combined with additional experimental constraints to reveal peptide-receptor interactions occurring in the dynamic, native, full-length receptor state.

  11. 胰高血糖素样肽-1及其类似物保护认知功能的研究进展%Protective effects of glucagon-like peptide-1 and its analogs on cognitive function

    张亮; 闵苏

    2014-01-01

    Background Cognitive dysfunction is defined as mental health disorder that affect learning,memory,thinking,judgment and other higher brain function.However,there are no definitive drugs to prevent the cognitive dysfunction.Type 2 diabetes mellitus is recognized as one risk factor for cognitive dysfunction.Glucagon-like peptide-1 (GLP-1) and its analogues,a class of antidiabetic agents,have the protective effects on cognitive function.Objective To provide the theoretical basis for the prevention and treatment of GLP-1 and its analogues on cognitive dysfunction.Content This review will focus on protective effects of GLP-1 and its analogs on cognitive function.Trend GLP-1 and its analogs are expected to become new drugs for prevention and treatment of neuropathic diseases such as cognitive dysfunction.%背景 认知功能障碍是指学习记忆、思维判断等大脑高级功能异常,目前尚无确切的防治药物.2型糖尿病被公认为发生认知功能障碍的危险因素.胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)及其类似物是一种针对2型糖尿病的新型降糖药,研究发现其还具有保护认知功能的作用. 目的 为GLP-1及其类似物应用于临床防治认知功能障碍提供理论依据. 内容 就GLP-1及其类似物的保护认知功能的研究现状作一综述. 趋向 有望成为防治认知功能障碍等神经病理性疾病的新型药物.

  12. Glucagon-like peptide-1-based therapies and pancreatic safety%胰高血糖素样肽-1类药物与胰腺安全性

    赵荷珺; 洪天配

    2015-01-01

    There has been a debate over the pancreatic safety of glucagon-like peptide-1-based hypoglycemic therapies in recent years,especially about their potential to promote acute pancreatitis,cause histological changes related to chronic pancreatitis,and possibly,in the long run,induce pancreatic cancer.Clearly conflicting data exist between epidemiologic studies and basic studies,some of which cannot be ignored.Therefore,a full summary and analysis of these studies will lay the foundation for the future investigation.%近年来,胰高血糖素样肽-1类降糖药物的胰腺安全性引起了广泛关注,主要是因为其可能促进急性胰腺炎的发生,诱发与慢性胰腺炎相关的组织学改变,远期还可能诱发胰腺癌.流行病学研究和基础研究中存在一些相互矛盾的研究数据,其中的一些研究问题不容被忽视.因此,对现有的研究资料进行回顾和分析可为后续研究的开展和问题的阐明奠定基础.

  13. Effects of glucagon-like peptide-1 receptor agonists on the central nervous system%胰高血糖素样肽-1受体激动剂对中枢神经系统的作用

    傅铮; 匡洪宇; 郝明

    2011-01-01

    Agonist of glucagon-like peptide-I receptor( GLP-1 R)can stimulate insulin secretion and improve the physiological state of islet cells effectively though binding its receptor. It has become a hot topic of diabetes. Studies have shown that GLP-I R was widely expressed in the central nervous system. Agonist of GLP-IR may play some effects in the central nervous system, such as protection of nerve cell, regulation of appetite, influence of cognitive function, etc. These can reflect its potential applications and value.%胰高血糖素样肽-1受体(GLP-1R)激动剂通过GLP-1R刺激胰岛素分泌并改善胰岛细胞的状态,现已成为糖尿病领域研究热点.已证实GLP-1R在中枢神经系统有广泛表达,中枢应用GLP-1R激动剂后其可发挥保护神经细胞、调节食欲、调节认知功能等一系列作用,体现了其在中枢神经系统应用的潜质与价值.

  14. Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice

    Shaocong Hou

    2015-01-01

    Full Text Available Glucagon like peptide-1 (GLP-1 receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

  15. Glucagon-like peptide-1 based therapy for type 2 diabetes%胰高糖素样肽及其衍生物与2型糖尿病的治疗

    于宝生

    2006-01-01

    肠促胰岛素(incretins)这一概念最早由La Barre于1932年提出,是指肠道衍生的具有食物依赖性促胰岛素分泌作用的肽类激素。在人类,incretins主要包括葡萄糖依赖性胰岛素释放肽(glucose-dependent insulinotropic polypeptide,,GIP)和胰高糖素样肽(glucagon-like peptide-1,GLP-1)。GIP和GLP-1分别于1970年、1985年被发现、分离,它们具有葡萄糖依赖性促胰岛素分泌作用,通过调节B细胞的增殖、再生和凋亡等,增大B细胞群,GLP-1还能抑制胃排空、胰高糖素分泌和食物摄取。2型糖尿病患者表现出相对的GIP抵抗,而对GLP-1R促效剂(agonist)则无。现就GLP-1和其类似物的生物学特征及其近年来在2型糖尿病治疗中的研究作一概述。

  16. 胰高血糖素样肽-1受体激动剂的心血管作用%The Cardiovascular Effect of Glucagon-like Peptide-1 Receptor Agonists

    韩江莉

    2013-01-01

    The glucagon-like peptide-1 ( GLP-1 ) receptor agonists exenatide and liraglutide are ideal drugs for treating diabetes melli-tus. However, recent preclinical and clinical trial data suggest additional cardiovascular protective effects related to GLP-1 receptor agonists therapy, including lowering blood pressure, improvements in left ventricular function and vascular endothelium function, protection of ische-mia-injuried cardiac myocytes. Novel preclinical and clinical studies of GLP-1 receptor agonists on cardiovascular effects are outlined in this review.%胰高血糖素样肽-1受体激动剂胰高血糖素样肽-1、Exenatide和Liraglutide是理想的降糖药物.近几年的研究显示,这些药物除降糖作用以外还有心血管保护作用,包括降低血压、改善左心室功能和血管内皮功能、保护缺血损伤的心肌细胞等.现对胰高血糖素样肽-1受体激动剂的心血管作用最新研究进展进行综述.

  17. Glucagon like peptide-1 receptor agonist and nonalcoholic fatty liver disease%胰高血糖素样肽-1受体激动剂与非酒精性脂肪性肝病

    王兴纯; 曲伸

    2014-01-01

    As new antidiabetic drugs,glucagon-like peptide-1 (GLP-1) receptor agonists have been widely used.Recent studies suggest that these drugs can reduce transaminase level to improve nonalcoholic fatty liver disease by improving blood lipid levels,decreasing the content of fat,reducing fatty degeneration of the liver,the degree of liver fibrosis and cell death.%胰高血糖素样肽-1(GLP-1)受体激动剂作为治疗糖尿病的新型药物得到广泛应用.近年来的研究显示,此类药物能够通过改善血脂水平、降低脂肪含量、减少肝脂肪变性、肝纤维化程度及细胞死亡等机制,实现降低转氨酶水平以改善非酒精性脂肪性肝病的作用.

  18. Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

    Hou, Shaocong; Li, Caina; Huan, Yi; Liu, Shuainan; Liu, Quan; Sun, Sujuan; Jiang, Qian; Jia, Chunming; Shen, Zhufang

    2015-01-01

    Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

  19. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

    den Besten, Gijs; Gerding, Albert; van Dijk, Theo H; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M

    2015-01-01

    The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

  20. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

    Gijs den Besten

    Full Text Available The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs, have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR γ repression and AMP-activated protein kinase (AMPK activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

  1. Glucagon-Like Peptide-1 and Pancreatic β Cells%胰高血糖素样肽1对胰腺β细胞的作用及其机制

    宋晓艳; 何文俊; 孙晓雅; 郝好杰; 韩为东; 母义明

    2015-01-01

    Glucagon-like peptide-1(GLP-1) is an incretin hormone released from intestinal L-cells in response to nutrients. GLP-1 stimulates insulin secretion from pancreatic β cells in a glucose-dependent manner. GLP-1 al⁃so has many other beneficial effects for glucose homeostasis such as slowing gastric emptying, suppressing appe⁃tite, reducing plasma glucagon, and stimulating glucose disposal. Therefore, there is increasing interest in incretin-based therapies for treatment of diabetes. In this review we discussed the current understanding of the effect of GLP-1 on pancreatic β cells.%胰高血糖素样肽1(GLP-1)是一种主要由肠道L细胞分泌的肠促胰素。GLP-1能通过葡萄糖依赖模式刺激胰岛素的分泌,同时有延缓胃排空、抑制胰高血糖素分泌、降低体重的作用,有利于维持体内血糖稳态。目前,基于GLP-1的药物作为新的糖尿病治疗手段已越来越受到重视。我们简要综述GLP-1对胰腺β细胞的作用及机制研究进展。

  2. 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;

    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...

  3. Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats

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

    2008-01-01

    compared to GLP-2. This indicates that EN potentiates the intestinotrophic action of GLP-2. Proliferation of enterocytes due to GLP-2 infusion was associated with greater expression of ileal proglucagon, GLP-2 receptor, IGF-I, IGF binding protein-3 mRNAs, and greater IGF-I peptide concentration in ileum (p......action in a physiological model of intestinal growth. Key words...

  4. 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

    . Venous blood was drawn frequently for measurement of glucose, insulin, C-peptide, glucagon, GLP-1, triglycerides and NEFA. RESULTS: GLP-1 administration lowered fasting and postprandial glycaemia (p... 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 (ptriglyceride levels was completely...... abolished by GLP-1 (change in triglycerides, -0.023+/-0.045 mmol/l; p

  5. The regions within the N-terminus critical for human glucagon like peptide-1 receptor (hGLP-1R) cell Surface expression

    Aiysha Thompson; Venkateswarlu Kanamarlapudi

    2014-01-01

    The hGLP-1R is a target for the treatment of type 2 diabetes and belongs to the class B family of GPCRs. Like other class B GPCRs, the GLP-1R contains an N-terminal signal peptide (SP) and undergoes N-linked glycosylation, which are important for its trafficking and maturation. This study analysed the role of the SP, the hydrophobic region after the SP (HRASP), glycosylation and the conserved residues within the N-terminus in GLP-1R trafficking. HGLP-1R targeted to the cell surface showed no ...

  6. 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

    concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations. RESULTS: The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared...... with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; PISR incr......, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART....

  7. 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

    2002-01-01

    and 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.......97). The 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...... during hypoglycemia with GLP-1 (P = 0.04). GLP-1 stimulated insulin secretion only at plasma glucose concentrations of at least 4.3 mmol/liter. In conclusion, the suppression of glucagon by GLP-1 does occur at euglycemia, but not at hypoglycemic plasma glucose concentrations (

  8. 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;

    2004-01-01

    , 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 intact GIP reached similar levels in both groups (P = 0.31 and P = 0.87, respectively). The concentrations of GIP (3-42) and GLP-1 (9-36 amide) were significantly higher in the patients than in the control subjects (P = 0.0021 and P = 0.027, respectively). During and after the exogenous infusion, GLP-1...... (9-36 amide) and GIP (3-42) reached higher plasma concentrations in the CRI patients than in the control subjects (P

  9. Glucagon-like peptide 1 (GLP-1) can reverse AMP-activated protein kinase (AMPK) and S6 kinase (P70S6K) activities induced by fluctuations in glucose levels in hypothalamic areas involved in feeding behaviour.

    Hurtado-Carneiro, Verónica; Sanz, Carmen; Roncero, Isabel; Vazquez, Patricia; Blazquez, Enrique; Alvarez, Elvira

    2012-04-01

    The anorexigenic peptide, glucagon-like peptide-1 (GLP-1), reduces glucose metabolism in the human hypothalamus and brain stem. The brain activity of metabolic sensors such as AMP-activated protein kinase (AMPK) responds to changes in glucose levels. The mammalian target of rapamycin (mTOR) and its downstream target, p70S6 kinase (p70S6K), integrate nutrient and hormonal signals. The hypothalamic mTOR/p70S6K pathway has been implicated in the control of feeding and the regulation of energy balances. Therefore, we investigated the coordinated effects of glucose and GLP-1 on the expression and activity of AMPK and p70S6K in the areas involved in the control of feeding. The effect of GLP-1 on the expression and activities of AMPK and p70S6K was studied in hypothalamic slice explants exposed to low- and high-glucose concentrations by quantitative real-time RT-PCR and by the quantification of active-phosphorylated protein levels by immunoblot. In vivo, the effects of exendin-4 on hypothalamic AMPK and p70S6K activation were analysed in male obese Zucker and lean controls 1 h after exendin-4 injection to rats fasted for 48 h or after re-feeding for 2-4 h. High-glucose levels decreased the expression of Ampk in the lateral hypothalamus and treatment with GLP-1 reversed this effect. GLP-1 treatment inhibited the activities of AMPK and p70S6K when the activation of these protein kinases was maximum in both the ventromedial and lateral hypothalamic areas. Furthermore, in vivo s.c. administration of exendin-4 modulated AMPK and p70S6K activities in those areas, in both fasted and re-fed obese Zucker and lean control rats.

  10. Comparative effects of the endogenous agonist glucagon-like peptide-1 (GLP-1)-(7-36) amide and the small-molecule ago-allosteric agent "compound 2" at the GLP-1 receptor.

    Coopman, Karen; Huang, Yan; Johnston, Neil; Bradley, Sophie J; Wilkinson, Graeme F; Willars, Gary B

    2010-09-01

    Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Small-molecule GLP-1R agonists have been sought due to difficulties with peptide therapeutics. Recently, 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (compound 2) has been described as a GLP-1R allosteric modulator and agonist. Using human embryonic kidney-293 cells expressing human GLP-1Rs, we extended this work to consider the impact of compound 2 on G protein activation, Ca(2+) signaling and receptor internalization and particularly to compare compound 2 and GLP-1 across a range of functional assays in intact cells. GLP-1 and compound 2 activated Galpha(s) in cell membranes and increased cellular cAMP in intact cells, with compound 2 being a partial and almost full agonist, respectively. GLP-1 increased intracellular [Ca(2+)] by release from intracellular stores, which was mimicked by compound 2, with slower kinetics. In either intact cells or membranes, the orthosteric antagonist exendin-(9-39), inhibited GLP-1 cAMP generation but increased the efficacy of compound 2. GLP-1 internalized enhanced green fluorescent protein-tagged GLP-1Rs, but the speed and magnitude evoked by compound 2 were less. Exendin-(9-39) inhibited internalization by GLP-1 and also surprisingly that by compound 2. Compound 2 displays GLP-1R agonism consistent with action at an allosteric site, although an orthosteric antagonist increased its efficacy on cAMP and blocked compound 2-mediated receptor internalization. Full assessment of the properties of compound 2 was potentially hampered by damaging effects that were particularly manifest in either longer term assays with intact cells or in acute assays with membranes.

  11. Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake

    Läppchen, Tilman; Tönnesmann, Roswitha; Eersels, Jos; Meyer, Philipp T.; Maecke, Helmut R.; Rylova, Svetlana N.

    2017-01-01

    GLP-1 receptors are ideal targets for preoperative imaging of benign insulinoma and for quantifying the beta cell mass. The existing clinical tracers targeting GLP-1R are all agonists with low specific activity and very high kidney uptake. In order to solve those issues we evaluated GLP-1R agonist Ex-4 and antagonist Ex(9–39) radioiodinated at Tyr40 side by side with [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 (68Ga-Ex-4) used in the clinic. The Kd, Bmax, internalization and binding kinetics of [Nle14,125I-Tyr40-NH2]Ex-4 and [Nle14,125I-Tyr40-NH2]Ex(9–39) were studied in vitro using Ins-1E cells. Biodistribution and imaging studies were performed in nude mice bearing Ins-1E xenografts. In vitro evaluation demonstrated high affinity binding of the [Nle14,125I-Tyr40-NH2]Ex-4 agonist to the Ins-1E cells with fast internalization kinetics reaching a plateau after 30 min. The antagonist [Nle14,125I-Tyr40-NH2]Ex(9–39) did not internalize and had a 4–fold higher Kd value compared to the agonist. In contrast to [Nle14,125I-Tyr40-NH2]Ex(9–39), which showed low and transient tumor uptake, [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated excellent in vivo binding properties with tumor uptake identical to that of 68Ga-Ex-4, but substantially lower kidney uptake resulting in a tumor-to-kidney ratio of 9.7 at 1 h compared to 0.3 with 68Ga-Ex-4. Accumulation of activity in thyroid and stomach for both peptides, which was effectively blocked by irenat, confirms that in vivo deiodination is the mechanism behind the low kidney retention of iodinated peptides. The 124I congener of [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated a similar favourable biodistribution profile in the PET imaging studies in contrast to the typical biodistribution pattern of [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4. Our results demonstrate that iodinated Ex-4 is a very promising tracer for imaging of benign insulinomas. It solves the problem of high kidney uptake of the radiometal-labelled tracers by improving the tumor

  12. 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.

  13. The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

    Suchankova, P; Yan, J; Schwandt, M L; Stangl, B L; Caparelli, E C; Momenan, R; Jerlhag, E; Engel, J A; Hodgkinson, C A; Egli, M; Lopez, M F; Becker, H C; Goldman, D; Heilig, M; Ramchandani, V A; Leggio, L

    2015-06-16

    The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

  14. Effects of glucagon-like peptide-1 receptor stimulation and blockade on food consumption and body weight in rats treated with a cannabinoid CB1 receptor agonist WIN 55,212-2

    Radziszewska, Elżbieta; Bojanowska, Ewa

    2013-01-01

    Background Glucagon-like peptide-1 (GLP-1) and endocannabinoids are involved in appetite control. Recently we have demonstrated that cannabinoid (CB)1 receptor antagonist and GLP-1 receptor agonist synergistically suppress food intake in the rat. The aim of the present study was to determine the effects of GLP-1 receptor stimulation or blockade on feeding behavior in rats treated with WIN 55,212-2, a CB1 receptor agonist. Material/Methods Experiments were performed on adult male Wistar rats. In the first experiment the effects of increasing doses (0.5–4.0 mg/kg) of WIN 55,212-2 injected intraperitoneally on 24-hour food consumption were tested. In further experiments a GLP-1 receptor antagonist, exendin (9-39), and WIN 55,212-2 or a GLP-1 receptor agonist, exendin-4, and WIN 55,212-2 were injected intraperitoneally at subthreshold doses (that alone did not change food intake and body weight) to investigate whether these agents may interact to affect food intake in rats. Results WIN 55,212-2 administered at low doses (0.5–2 mg/kg) did not markedly change 24-hour food consumption; however, at the highest dose, daily food intake was inhibited. Combined administration of WIN 55,212-2 and exendin (9-39) did not change the amount of food consumed compared to either the control group or to each agent injected alone. Combined injection of WIN 55,212-2 and exendin-4 at subthreshold doses resulted in a significant decrease in food intake and body weight in rats. Conclusions Stimulation of the peripheral CB1 receptor by its agonist WIN 55,212-2 can induce anorexigenic effects or potentiate, even at a subthreshold dose, the effects of exendin-4, a known anorectic agent. Hence, this dual action of the cannabinoid system should be considered in the medical use of CB1 agonists. PMID:23291632

  15. Real-world medication persistence and outcomes associated with basal insulin and glucagon-like peptide 1 receptor agonist free-dose combination therapy in patients with type 2 diabetes in the US

    Lin, Jay; Lingohr-Smith, Melissa; Fan, Tao

    2017-01-01

    Background Free-dose combination treatment with basal insulin and short-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduces hyperglycemia via complementary targeting of fasting and postprandial blood glucose levels, however, in the real world, due to injection burden and clinical inertia, the full efficacy may not be able to translate into clinical and economic benefits. Objective The aim of the study was to evaluate treatment persistence and associated outcomes in patients with type 2 diabetes (T2D) treated with a GLP-1 RA in free-dose combination with basal insulin. Methods Claims data were extracted on US adults with T2D with ≥1 prescription claim for both a GLP-1 RA and a basal insulin from July 1, 2008 to June 30, 2013, and continuous health plan coverage for 6 months prior to (baseline) and 12 months after the index date (follow-up period). Outcomes analyzed for patients stratified by treatment persistence included glycemic control, hypoglycemia, and health care costs and resource utilization. Multivariate analyses were used to examine factors associated with persistence or hypoglycemia. Results The analysis included 7,320 patients, of whom 16.9% were persistent with free-dose combination treatment. The median time to treatment discontinuation was 133 days. Compared with nonpersistent patients, persistent patients had greater glycated hemoglobin A1c (A1C) reductions (−0.80% vs −0.42%; P=0.032), were more likely to achieve A1C GLP-1 RA and basal insulin treatment is low, improved treatment persistence is associated with greater A1C reductions and lower total medical charges. PMID:28053550

  16. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression.

    Ojima, Ayako; Ishibashi, Yuji; Matsui, Takanori; Maeda, Sayaka; Nishino, Yuri; Takeuchi, Masayoshi; Fukami, Kei; Yamagishi, Sho-ichi

    2013-01-01

    Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.

  17. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists.

    Nakashima, Ryutaro; Yano, Tatsuya; Ogawa, Junko; Tanaka, Naomi; Toda, Narihiro; Yoshida, Masao; Takano, Rieko; Inoue, Masahiro; Honda, Takeshi; Kume, Shoen; Matsumoto, Koji

    2014-08-15

    G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes.

  18. Functional coupling of Cys-226 and Cys-296 in the glucagon-like peptide-1 (GLP-1) receptor indicates a disulfide bond that is close to the activation pocket.

    Mann, Rosalind J; Al-Sabah, Suleiman; de Maturana, Rakel López; Sinfield, John K; Donnelly, Dan

    2010-12-01

    G protein-coupled receptors (GPCRs) are seven transmembrane α-helical (7TM) integral membrane proteins that play a central role in both cell signaling and in the action of many pharmaceuticals. The crystal structures of several Family A GPCRs have shown the presence of a disulfide bond linking transmembrane helix 3 (TM3) to the second extracellular loop (ECL2), enabling ECL2 to stabilize and contribute to the ligand binding pocket. Family B GPCRs share no significant sequence identity with those in Family A but nevertheless share two conserved cysteines in topologically equivalent positions. Since there are no available crystal structures for the 7TM domain of any Family B GPCR, we used mutagenesis alongside pharmacological analysis to investigate the role of ECL2 and the conserved cysteine residues. We mutated Cys-226, at the extracellular end of TM3 of the glucagon-like peptide-1 (GLP-1) receptor, to alanine and observed a 38-fold reduction in GLP-1 potency. Interestingly, this potency loss was restored by the additional substitution of Cys-296 in ECL2 to alanine. Alongside the complete conservation of these cysteine residues in Family B GPCRs, this functional coupling suggested the presence of a disulfide bond. Further mutagenesis demonstrated that the low potency observed at the C226A mutant, compared with the C226A-C296A double mutant, was the result of the bulky nature of the released Cys-296 side chain. Since this suggested that ECL2 was in close proximity to the agonist activation pocket, an alanine scan of ECL2 was carried out which confirmed the important role of this loop in agonist-induced receptor activation.

  19. Glucagon-like peptides 1 and 2

    Kissow, Hannelouise

    2015-01-01

    PURPOSE OF REVIEW: Chemotherapy often causes adverse effects, including pain, bloating, diarrhea, and inflammation and ulceration of the mucous membranes lining the digestive tract, which are collectively referred to as mucositis. Unfortunately, no remedy has been found yet to manage these side...... 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....

  20. 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.

  1. 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.

  2. Physiological functions of glucagon-like peptide-1 (9-36) NH2%高血糖素样肽1(9-36) NH2的生理学功能

    郭莉霞; 刘建辉; 殷菲

    2011-01-01

    Many findings demonstrate that glucagon-like peptide-l( 9-36 )NH2[ GLP-1 (9-36 )NH2] , mostly a cleavage product of GLP-1 (7-36) NH2, has a lot of physiological functions. GLP-1 (9-36)NH2 can reduce postprandial glycemia independently of gastric emptying and insulin secretion, rapidly reverse heart failure, improve end diastolic pressure, markedly stimulate myocardial glucose uptake, exert antioxidant cardioprotective actions, reduce oxidative stress in vasculature tissues independently of GLP-1 receptor, suppress hepatic glucose production , and promote glycogen stores. Thus, GLP-1 (9-36) NH2 is an active peptide with important physiological functions , and it will play an important role in treating obesity and accompanying manifestations of metabolic syndrome, including insulin resistance, cardiovascular disease, and hepatic steatosis.%许多研究表明,高血糖素样肽1 (9-36) NH2[ GLP-1 (9-36) NH2]是GLP-1 (7-36) NH2被二肽基肽酶快速降解后的主要体内存在形式,具有许多的生理学功能.GLP-1 (9-36) NH2中除了具有非依赖于胃排空和胰岛素分泌所致的降低餐后血糖的作用外,GLP-1 (9-36) NH2更多的是直接对外周器官的保护作用,包括快速逆转心力衰竭、改善舒张末期压、快速刺激心肌葡萄糖摄取及减少缺血再灌注对心脏的损伤;以及它具有不依赖于GLP-1受体的血管系统的抗氧化作用和抑制肝脏糖原异生、促进肝糖原的合成.因此,可以说明GLP-1( 9-36) NH2在体内是一个具有重要生理功能的活性肽,而不仅仅是GLP-1 (7-36) NH2的代谢产物.GLP-1 (9-36) NH2对糖尿病及其包括胰岛素抵抗、心血管疾病、肝脏脂肪变性等并发症的治疗将会起到非常重要的作用.

  3. 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.

  4. 胰升糖素样肽1受体激动剂与糖尿病、肥胖和银屑病%Glucagon-like peptide-1 receptor agonists, diabetes, obesity, and psoriasis

    田景琰; 陈名道

    2012-01-01

    More and more extrapancreatic actions of incretin-based therapies have been demonstrated and recently case reports have linked glucagon-like peptide-1 (GLP-1) receptor agouist therapy with the improvements in psoriasis.Psoriasis is a common skin disorder characterized by chronic inflammation.Epideminological studies have showed that patients with psoriasis exhibit increased rates of cardiovascular disease,obesity,and type 2 diabetes,owing probably to the enhanced local and (or) systemic inflammation.The observations of anti-inflammatory actions of GLP-1,which exerts direct and indirect actions on immune function,together with the improved psoriasis,offer new insights into the investigation of non-classical anti-inflammatory actions of incretin-based therapeutics and provide a new direction for the research of the novel clinical application of GLP-1.%肠促胰素治疗具有越来越多的胰外作用,最近有病例报道胰升糖素样肽1( GLP-1)受体激动剂治疗能缓解银屑病的临床症状.银屑病是以慢性炎症为特征的常见皮肤病变,流行病学研究发现银屑病患者的心血管疾病、肥胖和糖尿病的发生率增加,这可能与增加的局部和(或)全身的炎症有关.GLP-1受体激动剂可以通过直接或间接的机制影响免疫功能产生抗炎作用,从而改善银屑病症状,这为进一步研究肠促胰素的非经典的抗炎机制提供了新的切入点,同时对拓展GLP-1的临床应用也提供了一个新的研究方向.

  5. Glucagon-like peptide-1 modulate sucrose solution intake in rats%胰高血糖素样肽-1对大鼠糖溶液摄入的影响

    王倩; 曹健; 朱永香; 杜俊凯

    2014-01-01

    目的:激活外周胰高血糖素样肽-1(GLP-1)受体,观察大鼠对可口蔗糖溶液摄入量及其喜好率的变化,探讨其参与摄食调控的可能机制。方法:给予大鼠腹腔注射Exendin-4(GLP-1受体激动剂)0.5μg/100g或同量生理盐水,利用双瓶选择实验,测量大鼠对8%蔗糖溶液/蒸馏水的摄入量,计算对蔗糖溶液的喜好率。结果:Exendin-4组与生理盐水组相比,大鼠摄入8%蔗糖溶液的量、对蔗糖溶液的喜好率以及3h总液体摄入量均显著减少(P<0.05),但对蒸馏水的摄入无显著影响(P>0.05)。结论:激动GLP-1外周受体后,可降低大鼠对蔗糖溶液的喜好程度,进而抑制对可口溶液的摄入。%Objective:To explore the effects of the periphery glucagon-like peptide-1(GLP-1) receptors in modulating sucrose solution intake in rats .Methods:The rats received intraperitoneal injection of GLP-1 receptors agonist exendin-4 or saline ,and then underwent two bottle choice test between 8% sucrose solution and distilled wa-ter .We measured the sucrose solution/distilled water intake and preference ratio of sucrose solution .Results :Com-pared with saline injection ,intraperitoneal injection of exendin-4 significantly decreased 8% sucrose solution intake , the preference ratio of sucrose solution and the total fluid intake in rats during 3h ,but had no effect on the distilled water intake .Conclusion :These results suggest that activation of the periphery GLP-1 receptors may be involved in inhibition of the tasty sucrose solution intake by reducing the preference for it .

  6. Progress in glucagon like peptide-1 treatment of type 2 diabetes%胰高血糖素样肽-1类似物治疗2型糖尿病的研究进展

    班绎娟; 许樟荣

    2014-01-01

    胰高血糖素样肽-1(GLP-1)受体激动剂(GLP-1RA)艾塞那肽(exenatide)和利拉鲁肽(liraglutide)的作用机制是增加胰岛素分泌,抑制胰高血糖素释放,减轻胰岛素抵抗,抑制食欲并减缓胃排空。这些降糖作用具有葡萄糖浓度依赖性可避免严重低血糖。除了有确切的降糖作用外,还有降血压、保护心血管、减轻脂肪肝、调脂和减轻体质量的作用,动物实验中,这类药物有助于保护β细胞功能,可以安全地与二甲双胍、磺酰脲类药物、噻唑烷二酮类和胰岛素联合治疗糖尿病,其代表性药物利拉鲁肽和艾塞那肽为控制高血糖和降低体质量提供了另一种治疗选择。%Glucagon like peptide-1 (GLP-1) receptor agonists (GLP-1RA), exenatide and liraglutide, exert their hypoglycemic effects by enhancing the secretion of insulin, inhibiting the release of glucagon, reducing insulin resistance, suppressing appetite and inhibiting gastric emptying. These effects are in a glucose level-dependent manner so as to prevent severe hypoglycemia. In addition to these definite hypoglycemic effects, the agents also decrease blood pressure, protect heart and blood vessels, attenuate fatty liver and reduce body mass. In animal experiments, these GLP-1RA drugs protect the function of β cells, and are safely combined with metformin, sulfonylureas, thiazolidinediones and insulin in the treatment of diabetes. Exenatide and liraglutide, as representatives of GLP-1RA, are a good option to control blood glucose and reduce body mass for diabetic patients.

  7. 胰高血糖素样肽1及其类似物的研究进展%Glucagon-like Peptide 1 and Its Derivatives in the Treatment of Diabetes-preclinical and Clinical Results

    卞爱琳

    2011-01-01

    Glucagon-like peptide-1( GLP-1 ) is an incretin hormone released by the L cell of gut in response to meal intake. It may address many of the needs of diabetes treatment such as glucose concentration-dependent hypoglycemia and β-cell protection, low risk of hypoglycemia, weight loss, reduction hypertension and unique cardiovascular protection. GLP-1 receptor agonist ( incretin mimetic ), exenatide and liraglutide have long half-live because of their stability to enzymatic inactivation, especially liraglutide has longer half-live and high homology to the native hormone. Preclinical and clinical results showed that exenatide and liraglutide significantly improved glucose control and decreased risks of cardiovascular with low rates of hypoglycemia occurrence. GLP-1 receptor agonist has unique ad-vantages for type 2 diabetes mellitus treatment and cardiovascular disease risk prevention.%胰高血糖素样肽1(GLP-1)是肠道L细胞分泌的肠促胰岛素激素,具有葡萄糖浓度依赖型降糖作用及β细胞保护作用,同时还具有减重、降压和降脂等心血管系统保护作用.艾塞那肽和利拉鲁肽均是天然GLP-1类似物,利拉鲁肽与人GLP-1同源性更高,且为长效制剂,它们克服了天然GLP-1易被降解的特点,保留了GLP-1的各种生理作用和治疗优势,发挥GLP-1的多效作用,降糖、β细胞保护、减重、降压、调脂全面干预多种心血管危险因素,且低血糖风险低,安全性好.GLP-1在治疗2型糖尿病及防治心血管风险方面具有独特优势.

  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. Real-world medication persistence and outcomes associated with basal insulin and glucagon-like peptide 1 receptor agonist free-dose combination therapy in patients with type 2 diabetes in the US

    Lin J

    2016-12-01

    Full Text Available Jay Lin,1 Melissa Lingohr-Smith,1 Tao Fan2 1Health Economics and Outcomes Research, Novosys Health, Green Brook, NJ, USA; 2North America Medical Affairs, Sanofi US, Inc., Bridgewater, NJ, USA Background: Free-dose combination treatment with basal insulin and short-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs reduces hyperglycemia via complementary targeting of fasting and postprandial blood glucose levels, however, in the real world, due to injection burden and clinical inertia, the full efficacy may not be able to translate into clinical and economic benefits. Objective: The aim of the study was to evaluate treatment persistence and associated outcomes in patients with type 2 diabetes (T2D treated with a GLP-1 RA in free-dose combination with basal insulin. Methods: Claims data were extracted on US adults with T2D with ≥1 prescription claim for both a GLP-1 RA and a basal insulin from July 1, 2008 to June 30, 2013, and continuous health plan coverage for 6 months prior to (baseline and 12 months after the index date (follow-up period. Outcomes analyzed for patients stratified by treatment persistence included glycemic control, hypoglycemia, and health care costs and resource utilization. Multivariate analyses were used to examine factors associated with persistence or hypoglycemia. Results: The analysis included 7,320 patients, of whom 16.9% were persistent with free-dose combination treatment. The median time to treatment discontinuation was 133 days. Compared with ­nonpersistent patients, persistent patients had greater glycated hemoglobin A1c (A1C reductions (–0.80% vs –0.42%; P=0.032, were more likely to achieve A1C <7.0% (39% vs 22%; P<0.001, and were less likely to experience hypoglycemia (9.5% vs 6.8%; P=0.002. Persistent patients also had significantly fewer hospitalizations and shorter hospital stays. While prescription costs were significantly higher (all-cause: $14,691 vs $10,791; P<0.001; diabetes-related: $8

  10. Frog skin peptides (tigerinin-1R, magainin-AM1, -AM2, CPF-AM1, and PGla-AM1) stimulate secretion of glucagon-like peptide 1 (GLP-1) by GLUTag cells.

    Ojo, O O; Conlon, J M; Flatt, P R; Abdel-Wahab, Y H A

    2013-02-01

    Skin secretions of several frog species contain host-defense peptides with multiple biological activities including in vitro and in vivo insulin-releasing actions. This study investigates the effects of tigerinin-1R from Hoplobatrachus rugulosus (Dicroglossidae) and magainin-AM1, magainin-AM2, caerulein precursor fragment (CPF-AM1) and peptide glycine leucine amide (PGLa-AM1) from Xenopus amieti (Pipidae) on GLP-1 secretion from GLUTag cells. Tigerinin-1R showed the highest potency producing a significant (Ppeptide and 0.3nM for the reduced form. All peptides from X. amieti significantly (Ppeptide stimulated release of the cytosolic enzyme, lactate dehydrogenase from GLUTag cells at concentrations up to 3μM indicating that the integrity of the plasma membrane had been preserved. The data indicate that frog skin peptides, by stimulating GLP-1 release as well as direct effects on insulin secretion, show therapeutic potential as agents for the treatment of type 2 diabetes.

  11. Research Progress of Glucagon-Like Peptide-1 in the Treatment of Type 2 Diabetes Mellitus%基于胰高血糖素样肽-1的Ⅱ型糖尿病治疗研究进展

    李闻; 田浤; 高向东

    2013-01-01

    Ⅱ型糖尿病的治疗是现今研究关注的热点.现有的抗糖尿病药物由于副作用以及对病程恶化无显著改善而限制了其临床应用.基于胰高血糖素样肽-1(GLP-1)的药物为Ⅱ型糖尿病治疗提供了新的思路,主要包括GLP-1类似物及二肽基肽酶-Ⅳ (DPP-Ⅳ)抑制剂,其安全性和有效性已被大量的临床试验证明.GLP-1能够葡萄糖依赖地促进胰岛素分泌,且能够促进胰岛细胞的增殖,降低糖化血红蛋白浓度.文章就GLP-1及二肽基肽酶抑制剂用于Ⅱ型糖尿病治疗的研究作了综述.%The purpose was to review the current development of therapies of Type 2 diabetes mellitus (T2DM) based on Glucagon Like Peptidde-1 (GLP-1 ). According to domestic and foreign literatures, GLP-1 analogue obtained by several methods and their pharmacodynamic effect were summarized. Dipeptidyl peptidase IV inhibitors were also studied. The results showed that nowadays, therapies of T2DM are causing much more attention. Existing treatments have limitations either because of their side effects or little impact on disease progression. GLP-1-based therapies offer a new therapeutic approach to the management of T2DM,which include GLP-1 analogues and dipeptidyl peptidase-4( DPP-IV) inhibitors. The efficacy and safety of GLP-1-based therapies have been clearly demonstrated by a very large number of clinical trials. GLP-1 displays glucose-dependent stimulation of insulin secretion, trophic effects on the pancreatic β-cells and reduction of HbAlc. From these results it could be concluded that GLP-1 analogue and dipeptidyl peptidase IV inhibitors opens a new path for the treatment of diabetes as the unique pharmacodynamics and glucose regulation mechanism of GLP-1.

  12. Application prospect of glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease%胰高血糖素样肽-1受体激动剂在非酒精性脂肪性肝病中的应用前景

    李强; 卓其斌; 陈良; 黄玉仙

    2015-01-01

    胰高血糖素样肽-l受体激动剂(glucagon-like peptide-1 receptor agonists,GLP-1 RAs)是基于肠促胰岛素的一种新型降糖药物.最新的研究表明GLP-1 RAs可以通过改善肝酶水平、减少肝脏脂肪含量、减轻肝脏脂肪变性、减轻肝纤维化程度及治疗代谢综合征等方面改善非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)病情.GLP-1 RAs可能成为NAFLD患者很有前景的药物治疗方法,因此本文概述了GLP-1RAs在治疗NAFLD方面的一些研究进展,以便临床医师对NAFLD的治疗有更多的了解.

  13. T herapy strategy for inadequately controlled patients with type 2 diabetes:glucagon-like peptide-1 receptor agonists or insulin?%口服降糖药血糖控制不佳的2型糖尿病患者的新选择

    石勇铨

    2015-01-01

    对于口服降糖药血糖控制不佳的2型糖尿病患者,传统的治疗方法为起始胰岛素治疗,但是近些年,随着新型注射类药物胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)受体激动剂的面市,胰岛素也许不再是唯一的选择。那么,胰岛素和GLP-1受体激动剂哪种方案更适用于口服降糖药血糖控制不佳的2型糖尿病患者?本文将针对此问题作一综述,以期为糖尿病血糖管理提供新的选择。

  14. 胰升糖素样肽1药物对2型糖尿病患者的心血管保护效应%Cardiovascular protective effects of glucagon-like peptide-1 agents in patients with type 2 diabetes

    柯静; 魏蕊; 洪天配

    2015-01-01

    [Summary] Glucagon-like peptide-1 ( GLP-1 ) agents play important roles in glycemic control in type 2 diabetes. Moreover, these agents also show various protective effects on cardiovascular system. GLP-1 agents improve vascular endothelial function, ameliorate the risk factors of cardiovascular disease including obesity, hyperglycemia, dyslipidemia and hypertension, delay the occurrence and progression of atherosclerosis, and protect against cardiac ischemia-reperfusion injury and heart failure. Therefore, GLP-1 agents may have beneficial effects on cardiovascular diseases at different stages and in multiple aspects.%胰升糖素样肽1(GLP-1)药物在2型糖尿病患者的血糖控制中具有重要作用。此外,GLP-1药物还具有一定的心血管保护效应,其可改善血管内皮功能,缓解肥胖、高血糖、血脂异常、高血压等心血管危险因素,延缓动脉粥样硬化的发生和发展,改善心肌缺血-再灌注损伤和心力衰竭。因此,GLP-1药物在心血管疾病发生发展的不同阶段和环节中可能具有保护作用。

  15. 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...

  16. Construction of yeast strains expressing long-acting glucagon-like peptide-1 (GLP-1) and their therapeutic effects on type 2 diabetes mellitus mouse model%长效促胰岛素降糖酵母的构建及其对糖尿病模型小鼠的治疗效果

    吴日; 李淼; 尼钢钢; 马百成; 李明刚; 马超; 李晓丹; 段会坤; 姬艳丽; 王宇; 姜苹哲; 王海松; 屠培培

    2015-01-01

    Probiotics, i.e., bacteria expressing therapeutic peptides (protein), are used as a new type of orally ad-ministrated biologic drugs to treat diseases. To develop yeast strains which could effectively prevent and treat type 2 diabetes mellitus, we firstly constructed the yeast integrating plasmid pNK1-PGK which could successfully express green fluorescent protein (GFP) in Saccharomyces cerevisiae. The gene encoding ten tandem repeats of glucagon-like peptide-1(10×GLP-1) was cloned into the vector pNK1-PGK and the resulting plasmids were then transformed into the S. cerevisiae INVSc1. The long-acting GLP-1 hypoglycemic yeast (LHY) which grows rapidly and expresses 10×GLP-1 stably was selected by nutrition screening and Western blotting. The amount of 10×GLP-1 produced by LHY reached 1.56 mg per gram of wet cells. Moreover, the oral administration of LHY significantly reduced blood glucose level in type 2 diabetic mice induced by streptozotocin plus high fat and high sugar diet.%益生菌生物药物是指通过口服表达药用多肽(蛋白)的重组益生菌活细胞达到治疗疾病的新型口服给药系统。为了构建一种能有效防治2型糖尿病的酵母生物药物,文章首先构建了酿酒酵母(S.cerevisiae)整合型表达载体pNK1-PGK,并且通过绿色荧光蛋白(GFP)证明其表达功能正常,利用该载体将10×GLP-1(Glucagon-like peptide-1)基因转化到酿酒酵母INVSc1中,通过营养缺陷型和Western blotting成功筛选出表达10×GLP-1的长效促胰岛素降糖酵母(Long-acting GLP-1 hypoglycemic yeast, LHY)。该酵母生长迅速,外源基因10×GLP-1表达稳定,表达量达到1.56 mg/g细胞湿重。通过链脲佐菌素和高脂高糖饮食联合诱导的方法构建了2型糖尿病小鼠模型,用LHY对其进行口服灌胃治疗,证明LHY具有较好疗效,明显降低血糖水平。

  17. 胰高糖素样肽-1受体激动剂对甲状腺髓样癌细胞生长和增殖的影响%Effects of Glucagon Like Peptide-1 Receptor on Cell Growth and Proliferation of Patients with Medullary Thy-roid Carcinoma

    郭锐; 刘睿; 关海霞

    2016-01-01

    Objective To investigate expression of glucagon like peptide-1 (GLP-1) receptor in cell line TT and its effects on cell growth and proliferation of patients with medullary thyroid cancer (MTC). Methods Expression of GLP-1 receptor in cell line TT was detected using Western blot method. Effects of two kinds of GLP-1 receptor agonist on cell proliferation and calcitonin secretion were evaluated by methyl thiazolyl tetrazolium ( MTT) assay, and associated protein expressions of cell signal pathways were detected using Western blot method. Results GLP-1 receptor expression was detected in cell line TT. No significant differences of absorbance values at all time points were found in cell line TT after 1, 10 and 100 nmol/L Liraglutide or Exenatide treatment compared with those by 0 nmol/L Liraglutide or Exenatide treatment, and there was no significant difference between same concentration of Liraglutide or Exenatide groups at the same time (P>0. 05). No significant differences of calcitonin concentration were found after cell line TT was treated by different concentrations Liraglutide or Exenatide for 24 h ( P>0. 05 ) . No significant changes of Akt and Erk1/2 phos-phorylation levels were found after 1, 10 and 100 nmol/L Liraglutide or Exenatide treatment compared with those by 0 nmol/L Liraglutide or Exenatide treatment. Conclusion GLP-1 receptor can be expressed in human MTC cell line TT, but GLP-1 receptor agonist has no obvious effect on cell proliferation, calcitonin secretion and associated protein expres-sions of cell signal pathways.%目的:探讨胰高糖素样肽-1(glucagon like peptide-1, GLP-1)受体在甲状腺髓样癌(medullary thyroid cancer, MTC)细胞系TT的表达情况及其对该细胞生长和增殖的影响。方法蛋白免疫印迹( Western blot)法检测TT细胞系GLP-1受体表达情况,采用甲基噻唑基四唑( MTT)评估两种GLP-1受体激动剂对细胞增殖及降钙素分泌的作用,Western blot法测定细胞信号通路

  18. Liraglutide, a human glucagon-like peptide-1 analogue, plays a role in reducing body weight in the patients with type 2 diabetes%人胰升糖素样肽1类似物利拉鲁肽减轻2型糖尿病患者体重的作用

    邹大进

    2011-01-01

    肥胖与多种代谢异常相关,包括胰岛素抵抗和2型糖尿病.减轻体重能有效改善胰岛素敏感性,并由此降低肥胖相关的2型糖尿病和心血管疾病风险.研究证实,人胰升糖素样肽1(GLP-1)类似物利拉鲁肽不论单用还是与其他降糖药物联用,都可更好地控制血糖,保护胰岛β细胞功能,并通过抑制摄食和延缓胃肠蠕动减轻体重,这为2型糖尿病患者的治疗提供了新的选择.%Obesity is associated with numerous metabolic abnormalities, including insulin resistance and type 2 diabetes. Losing weight is an effective way of improving insulin sensitivity, thus decreasing the risk of obesityassociated diabetes and chronic cardiovascular disease. There is evidence that Liraglutide, as a human glucagon-like peptide-1 ( GLP-1 ) analogue, either using alone or combining with other glucose-lowering drugs, has effect on improving glycemic control, protecting β-cell function, and reducing body weight via inhibiting feeding behavior and delaying gastrointestinal motility. Therefore, liraglutide is a new option for treating type 2 diabetes patients.

  19. Research Progress of Glucagon-like Peptide-1and Analogues for Cardiovascular Disease%胰高血糖素样肽-1及类似物在心血管疾病的作用及研究进展

    庾辉

    2011-01-01

    Diabetes and cardiovascular disease are closely related. Patients with diabetes are characterized by an increased risk of cardiovascular disease, such as coronary heart disease, heart failure, atherosclerosis and hypertention. Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine L cell in response to nutrient ingestion. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentration, and its characteristic which has led to its analogues as a treatment for type 2 diabetes mellilus. Recent studies have demonstrated that GLP-1 and its analogues may have wide-ranging cardiovascular actions. This review will discuss their emerging cardiovascular actions and mechanisms.%糖尿病与心血管疾病密切相关,合并糖尿病更易发生冠状动脉粥样硬化性心脏病,心力衰竭、动脉粥样硬化、高血压等心血管疾病.胰高血糖素样肽-1是一种主要由肠L细胞分泌的肠促胰素,具有葡萄糖浓度依赖性降糖作用,其类似物已用于2型糖尿病治疗.研究发现胰高血糖素样肽-1及类似物可能具有心血管保护作用,现就近年来有关胰高血糖素样肽-1及类似物心血管作用及机制的研究进展做一综述.

  20. The role of glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease%胰升糖素样肽-1受体激动剂对非酒精性脂肪性肝病的影响

    郭立新

    2014-01-01

    胰升糖素样肽-1(GLP-1)受体激动剂是基于肠促胰素治疗2型糖尿病的药物.近年来临床应用发现其除具有良好的血糖控制作用外,尚具有降糖外效应,本文着重讨论了其对非酒精性脂肪性肝病(NAFLD)的改善作用 了解和探讨GLP-1受体激动剂对NAFLD的治疗作用及其内在机制,对于认识糖尿病的发病机制,糖尿病与NAFLD的相互关系,对糖尿病及NAFLD的药物研发都具有重要的意义.本文就GLP-1受体激动剂对NAFLD的作用进行简述.%Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin-based drugs for type 2diabetes.In recent years,it has been proven in clinical practices that GLP-1 receptor agonists have protection effect beyond anti-hyperglycemic effects,such as improvement of non-alcoholic fatty liver disease (NAFLD).The cogent evaluation,understanding,and exploration of therapeutic effect and mechanism of GLP-1 receptor agonists in NAFLD are important.Besides,it would be of great significance to identify pathogenesis of diabetes,its correlation with NAFLD,and the development of new drugs.This article briefly reviews the therapeutic effect of GLP-1 receptor agonists on NAFLD.

  1. GLP-1对骨骼、中枢神经系统的影响及其机制研究进展%The research of the effects of glucagon-like peptide-1 on bone metabolism and central nervous system and its mechanism

    刘璐_; 戴如春

    2016-01-01

    [Summary] _ Osteoporosis and diabetes mellitus are diseases which affect public heath severely, and osteoporotic fracture risk is increased in patients with diabetes. During recent years, new anti-diabetes drugs glucagon-like peptide-1(GLP-1) analogues and its receptor agonists had been used for diabetes treatment. As the research continues, besides of anti-diabetes, GLP-1 analogues are also found to play a role in bone metabolism and central nervous system by stimulating bone formation, inhibiting bone resorption, and nerve protection/nutrition, etc, suggesting that it may play an important role in the treatment of other diseases such as osteoporosis.%骨质疏松症同糖尿病均是严重影响公共健康的重大疾病,且糖尿病患者发生骨折的风险升高。近年来,新型降糖药物胰升糖素样肽1( GLP-1)类似物及其受体激动剂均已应用于治疗2型糖尿病。随着研究不断深入,GLP-1不仅具有降糖作用,还发挥促进骨形成、抑制骨吸收及神经保护/神经营养等效应,这提示其可能在骨质疏松症等其他疾病的治疗中也发挥重要作用。

  2. 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.

  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 ...

  4. The physiology of glucagon-like peptide 1

    Holst, Jens Juul

    2007-01-01

    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 agonists...

  5. 胰高糖素样肽-1受体激动剂对甲状腺乳头状癌细胞生长和增殖的影响%Effect of agonist for Glucagon like peptide-1 receptor on growth and proliferation in papillary thyroid cancer cell

    刘睿; 王红; 郭慧玲; 关海霞; 单忠艳; 滕卫平

    2015-01-01

    目的:探讨甲状腺癌细胞中胰高糖素样肽-1(Glucagon like peptide-1,GLP-1)受体的表达情况,及其对癌细胞生长和增殖的影响.方法:Western blot法检测甲状腺乳头状癌(Papillary thyroid cancer,PTC)细胞系GLP-1受体表达情况.采用四甲基偶氮唑蓝法(MTT)评价两种GLP-1受体激动剂艾塞那肽和利拉鲁肽处理后细胞增殖情况.Western blot法测定细胞中蛋白激酶B(Protein kinase B,Akt)及细胞外信号调节蛋白激酶1/2(Extracellular signal-regulated kinase 1/2,Erk1/2)等细胞信号通路相关蛋白的表达.结果:PTC细胞系BCPAP、TPC-1中均可检测到GLP-1受体的表达.艾塞那肽和利拉鲁肽分别以1 nmol/L、10noml/L和100nmol/L作用于细胞24h、48h和72h后,实验组细胞增殖率与对照组相比无统计学差异.不同浓度艾塞那肽和利拉鲁肽作用细胞24h后,实验组Akt和Erk蛋白表达水平及其磷酸化程度与对照组相比无统计学差异.结论:人甲状腺乳头状癌细胞中有GLP-1受体的表达.但是,GLP-1受体激动剂对甲状腺癌细胞的增殖无明显促进作用.同时,GLP-1受体激动剂对与细胞增殖密切相关的Akt和Erk通路无明显作用.

  6. Glucagon-like peptide-1 excites firing and increases GABAergic miniature postsynaptic currents (mPSCs in gonadotropin-releasing hormone (GnRH neurons of the male mice via activation of nitric oxide (NO and suppression of endocannabinoid signaling pathways

    Imre Farkas

    2016-09-01

    Full Text Available Glucagon-like peptide-1 (GLP-1, a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM–5 μM elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9-39 (1 μM. Intracellular application of the G-protein inhibitor GDP-beta-S (2 mM impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO synthesis by L-NAME (100 μM or NPLA (1 μM or intracellular scavenging of NO by CPTIO (1 mM partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using CB1 inverse-agonist AM251 (1 μM. Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the TRPV1-antagonist AMG9810 (10 μM or the FAAH-inhibitor PF3845 (5 μM impeded the GLP-1-triggered endocannabinoid pathway indicating an anandamide-TRPV1-sensitive control of 2-AG production. Furthermore, GLP-1 immunoreactive axons innervated GnRH neurons in the hypothalamus suggesting that GLP-1 of both peripheral and neuronal sources can modulate GnRH neurons. RT-qPCR study confirmed the expression of GLP-1R and nNOS mRNAs in GnRH-GFP neurons. Immuno-electron microscopic analysis revealed the presence of neuronal nitric oxide synthase (nNOS protein in Gn

  7. Comparison of glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mettilus%GLP-1受体激动剂与二肽基肽酶4抑制剂治疗2型糖尿病的比较

    骆天红

    2012-01-01

    随着对肠促胰素在维持葡萄糖稳定作用认识的日益增多,促进了针对2型糖尿病患者肠促胰素活性缺乏治疗药物的研发.根据肠促胰素治疗药物不同的作用机制,可分为以下2类:(1)胰升糖素样肽1(GLP-1)受体激动剂,包括利拉鲁肽(liraglutide)、艾塞那肽每日2次制剂和艾塞那肽每周1次制剂;(2)二肽基肽酶4(DPP-4)抑制剂,包括西格列汀(sitagliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)和维格列汀(vildagliptin),DPP-4抑制剂可限制内源性GLP-1的降解.这2类药物具有某些共性,如葡萄糖依赖性刺激胰岛素分泌,低血糖发生率低.然而这2类药物在疗效方面的表现却有所不同.本文综述了这2类基于肠促胰素治疗药物的药代动力学及其临床方面的疗效和安全性,阐明了此类药物在2型糖尿病治疗中的地位.%Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus.lncretin-based therapies could be classified into 2 categories with different mechanisms of action:glucagon-like peptide 1 ( GLP-1 ) receptor agonists ( e.g.liraglutide,exenatide twice daily,and exenatide once weekly),and the dipeptidyl peptidase 4 ( DPP-4 ) inhibitors ( e.g.sitagliptin,linagliptin,saxagliptin,and vildagliptin),which inhibit the breakdown of endogenous GLP-1.Both categories share some specific characteristics,such as glucose-dependent insulin stimulation and low incidence of hypoglycemia.But there are also different profiles in efficacy between these 2 classes.This article reviews the pharmacokinetics and clinical aspects of efficacy and safety of these 2 classes of incretin-based therapies and elucidates their roles in treating type 2 diabetes mellitus.

  8. 2型糖尿病应用胰高血糖素样肽-1受体激动剂治疗的效果探讨%Discussion Glucagon-Like Peptide-1 Receptor Agonist Treatment of Type 2 Diabetes Application Effect

    敖文

    2015-01-01

    Objective To study the glucagon-like peptide -1 (GLP-1) receptor agonist clinical efficacy in patients with type 2 diabetes.Methods June 2008~June 2009 was diagnosed with type 2 diabetes in 54 patients for the study, and were randomly divided into two groups, the control group were treated with oral medications metformin, the test group of patients affected by the addition of GLP-1 agonist treatment.Results The experimental group in triglycerides, LDL, total cholesterol, transaminases, apolipoprotein -2 aspect compared with the control group, the experimental group was significantly lower, but little change in the control group, a statisticaly significant difference between groups (P<0.05); overal patient outcomes after the experimental group Mann-Whitney U rank sum test was significantly better than the control group, there was a significant difference statisticaly significant (P<0.01).Conclusion The clinical efficacy of GLP-1 receptor agonists in patients with type 2 diabetes significantly help to reduce the incidence of complications. worth in the clinical application and promotion.%目的 研究胰高血糖素样肽-1(GLP-1)受体激动剂对2型糖尿病患者的临床疗效.方法 选取2008年6月~2009年6月被确诊为2型糖尿病的54例患者为研究对象,并随机分为两组,对照组患者给予口服二甲双胍药物,试验组患者加用GLP-1受体激动剂治疗.结果试验组在甘油三酯、低密度脂蛋白、总胆固醇、转氨酶、载脂蛋白-2方面与对照组相比,试验组明显降低,而对照组变化不大,组间差异具有统计学意义(P<0.05);试验组患者整体治疗效果经Mann-Whitney U秩和检验后显著性优于对照组,存在显著性差异,具有统计学意义(P<0.01).结论 GLP-1受体激动剂对2型糖尿病患者的临床疗效显著,有利于减少并发症的发生.

  9. Effects of Glucagon-like Peptide-1 Receptor Agonists on Weight and β-cell Function in Newly Diagnosed Type 2 Diabetic Patients%胰高血糖素样肽-1类似物对2型糖尿病患者体质量及胰岛β细胞的影响

    叶林秀; 郭昆全; 朱梅; 阮华玲; 孙雪; 周丽荣; 杨坤; 邱红

    2013-01-01

    目的:探讨胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)类似物对2型糖尿病患者体质量及胰岛β细胞功能的影响.方法:新诊断的超重或肥胖2型糖尿病(DM)患者96例,随机分为GLP-1类似物治疗组(GLP-1组,n=40)及二甲双胍对照组(二甲双胍组,n=56),比较2组患者治疗前后腰围、体质量指数(Body Mass Index,BMI)、糖代谢指标(FPG,2 h PG,HbA1c)及胰岛β细胞功能的变化.结果:(1)治疗4月后与治疗前比较,两组FPG、2 h PG、HbA1C、FA均下降,GLP-1组2 h CP和腰围下降,差异均有统计学意义(P<0.05);(2)与二甲双胍组比较,GLP-1组HbA1c达标率更高(P<0.05),FCP和腰围改善明显,差异有统计学意义(P<0.05).对患者按体质量指数基线分层后,中重度肥胖2型糖尿病患者(BMI> 30 kg/m2)接受GLP-1治疗后体质量及腰围均下降;(3)多元逐步回归分析显示:FBG、BMI为FCP的重要影响因素,腰围、2 h PG为2 hCP的重要影响因素.结论:GLP-1类似物能有效改善2型糖尿病患者β细胞功能,降低空腹及餐后血糖,对中重度肥胖者兼有减重作用.%Objective To evaluate effects of glucagon-like peptide-1 receptor agonists on weight loss and β-cell function in overweight or obese patients with type 2 diabetes.Methods A total of 96 overweight or obese type 2 diabetic patients were randomly divided into GLP-1 group(n =40) and metformin group (n =56).The glycometabolism parameters including fasting plasma glucose(FPG),C-peptide(CP),oral glucose 2 h plasma glucose(2 h PG),2 h CP and hemoglobin(HbAlc),body mass index(BMI),waistline and β-cell function were measured.The changes of above indexes before and after therapy were compared between two groups.Results (1)Compared with before therapy,the levels of FPG,2 h PG,HbA1c,FA were significantly decreased in both group after therapy for 4 months,the 2 h CP and waistline were significantly decreased in GLP-1 group as well(all P <0.05) ;(2)Compared with metformin

  10. 胃旁路手术对糖耐量正常犬血糖、糖依赖性胰岛素释放肽和胰高血糖素样肽-1的影响%The effects of gastric bypass procedures on blood glucose, gastric inhibitory polypeptide and glucagon-like peptide-1 of normal glucose tolerance dogs

    潘立镇; 白日星; 宋茂民; 李有国; Lisa Zhou; 钟志强; 许俊; 袁辉生; 崔真

    2013-01-01

    目的 通过对糖耐量正常犬行胃旁路手术,观察术后糖耐量、糖依赖性胰岛素释放肽(gastric inhibitory polypeptide,GIP)和胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)的变化,探讨胃旁路手术治疗2型糖尿病的机制.方法 选取6只糖耐量正常犬行胃旁路手术,于术前、术后1、2、4周行口服与静脉糖耐量实验,观察各时点血糖、胰岛素、GIP、GLP-1变化,以及术前、术后4周胰腺组织形态改变.结果 与术前比较,术后第2周空腹血糖[(3.58 ±O.33) mmol/L]明显降低(t=3.571,P<0.05);术后第1周空腹及口服葡萄糖后30 min时GLP-1升高[分别为(0.90±0.21)、(0.91±0.19) pmol/L,t=-3.660、-2.971,P<0.05],第2周时开始下降;术后第4周各指标基本恢复至术前水平.术后第4周时与术前比较,胰岛组织形态、胰岛数量(分别为6.8±0.8、7.1±0.8)及胰岛细胞数量(分别为16.7±2.5、16.3±3.1)均无明显变化(P>0.05).结论 胃旁路手术对糖耐量正常犬的血糖、胰岛素及部分糖尿病相关胃肠激素仅有短暂的影响.%Objective To observe postoperative glucose tolerance,gastric inhibitory polypeptide (GIP),and glucogan-like peptide-1 (GLP-1) in normal glucose level dogs after undergoing gastric bypass procedures,and to explore the mechanism of gastric bypass procedures to treat type 2 diabetes.Methods The 6 dogs with normal glucose tolerance had undergone gastric bypass procedures,and measure preoperative and postoperative oral and intravenous glucose tolerance (at time points 1,2,and 4 weeks) through changes in blood glucose,insulin,gastric inhibitory polypeptide (GIP),glucagon-like peptide-1 (GLP-1),and measure preoperative and postoperative week 4 pancreatic tissue morphology.Results Second weeks after operation,the fasting blood sugar was (3.58 ± 0.33) mmol/L,and significantly lower than preoperative (t =3.571,P <0.05).The GLP-1 level before oral glucose tolerance test (OGTT) and 30 minutes after

  11. Protective Effects of Glucagon-like Peptide-1 Against Lung Ischemia-reperfusion Injury in Rats and The Initial Exploration for Its Mechanism%胰高糖素样肽1对大鼠肺缺血再灌注损伤的影响

    叶克俭; 张晓隆; 邱晓晓; 戴雍月

    2012-01-01

    Objective To observe protective effects of Glucagon - like peptide - 1 against lung ischemia - reperfusion injury in rats and investigate its potential mechanism. Methods Single lung in situ ischemia - reperfusion animal model was used. 40 SD rats were randomly divided into four groups; sham - operation group(S group, n = 10) , ischemia - reperfusion group(I/R group, n = 10) , dipepti-dyl peptidaselV inhibitors group(VP group, n = 10) and Glucagon -like peptide -1 + dipeptidyl peptidaselV inhibitors group (G group, n = 10). The VP group underwent the same experiment procedure as I/R group in addition to valine pyrrolidide(20mg/kg) injected sub-cutaneously just before ligation 30min. In the G group, an intravenous infusion of GLP - 1 [4. 8pmol/( kg -min) ] continued throughout the procedure, besides the treatment of VP. Malondialdehyde (MDA) , superoxide dismutase (SOD) and xanthine oxidase (XO) in serum were measured. The lung tissue sampled was assayed for wet/dry weight ratio (W/D) , contents of myeloperoxidase( MPO) at the end of the experiment, and ultrastructural changes were observed under electron microscope. Results The results showed that XO and MDA increased and SOD decreased in serum in I/R group and VP group, while the same changes happened in G group but less severely(P < 0. 01). The value of W/D and MPO was much higher in I/R group and VP group, but decreased in G group( P < 0. 01). Electron microscope showed obvious ultrastructural injury brought by LIRI in I/R group and VP group, which was greatly attenuated in G group. Conclusion GLP - 1 may attenuate lung ischemia - reperfusion injury through dropping oxygen free radical level, decreasing lipid perox-idation and inhibiting of neutrophil aggregation.%目的 探讨胰高糖素样肽1(GLP-1)对大鼠肺常温缺血再灌注损伤的影响.方法 健康SD大鼠40只,随机分为假手术组(S组)、缺血再灌注组(IR组)、二肽基肽酶Ⅳ抑制剂组(VP组)和胰高糖素样肽1+二肽基肽酶

  12. 胃转流术对2型糖尿病大鼠胰高血糖素样肽1及小肠黏膜的影响%The mechanism of glucagon-like peptide-1 on hypoglycemic effect of diabetic type 2 rats treated by gastric bypass operation

    任泽强; 章红; 张蓬波; 黄智龙; 张秀忠; 陈守坤

    2014-01-01

    目的 观察胃转流术(GBP)对2型糖尿病大鼠胰高血糖素样肽1(GLP-1)及小肠黏膜的影响,探讨GBP术降糖机制.方法 健康雄性SD大鼠随机分为正常手术组(NO组)、正常对照组(NC组)、糖尿病手术组(DO组)、糖尿病对照组(DC组).术前及术后第1、2、4、8周分别检测各组GLP-1、空腹血糖(FPG)、胰岛素.术后2个月苏木素-伊红(HE)染色观察末段回肠黏膜病理变化,测量肠黏膜厚度和绒毛高度.结果 DO、NO组GBP术后第8周空腹GLP-1分别由术前的(7.38±1.71) pmol/L和(7.23±1.59) pmol/L升高到(17.80±1.39) pmol/L和(15.48±1.21) pmol/L(P<0.05).DO组术后第8周FPG由术前的(17.71 ±1.99) mmol/L下降到(5.95 ±0.51) mmol/L (P<0.05).术后各时相点DO组GLP-1、FPG明显低于相应时间点DC组(P<0.05),NO组手术前后FPG无明显变化.DO组术后第8周胰岛素由术前的(11.93±0.75) mmol/L升高到(14.80±0.78) mmol/L(P<0.05).DO、NO组肠黏膜厚度和绒毛高度均显著高于DC组和NC组(P<0.05).结论 GBP术后肠黏膜的增生导致GLP-1升高可能为降糖机制之一.%Objective To observe the and influence on intestinal mucosa on type 2 diabetes rats and to research the function of glucagon-like peptide-1 (GLP-1).Methods Healthy male SD rats were randomly divided into normal operation group (NO),normal control group (NC),diabetic operation group (DO) and diabetic control group (DC).The GLP-1,plasma glucose and insulin were tested preoperatively and 1,2,4,8 weeks postoperatively.Intestinal mucosa were examined by hematoxylin and eosin (HE) stain 2 months after operation.The mucosal thickness and villus height were measured by histological analysis.Results The DO group' s and NO group' s GLP-1 increased from (7.38 ± 1.71) pmol/L and (7.23 ± 1.59) pmol/L to (17.80 ± 1.39) pmol/L and (15.48 ± 1.21) pmol/L (P < 0.05) at 8th week after gastric bypass operation respectively.The GLP-1 level of DO group was higher than that of DC and NC groups

  13. 胰高糖素样肽-1受体激动剂对人甲状腺髓样癌细胞生长和能量代谢的影响%Effect of glucagon-like peptide-1 receptor agonists on growth and energy metabolism in human medullary thyroid cancer cells

    王红; 张斯亮; 关海霞

    2016-01-01

    背景与目的:胰高糖素样肽-1(glucagon like peptide-1,GLP-1)受体激动剂是一种新型降糖药。在研发过程中,发现其可增加啮齿类动物患甲状腺C细胞肿瘤的风险。因此,该药物对人类甲状腺的影响引人关注。本研究旨在探讨GLP-1受体激动剂对人甲状腺髓样癌(medullary thyroid cancer,MTC)细胞增殖、降钙素的分泌和能量代谢的影响。方法:体外培养人MTC细胞系(TT)。分别以0、1、10和100 nmol/L艾塞那肽和利拉鲁肽处理细胞24、48和72 h后,采用细胞计数试剂盒(cell counting kit-8,CCK-8)检测GLP-1受体激动剂艾塞那肽和利拉鲁肽处理后细胞增殖情况;采用降钙素试剂盒测定细胞培养上清液中降钙素水平的变化;采用Seahorse能量代谢分析仪检测细胞糖酵解及线粒体呼吸的变化。结果:实验组细胞增殖率与对照组相比,差异无统计学意义(P>0.05),降钙素的量与对照组相比,差异无统计学意义(P>0.05),不同浓度艾塞那肽和利拉鲁肽处理细胞24 h后,与对照组相比,实验组艾塞那肽和利拉鲁肽对MTC细胞能量代谢并无明显影响(P>0.05),随着艾塞那肽和利拉鲁肽处理时间延长,TT细胞糖酵解和线粒体呼吸并无明显改变(P>0.05)。结论:GLP-1受体激动剂对人MTC发生、发展无明显促进作用,未来仍需大规模临床数据进一步证实GLP-1受体激动剂的安全性。%Background and purpose:This study aimed to investigate the effect of glucagon-like peptide-1 receptor agonists on proliferation, secretion of calcitonin and energy metabolism of medullary thyroid cancer (MTC) cell.Methods:The MTC cell line (TT) was culturedin vitro. After treatment with exenatide and liraglutide (0, 1, 10 and 100 nmol/L) for 24, 48 and 72 h, the proliferation of TT was analyzed by CCK-8 kit, the calcitonin was measured by calcitonin assay kits, and the energy metabolism of TT was measured by Seahorse XF

  14. 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。

  15. 不同营养餐对单纯性肥胖患者胰高糖素样肽-1的影响研究%Effect of meals with different nutrient contents on glucagon like peptide-1 in simple obesity

    李青; 曹卫娟; 周国艳; 谢安艳; 阳丽辉

    2015-01-01

    Objective To explore the effect of meals with different nutrient contents on glucagon like peptide-1(GLP-1) in simple obesity patients. Methods 40 cases of simple obesity with comparable age, sex and body mass index were en-rolled in our study and were randomly divided into four groups, who received corresponding isocaloric diets: high carbohydrate diet(HCD), high protein diet(HPD), high fat diet(HFD) and mediterranean diet (MD). Fasting and 2-hour postprandial blood samples were collected to measure blood sugar, plasma insulin and GLP-1, simultaneously. Results 1) Compared to patients in groups of HPD, HFD and MD, HCD group had significantly higher levels of 2-hour postprandial blood sugar and plasma insu-lin, but lowest levels of stimulated GLP-1. 2) When compared to groups of HPD and HFD, MD group had lowest levels of 2-hour postprandial blood sugar. 3) HPD group showed significantly higher levels of 2-hour postprandial blood sugar than HFD group. Conclusion In simple obesity patients, HCD tends to aggravate insulin resistance, and lowered levels of GLP-1 results in in-sulin releasing relatively deficient, which leads to high postprandial blood sugar. In advantage of inducing insulin resistance not quiet easy and can stimulating GLP-1 high secretion, MD will become a preferred balanced diet for obesity people.%目的:探讨单纯性肥胖患者在进食不同营养餐对胰高糖素样肽-1(GLP-1)的影响。方法:选择年龄、性别、体质指数基本匹配的40例单纯性肥胖患者随机分4组,各10例分别进食等热量的高碳水化合物饮食(HCD)、高蛋白饮食(HPD)、高脂饮食(HFD)、地中海饮食(MD),同步检测空腹及餐后2h 血糖、血浆胰岛素及 GLP-1水平。结果:与进食 HPD 组、HFD 组、MD 组比较,HCD 组的餐后2h 血糖、餐后2h 血浆胰岛素高,而刺激 GLP-1分泌的水平低;MD 组较 HPD 组、HFD 组餐后2h 血浆胰岛素分泌低;与 HFD 组对比,HPD

  16. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

    Farkas, Imre; Vastagh, Csaba; Farkas, Erzsébet; Bálint, Flóra; Skrapits, Katalin; Hrabovszky, Erik; Fekete, Csaba; Liposits, Zsolt

    2016-01-01

    Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM–5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9–39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N5-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid

  17. 胰升糖素样肽1类似物治疗2型糖尿病有效性和安全性的系统评价%Systematic review of efficacy and safety of glucagon-like peptide-1 analogue in the treatment of type 2 diabetes

    李晓华; 任健俐; 王荣环

    2011-01-01

    Objective To systematically review the efficacy and safety of glucagon-like peptide (GLP)-1analogue in the treatment of type 2 diabetes. Methods Literature search was conducted through Pubmed, Ovid, SpringerLink, Cochrane, CBM and Wanfang data by the end of September 2010. The selection of studies, assessment of methodological quality and data extraction were performed according to Cochrane Handbook for systematic reviews and predefined criteria. Meta analysis was carried out by the use of software RevMan4.2 and descriptive qualitative analysis was done when necessary. Results Twenty-three clinical trials met the inclusion criteria. The results of Meta-analysis indicated that GLP-1 analogue group showed better clinical outcomes than placebo group and other antidiabetic drug group, regarding the reduction of HbA1c and loss of body weight. Compared with placebo group, GLP-1 analogue group had higher hypoglycaemia rate, which was similar to the rate in other antidiabetic drug group. GLP-1 analogue group had high risk of gastrointestinal side effects. Conclusions The evidence currently available suggests that GLP-1 analogue has good efficacy and tolerability. The common adverse effects are gastrointestinal side effects.%目的 系统评价胰升糖素样1肽(GLP-1)类似物治疗2型糖尿病的有效性和安全性.方法 计算机检索Pubmed、Ovid、SpringerLink、Cochrane图书馆、中国生物医学文献数据库(CBM)及万方数据库.检索时间由建库截至2010年9月.按Cochrane系统评价的方法 评价研究的质量,应用RevMan4.2软件进行Meta分析;不能合并的数据,进行描述性分析.结果 本研究共纳入23个随机对照试验进行分析.Meta分析结果 显示在降低糖化血红蛋白[加权均数差(WMD)=-0.89,95%可信区间(CI)-1.02~-0.77,P<0.01]和降低体重方面(WMD=-1.16,95% CI-1.75~-0.56,P<0.01),GLP-1类似物组均优于安慰剂组或其他降糖药组.GLP-1类似物组的低血糖事件

  18. 胰高血糖素样肽-1受体激动剂对初发2型糖尿病患者血脂代谢影响的研究%Effects of glucagon-like peptide-1 receptor agonists on plasma lipid metabolism of primary type 2 diabetics

    李沫; 蔡寒青; 刘煜; 沈鸿

    2013-01-01

    目的:本课题观察胰高血糖素样肽-1( GLP-1)受体激动剂对2型糖尿病患者的治疗,通过对转氨酶、糖化血红蛋白、血脂及脂质运载蛋白-2的检测,探讨胰高血糖素样肽-1受体激动剂与血脂代谢间的关系,从而更有利于对2型糖尿病患者慢性并发症的控制。方法给药方法:两组初发2型糖尿病患者均口服二甲双胍1500 mg,根据治疗方式不同随机分成两组:二甲双胍联合GLP-1组(GL)24例,二甲双胍联合生理盐水组( NS)24例,共给药16周。试验中随访体重指数、转氨酶、糖化血红蛋白、血脂及载脂蛋白-2。试验前3周为导入期,均注射生理盐水1 ml,皮下注射;第4~7周GL组给予GLP-1受体激动剂5μg,每日2次;第8~16周给予GLP-1受体激动剂10μg,每日2次。结果(1)两组体重、体重指数、糖化血红均降低( P<0.05)。(2)GL组甘油三酯、总胆固醇、低密度脂蛋白、载脂蛋白-2明显降低(P<0.05),NS组无明显降低(P>0.05)。(3)GL组转氨酶明显降低(P<0.05)。结论二甲双胍或二甲双胍联合应用GLP-1受体激动剂均可降低初发2型糖尿病患者的体重及糖化血红蛋白。 GLP-1可更加显著地降低糖尿病患者甘油三酯、总胆固醇、低密度脂蛋白、脂质运载蛋白-2的水平。%Objective To observe the effect of glucagon-like peptide-1 receptor agonists ( GLP-1 ) on the lipid metabolism of primary type 2 diabetes by testing transaminase ,HbA1c,LCN-2.Methods All patients were randomly divided into two groups:GL group(n=24):treatmented with oral metformin(500 mg,3 times a day)and GLP-1 injection(5 μg,2 times a day for 4 weeks;10μg,2 times a day for 9 weeks).NS group(n=24):treated with oral metforminand normal saline injection for 16 weeks.Patients weight,transaminases,glycosylated hemoglobin,lipids and lipocalin-2 were followed up .Results After treatment ,the weight ,body

  19. GLP-1受体激动剂对小鼠棕色脂肪细胞基因表达和细胞分化的研究%Research on glucagon-like peptide-1 receptor agonist on the function and differentiation of brown adipocytes in mice

    沈山梅; 石欢; 毕艳; 冯文焕; 王维敏; 金玺; 韩小娟; 胡明玥; 朱大龙

    2013-01-01

    Objective To investigate the effects of glucagon-like peptide-1 (GLP-1) receptor agonist on the function and differentiation of brown adipocytes in mice.Methods Primary brown adipocytes in mice were cultivated in vitro.Before the induction,brown adipocytes were assigned to four groups:GLP-1 10-8mol/L group,GLP-1 10-9mol/L group,L-NAME 10-3 mol/L group,and control group.Finally,adipocytes were put under morphological observation.The expression levels of genes of brown adipocytes in different groups were detected by RT-PCR.The single factor analysis was used for data analysis.Results The lipid droplets of brown adipocytes in GLP-1 group increased significantly compared with the control group under morphological observation.The expressions of specific genes [uncoupling protein 1 (UCP1),cell death-inducing DFFA (DNA fragmentation factor a)-like effector a (Cidea),peroxisome proliferator-activated receptor γcoactive 1α (PGC1-α)],differentiation genes [PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16),peroxisome proliferators-activated receptor-γ(PPAR-γ)],nitric oxide pathway genes [endothelial nitric oxide synthase (eNOS),inducible nitric oxide synthase (iNOS)] in brown adipocytes in GLP-1 group were significantly increased as compared with the control group,F values were 17.36,29.57,66.76,13.78,4.14,105.47,346.57 respectively(all P<0.05).Conclusions GLP-1 receptor agonist may improve the differentiation and function of brown adipocytes in mice,thereby enhance the function and induce the differentiation of brown adipocytes,the effect is more evident in high concentration of GLP-1.%目的 研究胰升糖素样肽1(GLP-1)受体激动剂对小鼠棕色脂肪细胞功能基因表达和分化的作用.方法 体外培养小鼠棕色脂肪前体细胞,诱导分化前分4组:GLP-1(10-8 mol/L)组、GLP-1(10-9moL/L)组、L-NAME(一氧化氮合酶抑制剂,10-3mol/L)组和对照组.干预结束后对细胞进行形态学观察研究,应用荧光定量PCR检测棕色

  20. Glucagon-like peptide 1 receptor agonist protects high-glucose inducedβcells apoptosis via inhibition of NOX2-dependent ROS production%GLP-1Ra减少高糖诱导的β细胞凋亡作用机制探讨

    丁敏; 李春君; 邢云芝; 于倩; 王鹏华; 于德民

    2015-01-01

    Objective To investigate the possible mechanisms of glucagon-like peptide 1 receptor agonists (GLP-1Ra) protection against hyperglycemic induced beta cell apoptosis through depression of NOX2-dependent ROS production. Methods The rat model of type 2 diabetes (T2DM) was established by injecting small doses of streptozotocin (STZ) fol⁃lowed by 8-week high fat diet. The experimental animals were divided into three groups:normal control (N) group, diabetes (T2DM) group and GLP-1Ra group [treated with liraglutide 200 μg/(kg · d)for 12 weeks]. The blood glucose levels were compared before and after modeling, before treatment and 12-week after treatment with GLP-1Ra. The level of glycosylated hemoglobin (HbA1c) was detected by high-pressure liquid chromatography. Automatic biochemical analyzer was used to de⁃tect levels of aspertate aminotransferase (AST), creatinine (CR) and urea nitrogen (BUN). The apoptotic rates of islets were determined by TUNEL method and cleaved caspase 3 was detected by immunohistochemistry. DCFH-DA fluorescent probe was used to detect reactive oxygen species (ROS) levels of islets. Levels of NADPH oxidase (NOX) catalytic subunit (NOX 2) in islets were measured by immunohistochemistry. Results At the end of the study, glycemic control (average blood glucose/week and HbA1c) and lipid situation were improved significantly in the GLP-1Ra group than those of N group (P0.05). After application Apocynin for inhibition, there were no significant differences between three groups (P>0.05). The level of NOX2 was significantly lower in GLP-1Ra group compared to that of T2DM group (P<0.05). Conclusion GLP-1Ra can inhibit apoptosis ofβcells in diabetes rat, and the depression of NOX2-dependent ROS may be one of the important underly⁃ing mechanisms.%目的:探讨胰高血糖素样肽-1(GLP-1)受体激动剂(GLP-1Ra)减少高糖诱导的β细胞凋亡作用的可能机制。方法正常对照(N,普通饲料喂养)组、2型糖尿病(T2

  1. Effects of glucagon-like peptide-1 improving insulin sensitivity in obese type 2 diabetic rats%胰高血糖素样肽-1对肥胖2型糖尿病大鼠胰岛素敏感性的改善作用

    王晋竹; 葛凤; 娄宁; 胡晓琳; 董振华; 王文汇

    2015-01-01

    目的:探讨胰高血糖素样肽(GLP)-1对肥胖2型糖尿病(T2DM)大鼠胰岛素敏感性的改善作用及机制。方法12只6周龄雄性SD大鼠随机分为T2DM组、T2DM +GLP-1组及正常对照组(NC 组)。 T2DM 组及 T2DM +GLP-1组高脂喂养、NC 组普食喂养4 w,给予 T2DM 组及T2DM +GLP-1组链脲佐菌素(STZ)30 mg/kg腹腔注射建立 T2DM模型。受试大鼠进行高胰岛素-正葡萄糖钳夹实验。 T2DM +GLP-1组大鼠在钳夹实验前30 min开始持续输注GLP-1,检测钳夹实验120 min葡萄糖输注率及0、30、60、90、120 min血清胰岛素浓度。 Wester印迹法测定大鼠腓肠肌丝氨酸/苏氨酸激酶(Akt)磷酸化水平。结果与NC组比较,T2DM组钳夹实验120 min葡萄糖输注率降低(P<0.05),骨骼肌Akt磷酸化水平下降;与T2DM组比较,T2DM +GLP-1组钳夹实验120 min葡萄糖输注率增加(P<0.05),骨骼肌 Akt 磷酸化水平升高;各组间胰岛素浓度变化无差异(P>0.05)。结论 GLP-1可以增加平静状态T2DM大鼠葡萄糖摄取,改善骨骼肌的胰岛素敏感性,这一改善作用不依赖于胰岛素浓度的增加。%Objective To investigate the mechanism of Glucagon-like peptide(GLP)-1acted with insulin sensitivity in obese type 2 diabetic(T2DM)rats.Methods Twelve SD rats were randomized into T2DM,T2DM+GLP-1 and normal control(NC)groups.Rats of T2DM and T2DM+GLP-1 groups were fed with high fat diet for four weeks .The glucose infusion rate at 120 min and insulin concentration at 0,30, 60,90,120 min were measured by Hyperinsulinemic-euglycemic clamps.The gastrocnemius serine/threonine protein kinase(Akt)phosphoryl-ation was measured by Western blot .Results Compared with that of NC group ,the glucose infusion rate at 120 min of T2DM group was low-er〔(3.03±1.39)vs(6.52±1.73)mg・ kg-1min-1,P<0.05〕,the skeletal muscle Akt phosphorylation levels of T2DM group was decreased

  2. Efficacy and safety of recombinant human glucagon-like peptide-1 in combination with metformin in patients with type 2 diabetes mellitus%重组人胰高血糖素样肽-1联合二甲双胍治疗2型糖尿病的有效性和安全性评价

    侯新国; 周克华; 甄晓慧; 宋君; 张亮; 矫磊; 陈丽

    2011-01-01

    目的 评价在口服降糖药二甲双胍的基础上餐前皮下注射重组人胰高血糖素样肽-1(rhGLP-1)治疗2型糖尿病的有效性和安全性.方法 在随机、双盲、安慰剂对照的临床试验中,选取42例二甲双胍单药治疗的2型糖尿病患者,随机分为观察组和对照组,每组21例.在口服原剂量二甲双胍的基础上分别接受rhGLP-1 0.2 mg(观察组)或安慰剂(对照组)三餐前皮下注射治疗,随访12周,观察空腹血糖、餐后2h血糖和糖化血红蛋白(HbAlc)等有效性指标及低血糖、不良反应和肝肾功能等安全性指标.结果 观察组治疗后HbAlc、空腹及餐后血糖水平较前明显下降(P<0.05),且较对照组下降更为显著(P<0.05).两组治疗后体质量指数均显著下降(P<0.05),但组间比较无统计学差异(P>0.05);观察组体质量指数下降程度与基线值呈正相关(P<0.01).观察组和对照组均无确切证据的低血糖发生,两组间胃肠道不良反应发生率无统计学差异(P>0.05).结论 在口服二甲双胍的基础上给予rhGLP-1三餐前皮下注射治疗可有效降低2型糖尿病患者的空腹及餐后血糖,而不增加低血糖及其他不良事件的发生率.%Objective To evaluate the efficacy and safety of recombinant human glucagon-like peptide-1 (rhGLP-1) subcutaneously administered before meals in combination with oral metformin in patients with type 2 diabetes mellitus. Methods In this randomized, double-blind and placebo-controlled study, 42 patients with type 2 diabetes were randomly divided into the study group and the control group, 21 patients in each group. They were subcutaneously administrated with 0.2 mg of rhGLP-1 (7-36) or a placebo in addition to an original dose of metformin, and then they were followed for 12 weeks. The changes of glucose, HbAlc and other safety indexes from the baseline to the endpoint were observed. Results The levels of HbAlc, and fasting and postprandial blood glucose

  3. Glucagon-like peptide-1 protects the apoptosis of pancreatic β cells induced by endoplasmic reticulum stress%胰高血糖素样肽-1保护内质网应激诱导的胰岛β细胞凋亡

    张菲菲; 许世清; 姜永玮; 张文健; 娄晋宁; 门秀丽

    2011-01-01

    Objective To explore the potential protective mechanism of glucagon-like peptide-1(GLP-1) on thapsigargin (TG)induced pancreatic β cell apoptosis.Methods The rat pancreatic β cell line-r9 cells cultured in vitro were used to compare the pancreatic β cell apoptosis with the presence of GLP-1 and GLP-1 receptor agonists exendin-4 while endoplasmic retieulum (ER) stress was induced by thapsigargin.Further,we investigated the effects of GLP-1 and exendin-4 on the release of cytochrome c and generation of reactive oxygen species (ROS) during ER stress.This experiment was divided into four groups,normal group,TG group ( 100 nmol/L ),GLP-1 ( 10 nmol/L ) + TG ( 100 nmol/L ) group and Exendin-4( 100 nmol/L) + TG( 100 nmol/L) group,and apoptosis rate of the four groups was detected by DNA fragmentation,TUNEL staining,AnnexinV-PI double dye flow cytometric analysis.We used the Western Blot to test the release of cytochrome c,used fluorescence probe DCFH-DA to test the reactive oxygen species(ROS) level and used rhodamine-110(Z-DEVD-R110) dyeing to detect the cells Caspase3' s activity.We used t-testing to compare the difference between two groups and used one way analysis of variance to test the differences among the four groups.Results The apoptosis of the latter two groups which were tested by DNA fragmentation and TUNEL staining was significantly reduced compared with TG group (t =6.13 or 6.73,both P <0.01 ).The apoptosis rate of β cells tested by AnnexinV-PI double dye flow cytometry was 26%,which was reduced to 19.7% and 19.2% in the existence of GLP-1 and exendin-4,respectively.Further experiments showed that GLP-1 and exendin-4 reduced cytochrome c release,ROS generation and caspase3 activation.The Western blot of cytoplasm albumen showed that GLP-1 and exendin4 can reduce the release of eytochrome c in ER stress (t =5.37 or 7.26,both P<0.01 ).The detection of ROS in mitochondria showed that ROS,a certain amount of which in cytoplasm could be detected

  4. Effect of glucagon like peptide-1 receptor agonist combined human umbilical cord mesenchymal stem cells on the glucose metabolism and the islet β cell function in type 2 diabetic SD rats%胰高血糖素样肽1受体激动剂和脐带间充质干细胞联合治疗对2型糖尿病大鼠糖代谢和胰岛分泌功能的作用

    陈频; 徐向进; 黄勤; 温代芬; 邵珠林; 黄梁浒; 陈晨

    2015-01-01

    Objective To observe the efficacy of glucagon like peptide-1(GLP-1) receptor agonist liraglutide(LIRA) combined with umbilical cord mesenchymal stem cells(UC-MSCs) on the glucose metabolism and isletβcell function in type 2 diabetic SD rats. Methods Type 2 diabetic SD rats models were established by giving high-carbonhydrate-fat diet and then intraperitoneal injecting of streptozotocin. The rats models were randomly divided into four groups according the table of random number: type 2 diabetes mellitus(T2DM), T2DM+UC-MSC, T2DM+LIRA, T2DM+LIRA+UC-MSCs, 10 rats in each group. Rats of each group were given the appropriate drug therapy for 8 weeks respectively. Liraglutide was given by subcutaneous injection with 200 μg/kg dosage. UC-MSCs were given by tail vein injection with 5 × 106 cells. During the treatment period, the general condition indexs of each group were monitored. The serum glycated hemoglobin A1c(HbA1c), peptide C(C-P), glucagon(Glu), GLP-1, gastrin(GAS) and cholecystokinin (CCK) were measured respectively. Mean data between groups was compared with one-way ANOVA. Results After 8-week of treatment, compared with T2DM group, HbA1c of the T2DM+UC-MSCs, T2DM+LIRA and T2DM+LIRA+UC-MSCs group decreased significantly((9.1±0.4)% vs (7.2±0.4)%, (3.9± 0.3)%, (3.1±0.3)%, respectively, F=815.220, P0.05);but the C-P, GLP-1, GAS and CCK in T2DM+LIRA group and T2DM+LIRA+UC-MSCs group increased markably(t=-18.115-35.732, all P0.05);T2DM+LIRA组和T2DM+LIRA+UC-MSCs组C-P、GLP-1、GAS和CCK水平均明显升高(t=-18.115~35.732,均P<0.05),GLu降低(t=3.022、11.859,均P<0.05);与T2DM+LIRA组比较,T2DM+LIRA+UC-MSCs组C-P、GLP-1、GAS和CCK明显升高(t=-9.107、7.635、9.870、19.152,均P<0.05),Glu降低(t=-13.976,P<0.05).Pearson双变量分析发现,大鼠空腹血清C-P与GLP-1、GAS及CCK呈正相关(r=0.401、0.628、0.619,均P<0.01),与Glu呈负相关(r=-0.603,P<0.01).大鼠空腹血清GLu水平与GLP-1、GAS及CCK呈负相关(r=-0.827、-0.583、-0.516,

  5. 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

    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...

  6. Risk of dyspepsia and anorexia due to glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus:a Network Meta-analysis%胰高血糖素样肽1受体激动剂类降糖药致2型糖尿病患者消化不良和厌食发生风险的Network Meta分析

    李志霞; 曾宪涛; 柴三葆; 全晓驰; 武珊珊; 杨智荣; 詹思延; 孙凤

    2015-01-01

    Objective To evaluate the risk of dyspepsia and anorexia due to glucagon-like peptide-1 receptor agonist(GLP-1 RA)in patients with type 2 diabetes mellitus(T2DM). Methods The electronic database of Chinese BioMedical Literature Database( CBMdisc ), Chinese Medical Current Contents( CMCC),Medline,EMbase,the Cochrane Library and web site of ClinicalTrials. gov were searched from inception to May 1st 2014. Those randomized controlled trials whose inclusion criteria including patients with T2DM as the research object,comparisons of GLP-1 RA and placebo or other conventional anti-diabetic drugs as the intervention measures,and dyspepsia and anorexia as the outcomes were collected. A traditional Meta-analysis and a Network Meta-analysis were used and relational graph and rank ordering figure of all the intervention measures were drawn. Results A total of 42 randomized controlled trials were enrolled into this study involving 20 916 patients with T2DM and 13 kinds of intervention measures comprised 7 kinds of GLP-1 RAs( exenatide,exenatide release agent,liraglutide, lixisenatide,taspoglutide, albiglutide, and dulaglutide ), 5 kinds of conventional anti-diabetic drugs ( insulin, metformin, sulfonylureas, sitagliptin, and thiazolidinediones ketones ), and placebo. The traditional Meta-analysis showed that,compared with placebo,the whole of GLP-1 RAs could increase the risks of dyspepsia[odds ratio(OR)=3. 04,95% confidence interval(CI):1. 79-5. 16]and anorexia (OR=2. 57,95%CI:1. 69-3. 91)and there were statistically significant differences(P 1. 00 except for lixisenatide versus sitagliptin )and,of them,dulaglutide was at the greatest risk,48. 91,16. 65,36. 24,and 4. 75 times as high as that of insulin,sulfonylureas,thiazolidinediones ketones,and sitagliptin,respectively. There was no statistically significant difference between two kinds of GLP-1 RAs for risks of dyspepsia and anorexia( all P>0. 05). The risks of dyspepsia and anorexia due to the 13 kinds of intervention

  7. Cardioprotective effects of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors%GLP-1受体激动剂和DPP-4抑制剂对心血管系统的保护作用

    张雪松; 秦明照

    2013-01-01

      胰高糖素样肽1(GLP-1)受体激动剂和二肽基肽酶-4( DPP-4)抑制剂是近年上市的治疗2型糖尿病的新型药物。GLP-1主要通过抑制心肌细胞凋亡、改善内皮细胞功能、减轻体重、降低血糖、降低血压、改善心肌收缩力、舒张血管等直接或间接发挥其心脏保护作用,GLP-1受体激动剂和DPP-4抑制剂对体重、血压和血脂等心血管危险因素有改善作用。GLP-1受体激动剂和DPP-4抑制剂作用于新靶点,具有其独特的优点,将会是一类抗糖尿病新药。%Glucagon-like Peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are new kinds of drugs to treat type 2 diabetes mel itus. It was demonstrated that GLP-1 has an obvious cardioprotective effect mainly achieved by relaxing vascular vessels, improving endothelial function, improving endothelial function and promoting the functional recovery of pathological ventricle, which can directly or indirectly protect the heart. GLP-1 receptor agonists and DPP4 inhibitors also showed important effects on the body weight, blood pressure, lipids, and other cardiovascular risk factors. GLP-1 receptor agonists and DPP4 inhibitors have more advantages than other anti-diabetes drugs because they act on a new target. They wil be a useful new class of anti-diabetes drugs.

  8. 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 E M; Rubio-Gozalbo, Estela; de Vries, Maaike C; Janssen, Mirian C H; Boelen, Carolien C A; Burgerhof, Johannes G M; Blau, Nenad; Fokkema, Margaretha; 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 loadin

  9. Effects of glucagon-like peptide-1 on the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits in the heart of type 1 diabetic rats%胰高血糖素样肽1对1型糖尿病大鼠心肌烟酰胺腺嘌呤二核苷酸氧化酶亚单位表达的影响

    俞媛贤; 郭志新; 齐伟; 杜时晶; 刘晋津; 吴杰萍

    2013-01-01

    Objective To explore the effect of glucagon-like peptide-1 on the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22phox and Nox4 in the heart tissue of type 1 diabetic rats.Methods Forty-two male Sprague-Dawley(SD) rats were randomly divided into normal control group (group A,n=7) and diabetic model group (n =35) with the random number table.Type 1 diabetic model was established by intraperitoneal injection of streptozotocin.Twenty-nine successfully-induced diabetic rats were randomly divided into diabetic (group DM,n =10),diabetic treated with low-dose of GLP-1 (group DL,n =10) and diabetic treated with high-dose of GLP-1 (group DH,n =9) with the random number table method.The rats in group DL were given exenatide in dose of 1 μg/kg twice daily by subcutaneous injection.The rats in group DH were given exenatide in dose of 5 μg/kg twice daily by subcutaneous injection.All rats were sacrificed after exenatide treatment for eight weeks.The mRNA expression of myocardial p22phox and Nox4 in the rats of four groups was detected by real-time fluorescence quantitative polymerase chain reaction(PCR),and the protein expression of myocardial copper zinc-superoxide dismutase (Cu-Zn-SOD) was detected by immunohistochemical staining.Statistical analysis among groups was performed by using one way ANOVA.Results Compared with group NC,the mRNA expression of myocardial p22phox and Nox4 and the myocardial Cu-Zn-SOD protein expression increased significantly in group DM(t =5.77,5.36,59.91,all P <0.05).After exenatide treatment for 8 weeks,the mRNA expression of myocardial p22phox and Nox4 and the myocardial Cu-Zn-SOD protein expression decreased significantly in group DL and DH (t =16.86,7.66 and 16.11,7.59 and 56.00,47.05,and all P < 0.05).Compared with group DL,the mRNA expression of myocardial p22phox and Nox4 decreased significantly in group DH (t =10.14,8.67,both P < 0.05).There was no significant difference in the expression of

  10. 利拉鲁肽对新诊断的糖化血红蛋白>9%的2型糖尿病患者的有效性及安全性%The efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes with glycosylated hemoglobin A1c > 9%

    陈频; 陈晨; 邵珠林; 徐向进; 黄勤

    2015-01-01

    Objective To evaluate the efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes mellitus (T2DM) with glycosylated hemoglobin A1c (HbA1c) > 9%.Methods This was an open-labelled,randomized,parallel-group,treat-to-target trial.Newly diagnosed T2DM patients with HbA1c > 9% were enrolled.These patients were treated with metformin with repaglinide and randomized to receive once-daily liraglutide (LIRA,n =25) or the insulin glargine (IGla,n =24) at bedtime.Efficacy and safety were assessed and compared after 18-month treatment.Results (1) Compared with the baseline,patients with LIRA had significantly reduced mean body weight,BMI and waist circumference (P < 0.01),whereas,the above indexes were increased (P < 0.01) in patients treated with IGla.(2) After 18 months of treatment,fasting plasma glucose (FPG),2-hour plasma glucose after a 75g oral glucose load(2hPG) and HbA1c were significantly improved in all patients (P < 0.01),with 2hPG,mean blood glucose (MBG),the largest amplitude of glycemic excursions (LAGE),mean amplitude of glycemic excursions (MAGE) were significantly lower in LIRA group than in IGla group (all P < 0.05).(3) HOMA-IR decreased in both groups (P < 0.05).However,△I30/△G30,AUCCP180 and Matsuda index were only significantly increased in patients treated with LIRA (respectively,4.88 ± 1.55 vs 7.60 ± 1.91,9.23 ± 2.66 vs 13.18 ± 2.72,39.28 ± 20.35 vs 54.64 ± 23.34,all P < 0.01),while HOMA-IR reduced(4.41 ± 1.58 vs 3.52 ± 1.44,P <0.05).But in IGla group only HOMAIR was reduced (4.92 ± 1.84 vs 4.57 ± 1.80,P <0.05).The index of △I30/△G30,AUCCP180 and Matsuda index in LIRA group are higher than those of indexes in IGla group(respectively,7.60 ± 1.91 vs 4.18 ± 1.00,13.18 ± 2.72 vs 10.53 ± 2.68,54.64 ± 23.34 vs 41.65 ± 17.84,all P < 0.05),while HOMA-IR is lower (3.52 ± 1.44 vs 4.57 ± 1.80,P < 0.05).(4) The rate of HbA1 c ≤ 6.5 % and the dosages of oral

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

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

    2012-01-01

    : To determine whether endogenous GLP-1 contributes to the healing processes and if exogenous GLP-1 has a potential role in treating mucositis. METHODS: Mice were injected with 5-fluorouracil (5-FU) or saline to induce mucositis and were then treated with GLP-1, GLP-2, GLP-2 (3-33), exendin (9-39) or vehicle....... The mice were sacrificed 48 or 96 h after the 5-FU injections. The end points were intestinal weight, villus height, proliferation and histological scoring of mucositis severity. Rats were injected with 5-FU or saline, and after 48 h, blood was drawn and analysed for GLP-1 and GLP-2 concentration. RESULTS...

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

    Underwood, Christina Rye

    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....... Collectively, the work has contributed to a more detailed understanding of GLP-1R pharmacology in a number of ways. A crystal structure elucidated the molecular details of GLP- 1 binding to the ECD of GLP-1R and supported the existence of different binding modes of GLP-1 and exendin-4. In addition, the work...

  13. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain

    Simon C. Cork

    2015-10-01

    Conclusions: This study is a comprehensive description and phenotypic analysis of GLP-1R expression in the mouse CNS. We demonstrate the power of combining the GLP-1R-CRE mouse with a virus to generate a selective molecular handle enabling future in vivo investigation as to their physiological importance.

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

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

    2012-01-01

    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. Thus, GLP-1...

  15. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1

    Holst, Jens Juul

    2002-01-01

    effects include proliferation of existing beta cells, maturation of new cells from duct progenitor cells and inhibition of apoptosis. Furthermore, glucagon secretion is inhibited. Because of these effects, the hormone effectively improves metabolism in patients with type 2 diabetes mellitus. Thus...... shown remarkable efficacy in both experimental and clinical studies. The GLP-1-based therapy of type 2 diabetes, therefore, represents a new and attractive alternative....... satiety and promotes tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it is an essential incretin hormone. In addition, the hormone has been demonstrated to promote insulin biosynthesis and insulin gene expression and to have trophic effects on the beta cells. The trophic...

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

    Askov-Hansen, Carsten; Jeppesen, Palle B; Lund, Pernille

    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. Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes

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

    2001-01-01

    GLP-1 lowers blood glucose in fasting type 2 diabetic patients. To clarify the relation of the effect of GLP-1 to obesity, blood glucose, beta-cell function, and insulin sensitivity, GLP-1 (1.2 pmol/kg.min) was infused iv for 4-6 h into 50 fasting type 2 diabetic patients with a wide range of age...... the infusion. Grouped according to fasting plasma glucose (15 mmol/liter), Kg values were 0.45 +/- 0.03, 0.38 +/- 0.04, and 0.28 +/- 0.04%/min (P = 0.005), and Nadir plasma glucose values were 4.7 +/- 0.1 (3.9-5.9), 5.8 +/- 0.4 (4.3-8.4), and 8.7 +/- 1.4 (6.2-18.7) mmol/liter (P = 0.......0003). Nonresponders were not identified. Multiple regression analysis with Kg or Nadir plasma glucose as the dependent parameter and body mass index, age, gender, diabetes duration, and significantly correlated parameters (in multiple regression for Kg: fasting plasma glucose, fasting nonesterified fatty acid...

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

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

    2015-01-01

    , liraglutide has an added fatty acid (FA) moiety that causes oligomerization of liraglutide as suggested by small-angle x-ray scattering (SAXS) and multiangle static light scattering (MALS) results. SAXS data suggested a global shape of a hollow elliptical cylinder of size hexa-, hepta-, or octamer, whereas...... MALS data indicate a hexamer. To elaborate further on the stability of these oligomers and the role of the FA chains, a series of molecular-dynamics simulations were carried out on 11 different hexa-, hepta-, and octameric systems. Our results indicate that interactions of the fatty acid chains...

  19. Glucagon-like peptide-1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men.

    Asmar, Ali; Asmar, Meena; Simonsen, Lene; Madsbad, Sten; Holst, Jens J; Hartmann, Bolette; Sorensen, Charlotte M; Bülow, Jens

    2017-02-01

    In healthy subjects, we recently demonstrated that during acute administration of GLP-1, cardiac output increased significantly, whereas renal blood flow remained constant. We therefore hypothesize that GLP-1 induces vasodilation in other organs, for example, adipose tissue, skeletal muscle, and/or splanchnic tissues. Nine healthy men were examined twice in random order during a 2-hour infusion of either GLP-1 (1.5 pmol kg(-1) min(-1)) or saline. Cardiac output was continuously estimated noninvasively concomitantly with measurement of intra-arterial blood pressure. Subcutaneous, abdominal adipose tissue blood flow (ATBF) was measured by the (133)Xenon clearance technique. Leg and splanchnic blood flow were measured by Fick's Principle, using indocyanine green as indicator. In the GLP-1 study, cardiac output increased significantly together with a significant increase in arterial pulse pressure and heart rate compared with the saline study. Subcutaneous, abdominal ATBF and leg blood flow increased significantly during the GLP-1 infusion compared with saline, whereas splanchnic blood flow response did not differ between the studies. We conclude that in healthy subjects, GLP-1 increases cardiac output acutely due to a GLP-1-induced vasodilation in adipose tissue and skeletal muscle together with an increase in cardiac work.

  20. Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice

    Arora, Tulika; Wegmann, Udo; Bobhate, Anup;

    2016-01-01

    of the gluconeogenic genes G6pc and Pepck. RESULTS: Insulin release from primary islets of WT but not GLP1R-KO mice was higher following incubation with culture supernatant from LL-GLP1 compared with LL-UK200. In mice on chow, supplementation with LL-GLP1 versus LL-UK200 promoted increased vena porta levels of GLP-1...... (GLP1R-KO) mice with culture supernatant of these strains. In addition, we administered these strains to mice on chow or HFD. At the end of the study period, we measured plasma GLP-1 levels, performed intraperitoneal glucose tolerance and insulin tolerance tests, and determined hepatic expression...... in both WT and GLP1R-KO mice; however, LL-GLP1 promoted improved glucose tolerance in WT but not in GLP1R-KO mice, indicating a requirement for the GLP-1 receptor. In mice on HFD and thus with impaired glucose tolerance, supplementation with LL-GLP1 versus LL-UK200 promoted a pronounced improvement...

  1. Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport

    Jennifer Lee

    2017-03-01

    Conclusions: These findings reveal an important role for GLP-2R signaling in the physiological and pharmacological control of enteral amino acid sensing and assimilation, defining an enteroendocrine cell-enterocyte axis for optimal energy absorption.

  2. Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes

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

    2001-01-01

    , body mass index, HbA1c, and fasting plasma glucose. The effectiveness of GLP-1 was evaluated by calculation of a glucose disappearance constant for each individual (Kg, linear slope of log-transformed plasma glucose), and by the lowest stable glucose level (Nadir plasma glucose) obtained during.......0003). Nonresponders were not identified. Multiple regression analysis with Kg or Nadir plasma glucose as the dependent parameter and body mass index, age, gender, diabetes duration, and significantly correlated parameters (in multiple regression for Kg: fasting plasma glucose, fasting nonesterified fatty acid...

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

    Madsbad, Sten

    2016-01-01

    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...... gastric emptying, they have greater effects on postprandial glucose levels than the longer-acting agents, whereas the longer-acting compounds reduced plasma glucose throughout the 24-h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater...

  4. 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....

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

    Faurschou, Annesofie; Pedersen, Jens; Gyldenløve, Mette

    2013-01-01

    in either stimulated or unstimulated cultured human keratinocytes. Our results show increased presence of GLP-1Rs in psoriasis plaques and that this most likely is due to infiltration with immune cells. This offers a possible explanation for the positive effect of treatment with GLP-1R agonists in patients...

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

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

    2008-01-01

    is a common problem in preterm newborns resulting from the intestinal immaturity. The study included 20 term and 28 preterm neonates. Of preterm babies, 13 showed feeding intolerance fulfilling at least one of the following criteria: abdominal distension, increased gastric residual volume and presence of bile...

  7. Treatment of Type 2 diabetes mellitus based on glucagon-like peptide-1

    Holst, Jens Juul

    1999-01-01

    inhibition of gastrointestinal motility and secretion in the presence of nutrients in the lower small intestine). However, because of these same actions, the hormone can normalise the blood glucose of patients with Type 2 diabetes mellitus, and, in contradistinction to insulin and sulphonylurea, it does...

  8. Glucagon-like peptide-1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men

    Asmar, Ali; Asmar, Meena; Simonsen, Lene

    2017-01-01

    In healthy subjects, we recently demonstrated that during acute administration of GLP-1, cardiac output increased significantly, whereas renal blood flow remained constant. We therefore hypothesize that GLP-1 induces vasodilation in other organs, for example, adipose tissue, skeletal muscle, and....../or splanchnic tissues. Nine healthy men were examined twice in random order during a 2-hour infusion of either GLP-1 (1.5 pmol kg(-1) min(-1)) or saline. Cardiac output was continuously estimated noninvasively concomitantly with measurement of intra-arterial blood pressure. Subcutaneous, abdominal adipose...... and heart rate compared with the saline study. Subcutaneous, abdominal ATBF and leg blood flow increased significantly during the GLP-1 infusion compared with saline, whereas splanchnic blood flow response did not differ between the studies. We conclude that in healthy subjects, GLP-1 increases cardiac...

  9. 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

    or 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...... until inflammation was established, resulted in significant improvements in animal weights, mucosal inflammation indices (myeloperoxidase levels, histological mucosal scores), and reduced levels of inflammatory cytokines (IFN-gamma, TNF-alpha, IL-1beta) and inducible nitric oxide synthase......, with increased levels of IL-10 in TNBS ileitis and DSS colitis. Reduced rates of crypt cell proliferation and of apoptosis within crypts in inflamed tissues were also noted with GLP-2 treatment. These effects were abolished with coadministration of GLP-2 and the VIP antagonist. GLP-2 was shown to activate...

  10. 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......) and 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...

  11. 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...

  12. 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...... concentrations were similar in patients and controls. Patients with epigastric pain syndrome had higher postprandial insulin levels. Patients reported more satiety, nausea, and pain. Area under the curve (AUC) for GLP-1 correlated positively to nausea in patients and negatively to nausea in controls during...

  13. 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

    2000-01-01

    Neurophysiology, neuroanatomy, overweight/obesity, hypothalamus, brainstem, food intake behaviour......Neurophysiology, neuroanatomy, overweight/obesity, hypothalamus, brainstem, food intake behaviour...

  14. The 48-hour tetrahydrobiopterin loading test in patients with phenylketonuria : Evaluation of protocol and influence of baseline phenylalanine concentration

    Anjema, K.; Venema, G.; Hofstede, F. C.; Weber, E. C. Carbasius; Bosch, A. M.; Ter Horst, N. M.; Hollak, C. E. M.; Jonkers, C. F.; Rubio-Gozalbo, M. E.; van der Ploeg, E. M. C.; de Vries, M. C.; Janssen-Regelink, R. G.; Janssen, M. C. H.; Essen, H. Zweers-van; Boelen, C. C. A.; van der Herberg-van de Wetering, N. A. P.; Heiner-Fokkema, Rebecca; van Rijn, M.; van Spronsen, F. J.

    2011-01-01

    BACKGROUND: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 μmol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and

  15. Jejunal feeding is followed by a greater rise in plasma cholecystokinin, peptide YY, glucagon-like peptide 1, and glucagon-like peptide 2 concentrations compared with gastric feeding in vivo in humans

    Luttikhold, Joanna; van Norren, Klaske; Rijna, Herman;

    2016-01-01

    ± SD age: 21 ± 2 y) received continuous enteral nutrition that contained noncoagulating proteins for 12 h via a nasogastric tube or a nasojejunal tube placed 30-40 cm distal to the ligament of Treitz. Blood samples were collected during the 12-h postprandial period to assess the rise in plasma glucose...

  16. 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.

  17. 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

    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)-positive cells...

  18. 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...

  19. 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

    . SUBJECTS/METHODS: Eight healthy young volunteers were studied on four occasions in the fasting state. In one experiment, placebo was administered (a). in three more experiments (random order), synthetic GLP-1 (7 - 36 amide) at 1.2 pmol/kg/min was administered over a period of three hours. At 0 min, a bolus...

  20. Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice.

    Rachmany, Lital; Tweedie, David; Li, Yazhou; Rubovitch, Vardit; Holloway, Harold W; Miller, Jonathan; Hoffer, Barry J; Greig, Nigel H; Pick, Chaim G

    2013-10-01

    Mild traumatic brain injury (mTBI) represents a major and increasing public health concern and is both the most frequent cause of mortality and disability in young adults and a chief cause of morbidity in the elderly. Albeit mTBI patients do not show clear structural brain defects and, generally, do not require hospitalization, they frequently suffer from long-lasting cognitive, behavioral, and emotional problems. No effective pharmaceutical therapy is available, and existing treatment chiefly involves intensive care management after injury. The diffuse neural cell death evident after mTBI is considered mediated by oxidative stress and glutamate-induced excitotoxicity. Prior studies of the long-acting GLP-1 receptor agonist, exendin-4 (Ex-4), an incretin mimetic approved for type 2 diabetes mellitus treatment, demonstrated its neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer's and Parkinson's diseases, and, consequent to commonalities in mechanisms underpinning these disorders, Ex-4 was assessed in a mouse mTBI model. In neuronal cultures in this study, Ex-4 ameliorated H2O2-induced oxidative stress and glutamate toxicity. To evaluate in vivo translation, we administered steady-state Ex-4 (3.5 pM/kg/min) or saline to control and mTBI mice over 7 days starting 48 h prior to or 1 h post-sham or mTBI (30 g weight drop under anesthesia). Ex-4 proved well-tolerated and fully ameliorated mTBI-induced deficits in novel object recognition 7 and 30 days post-trauma. Less mTBI-induced impairment was evident in Y-maze, elevated plus maze, and passive avoidance paradigms, but when impairment was apparent Ex-4 induced amelioration. Together, these results suggest that Ex-4 may act as a neurotrophic/neuroprotective drug to minimize mTBI impairment.

  1. 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

    reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we...... report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression...... implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction....

  2. Acute Effects of the Glucagon-Like Peptide 2 Analogue, Teduglutide, on Intestinal Adaptation in Short Bowel Syndrome

    Thymann, Thomas; Stoll, B.; Mecklenburg, L.;

    2014-01-01

    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...

  3. The effects of variations in dose and method of administration on glucagon like peptide-2 activity in the rat

    Kaji, Tatsuru; Tanaka, Hiroaki; Holst, Jens Juul

    2008-01-01

    intestinal trophic activity. A rodent model of total parenteral nutrition (TPN) mucosal atrophy was used, examining intestinal morphology in the adult male rat after 5 days. Groups were: controls, maintained with TPN alone and GLP-2 treated groups (high dose; 240 microg/kg/day, low dose; 24 microg...

  4. 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...... 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' duration, teduglutide appears to be safe and well tolerated. Treatment with teduglutide was associated with enhancement...... or 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....

  5. Glucagon-like peptide-1 receptor signaling in acinar cells causes growth dependent release of pancreatic enzymes

    Albrechtsen, Nicolai Jacob Wewer; Albrechtsen, Reidar; Bremholm, l;

    2016-01-01

    Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon...

  6. Glucagon-Like Peptide-1 Agonists and Risk of Acute Pancreatitis in Patients with Type 2 Diabetes

    Storgaard, Heidi; Cold, Frederik; Gluud, Lise L;

    2017-01-01

    diabetes. We performed a systematic review with meta-analysis of long-term (minimum 24 months), placebo-controlled GLP-1RA RCTs in which AP was a predefined adverse event and adjudicated by blinded and independent adjudicating committees. Three high-quality RCTs included a total of 9,347 GLP-1RA...

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

    Orskov, C; Rabenhøj, L; Wettergren, A

    1994-01-01

    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......M. Thus, both amidated and glycine-extended GLP-I molecules are produced in the small intestine and in the pancreas in humans. Both amidated and glycine-extended GLP-I are measurable in fasting plasma.(ABSTRACT TRUNCATED AT 250 WORDS)...

  8. A Meta-Analysis of the Therapeutic Effects of Glucagon-Like Peptide-1 Agonist in Heart Failure

    Mohammed Munaf

    2012-01-01

    Full Text Available We conducted a meta-analysis of the existing literature of the therapeutic effects of using GLP-1 agonists to improve the metabolism of the failing heart. Animal studies showed significant improvement in markers of cardiac function, such as left ventricular ejection fraction (LVEF, with regular GLP-1 agonist infusions. In clinical trials, the potential effects of GLP-1 agonists in improving cardiac function were modest: LVEF improved by 4.4% compared to placebo (95% C.I 1.36–7.44, =0.005. However, BNP levels were not significantly altered by GLP-1 agonists in heart failure. In two trials, a modest increase in heart rate by up to 7 beats per minute was noted, but meta-analysis demonstrated this was not significant statistically. The small number of studies plus variation in the concentration and length of the regime between the trials would limit our conclusions, even though statistically, heterogeneity chi-squared tests did not reveal any significant heterogeneity in the endpoints tested. Moreover, studies in non-diabetics with heart failure yielded conflicting results. In conclusion, the use of GLP-1 agonists has at best a modest effect on ejection fraction improvement in heart failure, but there was no significant improvement in BNP levels in the meta-analysis.

  9. 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;

    2011-01-01

    and randomly assigned to treatment of a control (0.5% of BSA in saline; n=4) or GLP-2 (50 µg/kg of body weight of bovine GLP-2 in BSA; n=4) given subcutaneously every 12h for 10 d. Blood flow was measured on d 0 (acute) and d 10 (chronic) and included 3 periods: baseline (saline infusion), treatment (infusion...... of BSA or 1,000 pmol of GLP-2/kg of body weight per h), and recovery (saline infusion). On d 11, calves were killed 2h after injection of 5-bromo-2'-deoxyuridine (BrdU). Gastrointestinal tissues were weighed and epithelial samples were obtained to determine villus height, crypt depth, and BrdU staining...

  10. 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...

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

    Vilsbøll, Tina; Agersø, H; Krarup, T;

    2003-01-01

    of this study was to examine the pharmacokinetics of GLP-1 in healthy subjects and type 2 diabetic patients after iv bolus doses ranging from 2.5-25 nmol/subject. Bolus injections iv of 2.5, 5, 15, and 25 nmol of GLP-1 and a meal test were performed in six type 2 diabetic patients [age, mean (range): 56 (48...... 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....

  12. Radiation-induced oxidative injury of the ileum and colon is alleviated by glucagon-like peptide-1 and -2

    Mustafa Deniz

    2015-04-01

    Conclusion: Current findings suggest that GLP-1 and GLP-2 appear to have protective roles in the irradiation-induced oxidative damage of the gut by inhibiting neutrophil infiltration and subsequent activation of inflammatory mediators that induce lipid peroxidation.

  13. Secretion of glucagon-like peptide-2 responds to nutrient intake but not glucose provision in milk-fed calves

    Castro, J.J.; Morrison, S.Y.; Hosseinni, A.;

    2016-01-01

    GLP-2 secretion and no interaction with feed intake level was detected. In the second experiment, no effect of glucose supplementation was observed on intestinal growth, mucosal cell proliferation, or expression of genes related to the actions of GLP-2. Nonetheless, we observed that a pool of genes...

  14. 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

    /min), exceeded the amount which could be accounted for by glomerular filtration (4.2+/-0.5 pmol/min, presistance to enzymatic degradation, the increased stability of exendin-4 is the result of reduced differential organ extraction compared to GLP.......0+/-7.8%), whereas organ extraction of exendin-4 was limited to the kidneys (21.3+/-4.9%). While the renal extraction of exendin-4 (6.9+/-2.5 pmol/min) did not differ significantly from the amount undergoing glomerular filtration (8.4+/-2.0 pmol/min), the renal extraction of C-terminal GLP-1 (9.0+/-1.1 pmol......-1. The data suggest that in the anaesthetised pig, extraction occurs only in the kidney and can be fully accounted for by glomerular filtration....

  15. 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

    AND MEASUREMENTS: Eight patients with type 2 diabetes (five men, three women; age, 49+/-15 yrs; body mass index, 28+/-3 kg/m; glycosylated hemoglobin, 8.0%+/-1.9%), who had undergone major surgical procedures, were studied between the second and the eighth postoperative day with the intravenous administration...

  16. Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect of glucagon-like peptide-2 in rats and mice

    Hartmann, B; Thulesen, J; Kissow, Hannelouise;

    2000-01-01

    s.c. injection of GLP-2 with or without the specific DPP-IV inhibitor, valine-pyrrolidide (VP). Rats were injected s.c. with 40 microg GLP-2 or 40 microg GLP-2+15 mg VP. Plasma was collected at different time points and analyzed, by RIA, for intact GLP-2. Rats were treated for 14 days with: saline...

  17. 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

    , the presence of biologically active forms of GLP-1 and PC1/3 in alpha cells was demonstrated by immunofluorescence, and the release of GLP-1 from isolated P. obesus, mouse and human islets was investigated. Results During the development of diabetes in P. obesus, a significant increase in GLP-1 was detected...

  18. 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

    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...

  19. 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.

  20. 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

    -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...... and showed decreased infarction area compared with controls. Histological analysis showed reduced inflammation and a trend toward reduced apoptosis in the infarct zone. Increased collagen but fewer myofibroblasts were observed in infarcts of the bead-GLP-1 MSC and bead-MSC groups, and significantly more...

  1. Brain glucagon-like peptide–1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

    Knauf, Claude; Cani, Patrice D.; Perrin, Christophe; Iglesias, Miguel A.; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J.; Kahn, C. Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M.; Postic, Catherine; Burcelin, Rémy

    2005-01-01

    Intestinal glucagon-like peptide–1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9–39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state. PMID:16322793

  2. [Postoperative closed suction drainage following hip and knee aloarthroplasty: drain removal after 24 or after 48 hours?].

    Erceg, Marinko; Becić, Kristijan

    2008-01-01

    The use of closed-suction drainage systems after total hip and knee replacement is a common practice. It is believed that drainage reduces the haematomas and infection. The usual time to remove drains is 48 hours. Usefulness of the long time drainage of the haematomas and possible harmfulness of infection is still a subject of discussion. In this article, using our own operative material, we want to show the justification of the 48 hour duration of closed-suction drainage. The investigation was done on the patients with hip replacement (45 patients) and knee replacement (11 patients). The amount of blood in the drainage systems in the first 24 hours after the surgery and after 24 hours till the removal of drainage was observed. The results show that the amount of blood lost in the drainage system in the first 24 hours was on average 95.29%, and only 4.71% in the next 24 hours. This article supports the opinion that postoperative drainage has to be removed after 24 hours, i.e. the 48 hours-drainage seems not to be justified.

  3. 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.

  4. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

    de Heer, J; Rasmussen, C; Coy, D H

    2008-01-01

    and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas. RESULTS: In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion...

  5. 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...

  6. Posterior Reversible Encephalopathy Syndrome Resolving Within 48 Hours in a Normotensive Patient Who Underwent Thoracic Spine Surgery

    Vakharia, Kunal; Siasios, Ioannis; Dimopoulos, Vassilios G.; Pollina, John

    2016-01-01

    Posterior reversible encephalopathy syndrome (PRES) usually manifests with severe headaches, seizures, and visual disturbances due to uncontrollable hypertension. A patient (age in the early 60s) with a history of renal cell cancer presented with lower-extremity weakness and paresthesias. Magnetic resonance imaging (MRI) of the thoracic spine revealed a T8 vertebral body metastatic lesion with cord compression at that level. The patient underwent preoperative embolization of the tumor followed by posterior resection and placement of percutaneous pedicle screws and rods. Postoperatively, the patient experienced decreased visual acuity bilaterally. Abnormal MRI findings consisted of T2 hyperintense lesions and fluid-attenuated inversion recovery changes in both occipital lobes, consistent with the unique brain imaging pattern associated with PRES. The patient’s blood pressure was normal and stable from the first day of hospitalization. The patient was kept on high-dose steroid therapy, which was started intraoperatively, and improved within 48 hours after symptom onset. PMID:26858804

  7. 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.)

  8. Functional ontogeny of the proglucagon-derived peptide axis in the premature human neonate

    Amin, Harish; Holst, Jens Juul; Hartmann, Bolette

    2008-01-01

    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...

  9. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor. and Glucagon-Like Peptide-1

    den Besten, Gijs; Gerding, Albert; van Dijk, Theo H.; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K.; Reijngoud, Dirk-Jan; Bakker, Barbara M.

    2015-01-01

    The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that S

  10. 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

    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......, followed by an intravenous glucose bolus (0.3 g/kg) and hyperglycemic glucose clamp for 2 h. Blood was frequently collected for analyses of glucose, serum insulin and plasma total and active GLP-1 and area under the curve of glucose, insulin, total and active GLP-1 excursions calculated. Treatments were...

  11. 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

    after 7 days with continued EN sustained the majority of intestinal adaption and significantly increased expression of colonic proglucagon compared with PN + EN + GLP-2 for 18 days, and increased plasma GLP-2 concentrations compared with TPN alone. In summary, EN potentiate the intestinotrophic actions...

  12. Glucagon-like peptide-1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy

    Asmar, Ali; Simonsen, Lene; Asmar, Meena

    2016-01-01

    effects of GLP-1 in patients with type 2 diabetes under fixed sodium intake. During a 3-hour infusion of GLP-1 (1.5 pmol kg(-1) min(-1)) or saline, intra-arterial blood pressure and heart rate were measured continuously, concomitantly with cardiac output estimated by pulse contour analysis. Renal plasma...... flow, glomerular filtration rate, and uptake/release of hormones and ions were measured using Fick's Principle after catheterization of a renal vein. Urine collection was conducted throughout the experiments at voluntary voiding, and patients remained supine during the experiments. During the GLP-1...... infusion, systolic and diastolic blood pressure and cardiac output remained unchanged, whereas heart rate increased significantly. Arterio-venous gradients for GLP-1 exceeded glomerular filtrations significantly, but renal plasma flow and glomerular filtration rate as well as renal sodium and lithium...

  13. Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

    Plamboeck, A; Holst, Jens Juul; Carr, R D;

    2005-01-01

    glucose were unaffected by candoxatril, but glucose tolerance was improved (DeltaAUC(min 27-87) 118+/-5 to 74+/-14 min.mmol.l(-1); glucose elimination rate [k] 6.6+/-0.5 to 8.6+/-0.5%; pvaline pyrrolidide (a DPP-IV inhibitor), changes in C-terminal GLP-1...... pharmacokinetics mirrored those seen when candoxatril alone was administered (t(1/2) 2.7+/-0.3 and 7.7+/-0.8 min; MCR 17.3+/-2.6 and 6.5+/-0.8 ml.kg(-1).min(-1) for valine pyrrolidide without and with candoxatril, respectively). However, intact GLP-1 pharmacokinetics were improved (t(1/2) 2.8+/-0.3 and 7...

  14. Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity.

    Hwang, Injae; Park, Yoon Jeong; Kim, Yeon-Ran; Kim, Yo Na; Ka, Sojeong; Lee, Ho Young; Seong, Je Kyung; Seok, Yeong-Jae; Kim, Jae Bum

    2015-06-01

    Firmicutes and Bacteroidetes, 2 major phyla of gut microbiota, are involved in lipid and bile acid metabolism to maintain systemic energy homeostasis in host. Recently, accumulating evidence has suggested that dietary changes promptly induce the alteration of abundance of both Firmicutes and Bacteroidetes in obesity and its related metabolic diseases. Nevertheless, the metabolic roles of Firmicutes and Bacteroidetes on such disease states remain unclear. The aim of this study was to determine the effects of antibiotic-induced depletion of Firmicutes and Bacteroidetes on dysregulation of energy homeostasis in obesity. Treatment of C57BL/6J mice with the antibiotics (vancomycin [V] and bacitracin [B]), in the drinking water, before diet-induced obesity (DIO) greatly decreased both Firmicutes and Bacteroidetes in the gut as revealed by pyrosequencing of the microbial 16S rRNA gene. Concomitantly, systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated via augmentation of GLP-1 secretion (active form; 2.03-fold, total form; 5.09-fold) independently of obesity as compared with untreated DIO controls. Furthermore, there were increases in metabolically beneficial metabolites derived from the gut. Together, our data suggest that Firmicutes and Bacteroidetes potentially mediate insulin resistance through modulation of GLP-1 secretion in obesity.

  15. 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

    , 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...

  16. Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease

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

    2009-01-01

    stimulated GLP-1 levels and: (1) cardiovascular risk factors (blood pressure, lipids, urinary albumin, waist circumference and insulin sensitivity index [M/I] assessed by euglycaemic-hyperinsulinaemic clamp); and (2) impaired glucose tolerance (IGT) and type 2 diabetes mellitus. RESULTS: During the follow......-up period (maximum 13.8 years), of 294 participants with normal glucose tolerance (NGT), 69 experienced a CHD event (13.8 years), as did 42 of 141 with IGT and 32 of 74 with type 2 diabetes mellitus. DeltaGLP-1 did not predict CHD (HR 1.0, 95% CI 0.52-2.28). The prevalence of IGT was associated with Delta...

  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

    2005-01-01

    , in inflammatory bowel disease (IBD), the production and secretion of GLP-2 and PYY could be affected as a part of a regulatory mechanism. Therefore, tissue levels and meal-stimulated secretion of GLP-2 and PYY were studied in IBD patients and compared to controls. METHODS: Outpatients with IBD and control...... patients were included. Mucosal biopsies were taken from the ileum and colon and the content of GLP-2 and PYY was measured. After colonoscopy the patients took a mixed meal and plasma was collected for 90 min for plasma measurements of GLP-2 and PYY. RESULTS: Tissue levels of GLP-2 in control patients were...... highest in the terminal ileum (407+/-82 pmol/g tissue, n=10), whereas PYY was highest in the rectum (919+/-249 pmol/g tissue, n=10). In IBD patients with acute inflammation, the content of GLP-2 was similar to controls, whereas PYY was decreased to 72.1+/-17.7% (P=0.03, n=13) of control values. Neither...

  18. 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....

  19. 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 a rat model of human SBS that results in intestinal failure requiring total parenteral nutrition (TPN). Rats underwent 60% jejunoileal resection plus cecectomy and jugular vein cannulation and were maintained exclusively with TPN for 18 days in these treatments: TPN control (no GLP-2); sustained GLP-2...

  20. [Roles of rs 6923761 gene variant in glucagon-like peptide 1 receptor on weight, cardiovascular risk factor and serum adipokine levels in morbid obese patients].

    de Luis, Daniel Antonio; Pacheco, David; Aller, Rocío; Izaola, Olatz; Bachiller, Rosario

    2014-04-01

    Antecedentes: Los estudios de receptor de GLP-1 se han dirigido a la identificación de polimorfismos en el gen receptor de GLP- 1 que pueden ser un factor que contribuye en la patogénesis de la diabetes mellitus y factores de riesgo cardiovascular. Sin embargo, el papel de las variantes del receptor de GLP-1 variantes en el peso corporal, factores de riesgo cardiovasculares y adipocitoquinas sigue estando poco estudiado en pacientes con obesidad morbida. Objetivo: Nuestro objetivo fue analizar los efectos del polimorfismo del receptor de GLP-1 rs6923761 sobre el peso corporal, factores de riesgo cardiovascular y los niveles de adipocitoquinas séricas en pacientes con obesidad mórbida. Diseño: Se estudió una muestra de 175 obesos mórbidos. La glucosa en ayunas, proteína C reactiva (PCR), insulina, resistencia a la insulina ( HOMA), colesterol total, LDL- colesterol, HDL- colesterol, triglicéridos y la concentración de adipoquinas se midieron. También se determinaron el peso, índice de masa corporal, circunferencia de la cintura, masa grasa a través de bioimpedancia y la presión arterial. Resultados: Un total de 87 obesos (49,7%) tenían el genotipo GG y 88 (50,3%) de los sujetos del estudio tenían los siguientes genotipos; GA (71 obesos, el 40,6%) o AA (17 sujetos del estudio, el 9,7%) ( segundo grupo) . En el grupo con genotipo GG, los niveles de glucosa (4,4 ± 2,3 mg/dl, p < 0,05), triglicéridos (6,8 ± 4,3 mg/dl , p < 0,05), insulina (4,5 ± 2,3 UI/l , p < 0,05) y HOMA (1,5 ± 0,9 unidades, p < 0,05 ) fueron mayores que en el grupo mutante. No se detectaron diferencias en el resto de parámetros analizados Conclusión: Existe una asociación entre los parámetros metabólicos y el alelo mutante (A) del polimorfismo rs6923761 del receptor de GLP- 1 en pacientes con obesidad mórbida. Los niveles de triglicéridos, insulina y resistencia a la insulina son más elevados en los sujetos portadores del alelo A.