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John A Rudd - One of the best experts on this subject based on the ideXlab platform.

  • glp 1 receptors are involved in the glp 1 7 36 amide induced modulation of glucose homoeostasis emesis and feeding in suncus murinus house musk shrew
    European Journal of Pharmacology, 2020
    Co-Authors: Sze Wa Chan, Man Piu Ngan, John A Rudd
    Abstract:

    Abstract GLP-1 receptor agonists are used for the treatment of type 2 diabetes but they may reduce appetite and cause nausea and emesis. We investigated if GLP-1 (7–36) amide can modulate glucose homoeostasis, emesis and feeding via an Exendin (9–39)-sensitive mechanism in Suncus murinus. The effect of GLP-1 (7–36) amide on glucose homeostasis was examined using an intraperitoneal glucose tolerance test. In conscious fasted animals, food and water consumption and behavior were measured for 1 h following drug administration. c-Fos expression in the brain was measured using immunohistochemistry. GLP-1 (7–36) amide reduced blood glucose levels dose-dependently. Exendin (9–39) did not modify blood glucose levels but suppressed the glucose-lowering effect of GLP-1 (7–36) amide. GLP-1 (7–36) amide inhibited food and water intake, induced emesis and elevated c-Fos expression in the brainstem and hypothalamic nuclei in the brain. Exendin (9–39) antagonised the inhibition of food and water intake and emesis induced by GLP-1 (7–36) amide and the effects on c-Fos expression in the hypothalamus and brainstem, excepting for the bed nucleus of the stria terminalis. These data suggest that the action of GLP-1 (7–36) amide to modulate blood glucose, suppress food and water intake and induce emesis involve GLP-1 receptors in the hypothalamus and brainstem.

  • the differential antiemetic properties of glp 1 receptor antagonist Exendin 9 39 in suncus murinus house musk shrew
    Neuropharmacology, 2014
    Co-Authors: Sze Wa Chan, Zengbing Lu, Chi Kong Yeung, John A Rudd
    Abstract:

    Abstract The use of glucagon-like peptide-1 (7–36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Previous studies using Suncus murinus revealed that the GLP-1 receptor agonist, Exendin-4, induces emesis via the brainstem and/or hypothalamus. The present study investigated the mechanism of Exendin-4-induced emesis in more detail. Ondansetron (1 mg/kg, s.c.) and CP-99,994 (10 mg/kg, s.c) failed to reduce emesis induced by Exendin-4 (3 nmol, i.c.v.), suggesting that 5-HT3 and NK1 receptors are not involved in the mechanism. In other studies, the GLP-1 receptor antagonist, Exendin (9–39), antagonised emesis and c-Fos expression in the brainstem and the paraventricular hypothalamus induced by the chemotherapeutic drug cisplatin (30 mg/kg, i.p.; p   0.05), or copper sulphate pentahydrate (120 mg/kg, p.o.; p > 0.05). GLP-1 receptors may therefore represent a potential target for drugs to prevent chemotherapy-induced emesis in situations where 5-HT3 and NK1 receptor antagonists fail.

  • separation of emetic and anorexic responses of Exendin 4 a glp 1 receptor agonist in suncus murinus house musk shrew
    Neuropharmacology, 2013
    Co-Authors: Sze Wa Chan, Chi Kong Yeung, John A Rudd
    Abstract:

    Abstract The use of glucagon-like peptide-1 (7–36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Therefore, the present studies investigated the potential of GLP-1 receptor ligands to modulate emesis and feeding in Suncus murinus. Exendin-4, a selective GLP-1 receptor agonist, was administered subcutaneously (1–30 nmol/kg) or intracerebroventricularly (0.03–3 nmol) after 12-h of fasting. In other studies, animals were pretreated with the GLP-1 receptor antagonist, Exendin (9–39), or saline (5 μl) 15 min prior to Exendin-4 (3 nmol, i.c.v.). Behaviour of animals and food and water intake were then recorded for 1–2 h; c-Fos expression was also assessed in the brains of animals in the i.c.v. studies. The subcutaneous administration of Exendin-4 reduced food and water intake (p   0.05). The intracerebroventricular administration of Exendin-4 also prevented feeding, and induced emesis (p   0.05). These data suggest that Exendin-4 exerts its emetic effects in the brainstem and/or hypothalamus via GLP-1 receptors. The action of Exendin-4 to suppress feeding may involve non-classical GLP-1 receptors or other mechanisms.

  • action of glp 1 7 36 amide and Exendin 4 on suncus murinus house musk shrew isolated ileum
    European Journal of Pharmacology, 2007
    Co-Authors: Sze Wa Chan, John A Rudd, Jufang He, Kouichi Yamamoto
    Abstract:

    Glucagon-like peptide-1 (GLP-1) receptor agonists have been reported to modulate gastrointestinal motility but the mechanism is essentially unknown. In the present studies, we investigated the potency and mechanism of action of GLP-1 receptor ligands on the isolated ileum of Suncus murinus, an insectivore used in anti-emetic research. Ileal segments were mounted in organ baths containing Kreb's solution. Cumulative concentration–response curves to GLP-1 (7-36) amide (0.1–300 nM) and Exendin-4 (0.1–100 nM) were constructed in the absence and presence of Exendin (9-39) amide (0.3–3 nM). GLP-1 (7-36) amide and Exendin-4 induced concentration-dependent contractions yielding pEC50 values of 8.4 ± 0.2 and 8.4 ± 0.4, respectively. Exendin (9-39) antagonized the action of both agonists in a non-competitive reversible manner, with apparent pKB values of 9.5 and 9.7, respectively. Tetrodotoxin (1 μM), atropine (1 μM) and hexamethonium (500 μM) were used to determine the contractile mechanism of action of Exendin-4. Tetrodotoxin and atropine significantly antagonized (P < 0.01) the contractile action of Exendin-4 (10 nM); hexamethonium (500 μM) had no action. These studies suggest that GLP-1 receptor agonists contract the ileum indirectly via postganglionic enteric neurones and an involvement of muscarinic receptors. These studies provide information relevant to the use of this species to estimate the therapeutic indexes of GLP-1 receptor agonists.

Sze Wa Chan - One of the best experts on this subject based on the ideXlab platform.

  • glp 1 receptors are involved in the glp 1 7 36 amide induced modulation of glucose homoeostasis emesis and feeding in suncus murinus house musk shrew
    European Journal of Pharmacology, 2020
    Co-Authors: Sze Wa Chan, Man Piu Ngan, John A Rudd
    Abstract:

    Abstract GLP-1 receptor agonists are used for the treatment of type 2 diabetes but they may reduce appetite and cause nausea and emesis. We investigated if GLP-1 (7–36) amide can modulate glucose homoeostasis, emesis and feeding via an Exendin (9–39)-sensitive mechanism in Suncus murinus. The effect of GLP-1 (7–36) amide on glucose homeostasis was examined using an intraperitoneal glucose tolerance test. In conscious fasted animals, food and water consumption and behavior were measured for 1 h following drug administration. c-Fos expression in the brain was measured using immunohistochemistry. GLP-1 (7–36) amide reduced blood glucose levels dose-dependently. Exendin (9–39) did not modify blood glucose levels but suppressed the glucose-lowering effect of GLP-1 (7–36) amide. GLP-1 (7–36) amide inhibited food and water intake, induced emesis and elevated c-Fos expression in the brainstem and hypothalamic nuclei in the brain. Exendin (9–39) antagonised the inhibition of food and water intake and emesis induced by GLP-1 (7–36) amide and the effects on c-Fos expression in the hypothalamus and brainstem, excepting for the bed nucleus of the stria terminalis. These data suggest that the action of GLP-1 (7–36) amide to modulate blood glucose, suppress food and water intake and induce emesis involve GLP-1 receptors in the hypothalamus and brainstem.

  • the differential antiemetic properties of glp 1 receptor antagonist Exendin 9 39 in suncus murinus house musk shrew
    Neuropharmacology, 2014
    Co-Authors: Sze Wa Chan, Zengbing Lu, Chi Kong Yeung, John A Rudd
    Abstract:

    Abstract The use of glucagon-like peptide-1 (7–36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Previous studies using Suncus murinus revealed that the GLP-1 receptor agonist, Exendin-4, induces emesis via the brainstem and/or hypothalamus. The present study investigated the mechanism of Exendin-4-induced emesis in more detail. Ondansetron (1 mg/kg, s.c.) and CP-99,994 (10 mg/kg, s.c) failed to reduce emesis induced by Exendin-4 (3 nmol, i.c.v.), suggesting that 5-HT3 and NK1 receptors are not involved in the mechanism. In other studies, the GLP-1 receptor antagonist, Exendin (9–39), antagonised emesis and c-Fos expression in the brainstem and the paraventricular hypothalamus induced by the chemotherapeutic drug cisplatin (30 mg/kg, i.p.; p   0.05), or copper sulphate pentahydrate (120 mg/kg, p.o.; p > 0.05). GLP-1 receptors may therefore represent a potential target for drugs to prevent chemotherapy-induced emesis in situations where 5-HT3 and NK1 receptor antagonists fail.

  • separation of emetic and anorexic responses of Exendin 4 a glp 1 receptor agonist in suncus murinus house musk shrew
    Neuropharmacology, 2013
    Co-Authors: Sze Wa Chan, Chi Kong Yeung, John A Rudd
    Abstract:

    Abstract The use of glucagon-like peptide-1 (7–36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Therefore, the present studies investigated the potential of GLP-1 receptor ligands to modulate emesis and feeding in Suncus murinus. Exendin-4, a selective GLP-1 receptor agonist, was administered subcutaneously (1–30 nmol/kg) or intracerebroventricularly (0.03–3 nmol) after 12-h of fasting. In other studies, animals were pretreated with the GLP-1 receptor antagonist, Exendin (9–39), or saline (5 μl) 15 min prior to Exendin-4 (3 nmol, i.c.v.). Behaviour of animals and food and water intake were then recorded for 1–2 h; c-Fos expression was also assessed in the brains of animals in the i.c.v. studies. The subcutaneous administration of Exendin-4 reduced food and water intake (p   0.05). The intracerebroventricular administration of Exendin-4 also prevented feeding, and induced emesis (p   0.05). These data suggest that Exendin-4 exerts its emetic effects in the brainstem and/or hypothalamus via GLP-1 receptors. The action of Exendin-4 to suppress feeding may involve non-classical GLP-1 receptors or other mechanisms.

  • action of glp 1 7 36 amide and Exendin 4 on suncus murinus house musk shrew isolated ileum
    European Journal of Pharmacology, 2007
    Co-Authors: Sze Wa Chan, John A Rudd, Jufang He, Kouichi Yamamoto
    Abstract:

    Glucagon-like peptide-1 (GLP-1) receptor agonists have been reported to modulate gastrointestinal motility but the mechanism is essentially unknown. In the present studies, we investigated the potency and mechanism of action of GLP-1 receptor ligands on the isolated ileum of Suncus murinus, an insectivore used in anti-emetic research. Ileal segments were mounted in organ baths containing Kreb's solution. Cumulative concentration–response curves to GLP-1 (7-36) amide (0.1–300 nM) and Exendin-4 (0.1–100 nM) were constructed in the absence and presence of Exendin (9-39) amide (0.3–3 nM). GLP-1 (7-36) amide and Exendin-4 induced concentration-dependent contractions yielding pEC50 values of 8.4 ± 0.2 and 8.4 ± 0.4, respectively. Exendin (9-39) antagonized the action of both agonists in a non-competitive reversible manner, with apparent pKB values of 9.5 and 9.7, respectively. Tetrodotoxin (1 μM), atropine (1 μM) and hexamethonium (500 μM) were used to determine the contractile mechanism of action of Exendin-4. Tetrodotoxin and atropine significantly antagonized (P < 0.01) the contractile action of Exendin-4 (10 nM); hexamethonium (500 μM) had no action. These studies suggest that GLP-1 receptor agonists contract the ileum indirectly via postganglionic enteric neurones and an involvement of muscarinic receptors. These studies provide information relevant to the use of this species to estimate the therapeutic indexes of GLP-1 receptor agonists.

Burkhard Göke - One of the best experts on this subject based on the ideXlab platform.

  • reduction of the incretin effect in rats by the glucagon like peptide 1 receptor antagonist Exendin 9 39 amide
    Diabetes, 1995
    Co-Authors: Frank Kolligs, Hans Christoph Fehmann, Rudiger Goke, Burkhard Göke
    Abstract:

    Glucagon-like peptide 1 (7–37)/(7–36) amide (GLP-1) is derived from the intestinal proglucagon processing. It is considered an important insulin-releasing gut hormone. This study uses Exendin (9–39) amide as a GLP-1 receptor antagonist to evaluate the contribution of GLP-1 to the incretin effect. Anesthetized rats were challenged by an intraduodenal glucose infusion to evaluate maximally occurring GLP-1 and gastric inhibitory polypeptide (GIP) plasma levels. Maximal immunoreactive (IR) GLP-1 plasma levels amounted to 10 pmol/l (IR-GIP 11 pmol/l). Exendin (9–39) amide abolished the insulin-stimulatory effect of 60 pmol of GLP-1 or of the GLP-1 agonist Exendin-4 (0.5 nmol) injected as bolus, respectively. An intravenous bolus injection of 5.94 nmol of Exendin (9–39) amide 3 min before enteral glucose infusion grossly reduced the total insulin secretory response (by 60%) and significantly increased circulating blood glucose levels ( P

  • stable expression of the rat glp i receptor in cho cells activation and binding characteristics utilizing glp i 7 36 amide oxyntomodulin Exendin 4 and Exendin 9 39
    Peptides, 1994
    Co-Authors: Hans Christoph Fehmann, Jiwen Jiang, Johannes Schweinfurth, Michael B. Wheeler, Aubrey E. Boyd, Burkhard Göke
    Abstract:

    Abstract Glucagon-like peptide-I (GLP-I) is a potent insulinotropic peptide that mediates its actions at pancreatic B-cells via specific receptors. In the present study we stably expressed the rat B-cell GLP-I receptor in CHO cells and studied binding characteristics and receptor activation utilizing the naturally occuring receptor agonist GLP-I(7–36)-amide (GLP-I), the proglucagon-derived GLP-I-related peptide oxyntomodulin, the GLP-I receptor agonist Exendin-4, and the specific antagonist Exendin(9–39). The potencies to displace [ 125 I]GLP-I from the receptor were GLP-I > Exendin-4 > Exendin(9–39) > oxyntomodulin , and to displace [ 125 I]Exendin-4 GLP-I = Exendin-4 > Exendin(9–39) > oxyntomodulin . cAMP production was stimulated equally by GLP-I and Exendin-4. Oxyntomodulin was less potent to stimulate cAMP generation. Exendin(9–39) blocked the stimulatory action of GLP-I and Exendin-4 on cAMP production, but not that of oxyntomodulin. This study shows that GLP-I and Exendin-4 are potent agonists at the transfected rat B-cell GLP-I receptor whereas oxyntomodulin is only a weak GLP-I receptor agonist. Furthermore, Exendin(9–39) is a potent GLP-I receptor antagonist. This peptide is a valuable tool to further study the physiological actions of GLP-I.

  • rat gastric somatostatin and gastrin release interactions of Exendin 4 and truncated glucagon like peptide 1 glp 1 amide
    Life Sciences, 1994
    Co-Authors: R. Eissele, Burkhard Göke, E Bothesandfort, J Eng, R Arnold, H Koop
    Abstract:

    The effect of Exendin-4, a peptide of the secretin-glucagon family with high homology of amino acid sequence with glucagon-like peptide-1 (GLP-1), on gastric hormone release was investigated in the isolated perfused rat stomach. Exendin-4 dose dependently stimulated somatostatin release up to 9-fold at a concentration of 10(-7) M whereas gastrin release was inversely inhibited by up to 63%. These effects could partially be reduced by concomitant perfusion of truncated Exendin-4, Exendin(9-39)amide. Similarly, stimulation of somatostatin secretion and inhibition of gastrin release induced by GLP-1(7-36)amide was partially reversed by Exendin-4 (9-39)amide. These data are consistent with the assumption that Exendin-4 and truncated GLP-1amide exert their effects on gastric D and G cell by interaction with the same receptor.

  • Exendin 4 is a high potency agonist and truncated Exendin 9 39 amide an antagonist at the glucagon like peptide 1 7 36 amide receptor of insulin secreting beta cells
    Journal of Biological Chemistry, 1993
    Co-Authors: Rudiger Goke, Hans Christoph Fehmann, T Linn, Harald Schmidt, M Krause, Burkhard Göke
    Abstract:

    Abstract Exendin-4 purified from Heloderma suspectum venom shows structural relationship to the important incretin hormone glucagon-like peptide 1-(7-36)-amide (GLP-1). We demonstrate that Exendin-4 and truncated Exendin-(9-39)-amide specifically interact with the GLP-1 receptor on insulinoma-derived cells and on lung membranes. Exendin-4 displaced 125I-GLP-1, and unlabeled GLP-1 displaced 125I-Exendin-4 from the binding site at rat insulinoma-derived RINm5F cells. Exendin-4 had, like GLP-1, a pronounced effect on intracellular cAMP generation, which was reduced by Exendin-(9-39)-amide. When combined, GLP-1 and Exendin-4 showed additive action on cAMP. They each competed with the radio-labeled version of the other peptide in cross-linking experiments. The apparent molecular mass of the respective ligand-binding protein complex was 63,000 Da. Exendin-(9-39)-amide abolished the cross-linking of both peptides. Exendin-4, like GLP-1, stimulated dose dependently the glucose-induced insulin secretion in isolated rat islets, and, in mouse insulinoma beta TC-1 cells, both peptides stimulated the proinsulin gene expression at the level of transcription. Exendin-(9-39)-amide reduced these effects. In conclusion, Exendin-4 is an agonist and Exendin-(9-39)-amide is a specific GLP-1 receptor antagonist.

Jens J Holst - One of the best experts on this subject based on the ideXlab platform.

  • 1909 p the natriuretic action of glucagon like peptide 1 in humans is abolished by the glp 1 receptor antagonist Exendin 9 39
    Diabetes, 2020
    Co-Authors: Ali Asmar, Jens J Holst, Per K Cramon, Meena Asmar, Lene Simonsen, Sten Madsbad, Charlotte Mehlin Sorensen, Bolette Hartmann, Peter Hovind, Boye L Jensen
    Abstract:

    We have recently demonstrated that renal extraction of GLP-1 is ∼45% and that extracellular fluid volume expansion in healthy participants uncovered a natriuretic action of GLP-1 probably via a tubular mechanism secondary to suppression of angiotensin II (ANG II) and independent of changes in renal hemodynamics. It is not known whether the high extraction is due to receptor binding. The present study was designed to test the hypotheses that the renal extraction and natriuretic effect of GLP-1 are mediated via GLP-1 receptor. Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study1 and examined during a 3-h infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-h infusion of the GLP-1 receptor antagonist, Exendin 9-39 (Ex 9-39) (900 pmol/kg/min), initiated 30 minutes before start of GLP-1 infusion. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and renal extraction of GLP-1 were measured via Fick’s principle after catheterization of a renal vein. Renal extraction of GLP-1 was ∼45% during infusion of GLP-1 alone and decreased significantly to ∼25% during co-infusion of GLP-1 and Ex 9-39. Urinary sodium and osmolar excretions remained at baseline levels during co-infusion of GLP-1 and Ex 9-39 compared to a mean 2-fold natriuretic effect during GLP-1 infusion alone. Arterial plasma ANG II levels were unaffected during the co-infusions, whereas ANG II decreased significantly during GLP-1 alone. Arterial plasma renin levels decreased similarly on the two study days, and arterial aldosterone levels remained unchanged on both days. RPF and GFR remained unchanged on both days. In conclusion, renal extraction of GLP-1 is partially and natriuresis is fully dependent on GLP-1 receptor activation, probably via GLP-1-mediated ANG II suppression. 1Asmar A et al. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519. Disclosure A. Asmar: None. P.K. Cramon: None. M. Asmar: None. L. Simonsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C.M. Sorensen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. P. Hovind: None. B.L. Jensen: None. J. Bulow: None.

  • glucagon like peptide 1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans
    The Journal of Clinical Endocrinology and Metabolism, 2018
    Co-Authors: Abdul Halim, Jens J Holst, Marie Degerblad, Magnus Sundbom, Urban Karlbom, Dominicluc Webb, Per M Hellstrom
    Abstract:

    Context: Glucagon-like peptide-1 (GLP-1) secretion from L-cells and postprandial inhibition of gastrointestinal motility.Objective: Investigate whether physiological plasma concentrations of GLP-1 can inhibit human postprandial gastrointestinal motility; determine target mechanism of GLP-1 and analogue ROSE-010 action.Design: Single-blind parallel study.Setting: University research laboratory.Participants: Healthy volunteers investigated with antroduodenojejunal manometry. Human gastric, intestinal and colonic muscle strips.Interventions: Motility indices (MI) obtained before and during infusion of saline or GLP-1 were compared. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips, pre-contracted with bethanechol/electric field stimulation (EFS), investigated for GLP-1- or ROSE-010-induced relaxation. GLP-1, GLP-2 and their receptors localized by immunohistochemistry. Action mechanisms studied employing Exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2´,5´-dideoxyadenosine (DDA), tetrodotoxin (TTX).Main outcome measures: Hypothesize postprandial gastric relaxation induced by GLP-1, the mechanism of which intrinsic neuronally-mediated.Results: Food intake increased MI to 6.4±0.3 (antrum), 5.7±0.4 (duodenum) and 5.9±0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg·min significantly suppressed MI to 4.6±0.2, 4.7±0.4 and 5.0±0.2, respectively, while 1.2 pmol/kg·min suppressed corresponding MI to 5.4±0.2, 4.4±0.3 and 5.4±0.3 (p<0.0001-0.005). GLP-1 and ROSE-010 prevented bethanechol- or EFS-induced muscle contractions (p <0.005-0.05). Inhibitory responses to GLP-1 and ROSE-10 were blocked by Exendin(9-39)amide, L-NMMA, DDA or TTX (all p <0.005-0.05). GLP-1 and GLP-2 were localized to epithelial cells; GLP-1 also in myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle, GLP-1R also in epithelial cells.Conclusions: GLP-1 inhibits postprandial motility through GLP-1R at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.

  • Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice
    2016
    Co-Authors: Cendrine Cabou, Jens J Holst, Myriam Masseboeuf, Pierre Cattan, Mattieu Armanet, Julien Castel, Celine Garret, Adriano Maida, Thierry Sulpice, Daniel J Drucker
    Abstract:

    Inhibitionofdipeptidyl peptidase-4 (DPP-4) activity improvesglucosehomeostasis throughamode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressedon the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemicDPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia inmice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r/ and Gipr/mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an iv infusion of the corresponding receptor antagonist Exendin (9–39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitroon isolated islets.Wedemonstrate that very lowdoses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but no

  • quantification of the contribution of glp 1 to mediating insulinotropic effects of dpp 4 inhibition with vildagliptin in healthy subjects and patients with type 2 diabetes using Exendin 9 39 as a glp 1 receptor antagonist
    Diabetes, 2016
    Co-Authors: Matthias A Nauck, Lise Kjems, Carolyn F Deacon, Joachim Kind, Lars D Kothe, Matthias Broschag, Jens J Holst, James E Foley
    Abstract:

    We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist Exendin [9-39] in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes and 29 age- and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of Exendin [9-39]. The main end point was the ratio of the areas under the curve (AUCs) of integrated insulin secretion rates (total AUCISR) and glucose (total AUCglucose) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUCISR/AUCglucose in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and Exendin [9-39] reduced it (both P < 0.0001). The percentage reduction in the AUCISR/AUCglucose ratio achieved with Exendin [9-39] was significantly smaller after vildagliptin treatment than after placebo treatment (P = 0.026) and was equivalent to 47 ± 5% of the increments due to vildagliptin. Thus, other mediators appear to contribute significantly to the therapeutic effects of DPP-4 inhibition.

  • involvement of endogenous glucagon like peptide 1 in regulation of gastric motility and pancreatic endocrine secretion
    Scandinavian Journal of Gastroenterology, 2011
    Co-Authors: Annebarbara Witte, Jens J Holst, Per M Hellstrom, Per Gryback, Hans Jacobsson, Erik Naslund, Linda Hilsted, Peter T Schmidt
    Abstract:

    Abstract 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 concentrations of insulin, glucagon and glucose were measured during infusion of saline or the GLP-1 receptor antagonist Exendin(9-39)amide (Ex(9-39)) at 300 pmol·kg−1·min−1. Results. Ex(9-39) infusion had no effect on the total gastric emptying curve, but changed the intra-gastric distribution of the meal. During infusion of Ex(9-39), more content stayed in the upper stomach (79.1 ± 2.5% of total during Ex(9-39) compared to 66.6 ± 5.7% during saline at 5 min). During Ex(9-39) infusion, higher concentrations of plasma glucagon were measured both before (after 40 min of Ex(9-39) infusion the glucagon level was 15.1 ± 0.7 pmol·L−1 compared to 5.4 ± 1.4 during saline) and after the meal, and postprandial GLP...

Daniel J Drucker - One of the best experts on this subject based on the ideXlab platform.

  • Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice
    2016
    Co-Authors: Cendrine Cabou, Jens J Holst, Myriam Masseboeuf, Pierre Cattan, Mattieu Armanet, Julien Castel, Celine Garret, Adriano Maida, Thierry Sulpice, Daniel J Drucker
    Abstract:

    Inhibitionofdipeptidyl peptidase-4 (DPP-4) activity improvesglucosehomeostasis throughamode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressedon the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemicDPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia inmice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r/ and Gipr/mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an iv infusion of the corresponding receptor antagonist Exendin (9–39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitroon isolated islets.Wedemonstrate that very lowdoses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but no

  • glucagon like peptide glp 1 9 36 amide mediated cytoprotection is blocked by Exendin 9 39 yet does not require the known glp 1 receptor
    Endocrinology, 2010
    Co-Authors: Kiwon Ban, Kyounghan Kim, Chankyung J Cho, Meghan Sauve, Eleftherios P Diamandis, Peter H Backx, Daniel J Drucker, Mansoor Husain
    Abstract:

    The widely expressed dipeptidyl peptidase-4 enzyme rapidly cleaves the gut hormone glucagon-like peptide-1 [GLP-1(7-36)amide] at the N terminus to generate GLP-1(9-36)amide. Both intact GLP-1(7-36)amide and GLP-1(9-36)amide exert cardioprotective actions in rodent hearts; however, the mechanisms underlying the actions of GLP-1(9-36)amide remain poorly understood. We used mass spectrometry of coronary effluents to demonstrate that isolated mouse hearts rapidly convert infused GLP-1(7-36)amide to GLP-1(9-36)amide. After ischemia-reperfusion (I/R) injury of isolated mouse hearts, administration of GLP-1(9-36)amide or Exendin-4 improved functional recovery and reduced infarct size. The direct actions of these peptides were studied in cultured neonatal mouse cardiomyocytes. Both GLP-1(9-36)amide and Exendin-4 increased levels of cAMP and phosphorylation of ERK1/2 and the phosphoinositide 3-kinase target protein kinase B/Akt. In I/R injury models in vitro, both peptides improved mouse cardiomyocyte viability and reduced lactate dehydrogenase release and caspase-3 activation. These effects were attenuated by inhibitors of ERK1/2 and phosphoinositide 3-kinase. Unexpectedly, the cardioprotective actions of GLP-1(9-36)amide were blocked by Exendin(9-39) yet preserved in Glp1r(-/-) cardiomyocytes. Furthermore, GLP-1(9-36)amide, but not Exendin-4, improved the survival of human aortic endothelial cells undergoing I/R injury, actions sensitive to the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). In summary, our findings demonstrate separate actions for GLP-1(9-36)amide vs. the GLP-1R agonist Exendin-4 and reveal the existence of a GLP-1(9-36)amide-responsive, Exendin(9-39)-sensitive, cardioprotective signaling pathway distinct from that associated with the classical GLP-1 receptor.

  • glucagon like peptide glp 1 9 36 amide mediated cytoprotection is blocked by Exendin 9 39 yet does not require the known glp 1 receptor
    Endocrinology, 2010
    Co-Authors: Meghan Sauve, Eleftherios P Diamandis, Peter H Backx, Daniel J Drucker, Mansoor Husain
    Abstract:

    The widely expressed dipeptidyl peptidase-4 enzyme rapidly cleaves the gut hormone glucagon-like peptide-1 [GLP-1(7-36)amide] at the N terminus to generate GLP-1(9-36)amide. Both intact GLP-1(7-36)amide and GLP-1(9-36)amide exert cardioprotective actions in rodent hearts; however, the mechanisms underlying the actions of GLP-1(9-36)amide remain poorly understood. We used mass spectrometry of coronary effluents to demonstrate that isolated mouse hearts rapidly convert infused GLP-1(7-36)amide to GLP-1(9-36)amide. After ischemia-reperfusion (I/R) injury of isolated mouse hearts, administration of GLP-1(9-36)amide or Exendin-4 improved functional recovery and reduced infarct size. The direct actions of these peptides were studied in cultured neonatal mouse cardiomyocytes. Both GLP-1(9-36)amide and Exendin-4 increased levels of cAMP and phosphorylation of ERK1/2 and the phosphoinositide 3-kinase target protein kinase B/Akt. In I/R injury models in vitro, both peptides improved mouse cardiomyocyte viability an...

  • improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon like peptide 1 receptor
    Diabetes, 2006
    Co-Authors: Patrice D Cani, Daniel J Drucker, Claude Knauf, Miguel A Iglesias, Nathalie M Delzenne, Remy Burcelin
    Abstract:

    Nondigestible fermentable dietary fibers such as oligofructose (OFS) exert an antidiabetic effect and increase the secretion of glucagon-like peptide 1 (GLP-1). To determine the importance of GLP-1 receptor-dependent mechanisms for the actions of OFS, we studied high-fat-fed diabetic mice treated with OFS for 4 weeks in the presence or absence of the GLP-1 receptor antagonist Exendin 9-39 (Ex-9). OFS improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, and insulin-sensitive hepatic glucose production and reduced body weight gain. Ex-9 totally prevented the beneficial effects of OFS. Furthermore, GLP-1 receptor knockout mice (GLP-1R(-/-)) were completely insensitive to the antidiabetic actions of OFS. At the molecular level, the effects of OFS on endogenous glucose production correlated with changes of hepatic IRS (insulin receptor substrate)-2 and Akt phosphorylation in an Ex-9-dependent manner. As inflammation is associated with diabetes and obesity, we quantified nuclear factor-kappaB and inhibitor of kappaB kinase beta in the liver. The activity of both intracellular inflammatory effectors was reduced by OFS but, importantly, this effect could not be reverted by Ex-9. In summary, our data show that the antidiabetic actions of OFS require a functional GLP-1 receptor. These findings highlight the therapeutic potential of enhancing endogenous GLP-1 secretion for the treatment of type 2 diabetes.

  • brain glucagon like peptide 1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage
    Journal of Clinical Investigation, 2005
    Co-Authors: Claude Knauf, Daniel J Drucker, Patrice D Cani, Miguel A Iglesias, C Perrin, Jean Francois Maury, Elodie Bernard, Fadilha Benhamed, T Gremeaux, Ronald C Kahn
    Abstract:

    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.