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The incretins: a link between nutrients and well-being

Published online by Cambridge University Press:  08 March 2007

Rémy Burcelin
Rémy Burcelin*
Affiliation:
UMR 5018 CNRS-UPS and IFR 31, Rangueil Hospital, L1 Bldg, BP 84225, Toulouse, 31432 cedex 4, France
*
*Corresponding author: Dr Rémy Burcelin, fax +33 562 17 09 05, email [email protected]
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Abstract

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The glucoincretins, glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), are intestinal peptides secreted in response to glucose or lipid intake. Data on isolated intestinal tissues, dietary treatments and knockout mice strongly suggest that GIP and GLP-1 secretion requires glucose and lipid metabolism by intestinal cells. However, incretin secretion can also be induced by non-digestible carbohydrates and involves the autonomic nervous system and endocrine factors such as GIP itself and cholecystokinin. The classical pharmacological approach and the recent use of knockout mice for the incretin receptors have shown that a remarkable feature of incretins is the ability to stimulate insulin secretion in the presence of hyperglycaemia only, hence avoiding any hypoglycaemic episode. This important role is the basis of ongoing clinical trials using GLP-1 analogues. Since most of the data concern GLP-1, we will focus on this incretin. In addition, GLP-1 is involved in glucose sensing by the autonomic nervous system of the hepato-portal vein controlling muscle glucose utilization and indirectly insulin secretion. GLP-1 has been shown to decrease glucagon secretion, food intake and gastric emptying, preventing excessive hyperglycaemia and overfeeding. Another remarkable feature of GLP-1 is its secretion by the brain. Recently, elegant data showed that cerebral GLP-1 is involved in cognition and memory. Experiments using knockout mice suggest that the lack of the GIP receptor prevents diet-induced obesity. Consequently, macronutrients controlling intestinal glucose and lipid metabolism would control incretin secretion and would consequently be beneficial for health. The control of incretin secretion represents a major goal for new therapeutic as well as nutrition strategies for treating and/or reducing the risk of hyperglycaemic syndromes, excessive body weight and thus improvement of well-being.

Keywords

DiabetesInsulin secretionIncretinsInulin-type fructans
Type
Research Article
Information
British Journal of Nutrition , Volume 93 , Issue S1 , April 2005 , pp. S147 - S156
Copyright
Copyright © The Nutrition Society 2005

References

Adachi, A, Shimizu, N, Oomura, Y & Kobashi, M (1984) Convergence of hepatoportal glucose-sensitive afferent signals to glucose-sensitive units within the nucleus of the solitary tract. Neurosci Lett 46, 215–218.CrossRefGoogle ScholarPubMed
Ahrén, B (2004) Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice. Am J Physiol Regul Integr Comp Physiol 286, R269–R272.CrossRefGoogle ScholarPubMed
Ahrén, B & Pacini, G (1999) Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice. Am J Physiol 277, E996–E1004.Google ScholarPubMed
Ahrén, B, Larsson, H & Holst, JJ (1997) Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82, 473–478.Google ScholarPubMed
Ahrén, B, Holst, J, Martensson, H & Balkan, B (2000) Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur J Pharmacol 404, 239–245.CrossRefGoogle ScholarPubMed
Alvarez, E, Roncero, I, Chowen, JA, Thorens, B & Blazquez, E (1996) Expression of the glucagon-like peptide-1 receptor gene in rat brain. J Neurochem 66, 920–927.CrossRefGoogle ScholarPubMed
Balkan, B & Li, X (2000) Portal GLP1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol 279, R1449–R1454.Google ScholarPubMed
Balks, HJ, Holst, JJ, von zur Muhlen, A, Brabant, G (1997) Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. J Clin Endocrinol Metab 82, 786–790.Google ScholarPubMed
Banting, FG & Best, CH (1922) The internal secretion of the pancreas. J Lab Clin Med 7, 251–266.Google Scholar
Bayliss, WM & Starling, EH (1902) The mechanisms of pancreatic secretion. J Physiol 22, 325–330.CrossRefGoogle Scholar
Bell, G, Sanchez-Pescador, R, Laybourn, P & Najarian, R (1983) Exon duplication and divergence in the human preproglucagon gene. Nature 304, 368–371.CrossRefGoogle ScholarPubMed
Berthoud, HR, Niijima, A, Sauter, JF & Jeanrenaud, B (1983) Evidence for a role of the gastric, coeliac and hepatic branches in vagally stimulated insulin secretion in the rat. J Auton Nerv Syst 7, 97–110.CrossRefGoogle ScholarPubMed
Biggers, DW, Myers, SR, Neal, D, Stinson, R, Cooper, NB, Jaspan, JB, Williams, PE, Cherrington, AD & Frizzell, RT (1989) Role of brain in counterregulation of insulin-induced hypoglycemia in dogs. Diabetes 38, 7–16.CrossRefGoogle ScholarPubMed
Blazquez, E, Alvarez, E, Navarro, M, Roncero, I, Rodriguez-Fonseca, F, Chowen, JA & Zueco, JA (1998) Glucagon-like peptide-1 (7–36) amide as a novel neuropeptide. Mol Neurobiol 18, 157–173.CrossRefGoogle ScholarPubMed
Brown, JC (1971) A gastric inhibitory peptide. I. The amino acid composition and the tryptic peptides. Can J Biochem 49, 255–261.CrossRefGoogle ScholarPubMed
Brown, JC & Pederson, R (1970) A multiparameter study on the action of preparations containing cholecystokinin pancreozymin. Scand J Gastroenterol 5, 537–541.CrossRefGoogle Scholar
Brubaker, PL (1991) Regulation of intestinal proglucagon-derived peptide secretion by intestinal regulatory peptides. Endocrinology 128, 3175–3182.CrossRefGoogle ScholarPubMed
Buchan, A, Polak, J, Capella, C, Solcia, E & Pearse, A (1978) Electron immunocytochemical evidence for the K-cell. Localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry 56, 37–44.CrossRefGoogle Scholar
Burcelin, R & Thorens, B (2001) Evidence that extrapancreatic GLUT2-dependent glucose sensors control glucagon secretion. Diabetes 50, 1282–1289.CrossRefGoogle ScholarPubMed
Burcelin, R, Rolland, E, Dolci, W, Germain, S, Carrel, V & Thorens, B (1999) Encapsulated, genetically engineered cells, secreting glucagon-like peptide-1 for the treatment of non-insulin-dependent diabetes mellitus. Ann NY Acad Sci 875, 277–285.CrossRefGoogle ScholarPubMed
Burcelin, R, Dolci, W & Thorens, B (2000a) Glucose sensing by the hepatoportal sensor is GLUT-2 dependent; in vivo analysis in GLUT-2 null mice. Diabetes 49, 1643–1648.CrossRefGoogle Scholar
Burcelin, R, Dolci, W & Thorens, B (2000b) Portal glucose infusion in the mouse induces hypoglycemia. Evidence that the hepatoportal glucose sensor stimulates glucose utilization. Diabetes 49, 1635–1642.CrossRefGoogle ScholarPubMed
Burcelin, R, Da Costa, A, Drucker, D, Thorens, B (2001) Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes 50, 1720–1728.CrossRefGoogle ScholarPubMed
Byrne, MM & Goke, B (1996) Human studies with glucagon-like-peptide-1: potential of the gut hormone for clinical use. Diabet Med 13, 854–860.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Campos, RV, Lee, YC & Drucker, DJ (1994) Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology 134, 2156–2164.CrossRefGoogle ScholarPubMed
Creutzfeldt, W (1979) The incretin concept today. Diabetologia 16, 75–85.CrossRefGoogle ScholarPubMed
Creutzfeldt, W (1992) Entero-insular axis and diabetes mellitus. Horm Metab Res 26, Suppl, 13–18.Google ScholarPubMed
Creutzfeldt, WO, Kleine, N, Willms, B, Orskov, C, Holst, JJ & Nauck, MA (1996) Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7–36) amide in type I diabetic patients. Diabetes Care 19, 580–586.CrossRefGoogle ScholarPubMed
Cryer, P (1981) Glucose counterregulation in man. Diabetes 30, 261–264.CrossRefGoogle ScholarPubMed
Damholt, A, Kofod, H & Buchan, A (1999) Immunocytochemical evidence for a paracrine interaction between GIP and GLP-1-producing cells in canine small intestine. Cell Tissue Res 298, 287–293.CrossRefGoogle ScholarPubMed
Deacon, CF, Johnsen, AH & Holst, JJ (1995a) Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 80, 952–957.Google Scholar
Deacon, CF, Nauck, MA, Toft-Nielsen, M, Pridal, L, Willms, B & Holst, JJ (1995b) Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44, 1126–1131.CrossRefGoogle ScholarPubMed
Donahey, J, Van Dijk, G, Woods, S & Seeley, R (1998) Intraventricular GLP-1 reduced short but not long term food intake or body weight in lean and obese rats. Brain Res 779, 75–83.CrossRefGoogle ScholarPubMed
Drucker, DJ (1990) Glucagon and the glucagon-like peptides. Pancreas 5, 484–488.CrossRefGoogle ScholarPubMed
Drucker, DJ (1998) Glucagon-like peptides. Diabetes 47, 159–169.CrossRefGoogle ScholarPubMed
During, M, Cao, L & Zuzga, D (2003) Glucagon like peptide 1 receptor is involved in learning and neuroprotection. Nat Med 9, 1173–1179.CrossRefGoogle ScholarPubMed
Ebert, R & Creutzfeldt, W (1982) Influence of gastric inhibitory polypeptide antiserum on glucose induced insulin secretion in rats. Endocrinology 111, 1601–1606.CrossRefGoogle ScholarPubMed
Ebert, R, Unger, H & Creutzfeldt, W (1983) Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption. Diabetologia 24, 449–454.CrossRefGoogle ScholarPubMed
Fehmann, HC, Goke, B, Weber, V, Goke, R, Trautmann, ME, Richter, G & Arnold, R (1990) Interaction of glucagon-like peptide-1 (7–36) amide and cholecystokinin-8 in the endocrine and exocrine rat pancreas. Pancreas 5, 361–365.CrossRefGoogle ScholarPubMed
Fehmann, HC, Goke, R, Goke, B, Bachle, R, Wagner, B & Arnold, R (1991) Priming effect of glucagon-like peptide-1 (7–36) amide, glucose-dependent insulinotropic polypeptide and cholecystokinin-8 at the isolated perfused rat pancreas. Biochim Biophys Acta 1091, 356–363.CrossRefGoogle ScholarPubMed
Fridolf, T & Ahren, B (1991) GLP-1(7–36) amide stimulates insulin secretion in rat islets: studies on the mode of action. Diabetes Res 16, 185–191.Google ScholarPubMed
Fridolf, T & Ahren, B (1993) Effects of glucagon like peptide-1(7–36) amide on the cytoplasmic Ca(2+)-concentration in rat islet cells. Mol Cell Endocrinol 96, 85–90.Google ScholarPubMed
Frizzell, RT, Jones, EM, Davis, SN, Biggers, DW, Myers, SR, Connolly, CC, Neal, DW, Jaspan, JB & Cherrington, AD (1993) Counterregulation during hypoglycemia is directed by widespread brain regions. Diabetes 42, 1253–1261.CrossRefGoogle ScholarPubMed
Fukase, N, Takahashi, H, Manaka, H, Igarashi, M, Yamatani, K, Daimon, M, Sugiyama, K, Tominaga, M & Sasaki, H (1992) Differences in glucagon-like peptide-1 and GIP responses following sucrose ingestion. Diabetes Res Clin Pract 15, 187–195.CrossRefGoogle ScholarPubMed
Fukase, N, Igarashi, M, Takahashi, H, Manaka, H, Yamatani, K, Daimon, M, Tominaga, M & Sasaki, H (1993) Hypersecretion of truncated glucagon-like peptide-1 and gastric inhibitory polypeptide in obese patients. Diabet Med 10, 44–49.CrossRefGoogle ScholarPubMed
Furuse, M, Matsumoto, M, Okumura, J, Sugahara, K & Hasegawa, S (1997) Intracerebroventricular injection of mammalian and chicken glucagon-like peptide-1 inhibits food intake of the neonatal chick. Brain Res 755, 167–169.CrossRefGoogle ScholarPubMed
Gallwitz, B, Witt, M, Folsch, UR, Creutzfeldt, W & Schmidt, WE (1993) Binding specificity and signal transduction of receptors for glucagon-like peptide-1(7–36)amide and gastric inhibitory polypeptide on RINm5F insulinoma cells. J Mol Endocrinol 10, 259–268.CrossRefGoogle ScholarPubMed
Gardemann, A, Strulik, H & Jungermann, K (1986) A portal–arterial glucose concentration gradient as a signal for an insulin-dependent net glucose uptake in perfused rat liver. FEBS Lett 202, 255–259.CrossRefGoogle ScholarPubMed
Gerich, J, Cryer, P & Rizza, R (1990) Hormonal mechanisms in acute glucose counterregulation: the relative role of glucagon, epinephrine, norepinephrine, growth hormone, and cortisol. Metabolism 29, 1164–1175.CrossRefGoogle Scholar
Goke, B, Fehmann, HC, Schirra, J, Hareter, A & Goke, R (1997) The intestinal hormone glucagon-like peptide 1 (GLP-1): from experiment to the clinic. Z Gastroenterol 35, 285–294.Google ScholarPubMed
Goke, R, Trautmann, ME, Haus, E, Richter, G, Fehmann, HC, Arnold, R & Goke, B (1989) Signal transmission after GLP-1(7–36)amide binding in RINm5F cells. Am J Physiol 257, G397–G401.Google ScholarPubMed
Goke, R, Wagner, B, Fehmann, HC & Goke, B (1993) Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7–36) amide on the rat pancreas. Res Exp Med 193, 97–103.CrossRefGoogle ScholarPubMed
Goke, R, Larsen, PJ, Mikkelsen, JD & Sheikh, SP (1995) Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci 7, 2294–2300.CrossRefGoogle ScholarPubMed
Goldstone, AP, Morgan, I, Mercer, JG, Morgan, DG, Moar, KM, Ghatei, MA & Bloom, SR (2000) Effect of leptin on hypothalamic GLP-1 peptide and brain-stem pre-proglucagon mRNA. Biochem Biophys Res Commun 269, 331–335.CrossRefGoogle ScholarPubMed
Gulpinar, MA, Bozkurt, A, Coskun, T, Ulusoy, NB & Yegen, BC (2000) Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats. Am J Physiol Gastrointest Liver Physiol 278, G924–G929.CrossRefGoogle ScholarPubMed
Hargrove, DM, Nardone, NA, Persson, LM, Parker, JC & Stevenson, RW (1995) Glucose-dependent action of glucagon-like peptide-1 (7–37) in vivo during short- or long-term administration. Metabolism 44, 1231–1237.CrossRefGoogle ScholarPubMed
Herrmann, C, Goke, R, Richter, G, Fehmann, HC, Arnold, R & Goke, B (1995) Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 56, 117–126.CrossRefGoogle ScholarPubMed
Herrmann-Rinke, C, Voge, A, Hess, M & Goke, B (1995) Regulation of glucagon-like peptide-1 secretion from rat ileum by neurotransmitters and peptides. J Endocrinol 147, 25–31.CrossRefGoogle ScholarPubMed
Hevener, AL, Bergman, RN & Donovan, CM (1997) Novel glucosensor for hypoglycemic detection localized to the portal vein. Diabetes 46, 1521–1525.CrossRefGoogle ScholarPubMed
Hevener, AL, Bergman, RN & Donovan, CM (2000) Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia. Diabetes 49, 8–12.CrossRefGoogle ScholarPubMed
Holst, JJ (1977) Extraction, gel filtration pattern, and receptor binding of porcine gastrointestinal glucagon-like immunoreactivity. Diabetologia 13, 159–169.CrossRefGoogle ScholarPubMed
Holst, JJ (1994) Glucagon like peptide 1: a newly discovered gastrointestinal hormone. Gastroenterology 107, 1848–1855.CrossRefGoogle ScholarPubMed
Holst, JJ (1996) GLP-1 in NIDDM. Diabet Med 13, S156–S160.CrossRefGoogle ScholarPubMed
Holst, JJ (1997) Enteroglucagon. Annu Rev Physiol 59, 257–271.CrossRefGoogle ScholarPubMed
Holst, JJ, Orskov, C, Nielsen, OV & Schwartz, TW (1987) Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett 211, 169–174.CrossRefGoogle ScholarPubMed
Holz, GGt, Kuhtreiber, WM & Habener, JF (1993) Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7–37). Nature 361, 362–365.CrossRefGoogle ScholarPubMed
Holz, GGt, Leech, CA & Habener, JF (1995) Activation of a cAMP-regulated Ca(2+)-signaling pathway in pancreatic beta-cells by the insulinotropic hormone glucagon-like peptide-1. J Biol Chem 270, 17749–17757.CrossRefGoogle ScholarPubMed
Ikeda, T, Ochi, H, Ohtani, I, Fujiyama, K, Hoshino, T, Tanaka, Y, Takeuchi, T & Mashiba, H (1993) Possible role of the adrenergic mechanism in gastric inhibitory polypeptide- and glucagon-like peptide-1 (7–36) amide-induced insulin release in the rat. Metabolism 42, 209–213.CrossRefGoogle ScholarPubMed
Imeryuz, N, Yegen, BC, Bozkurt, A, Coskun, T, Villanueva-Penacarrillo, ML & Ulusoy, NB (1997) Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol 273, G920–G927.Google ScholarPubMed
Jehle, PM, Jehle, D, Fussganger, RD & Adler, G (1995) Effects of glucagon-like peptide-1 (GLP-1) in RINm5F insulinoma cells. Stimulation of insulin secretion, insulin content, and insulin receptor binding. Exp Clin Endocrinol Diabetes 2, 31–36.Google Scholar
Juhl, C, Schmitz, O, Pincu, S, Holdt, J, Veldhuis, J & Porksen, N (2000) Short-term treatment with GLP-1 increases pulsatile insulin secretion in type II diabetes with no effect on orderliness. Diabetologia 43, 583–588.CrossRefGoogle ScholarPubMed
Kanse, SM, Kreymann, B, Ghatei, MA & Bloom, SR (1988) Identification and characterization of glucagon-like peptide-1 7–36 amide-binding sites in the rat brain and lung. FEBS Lett 241, 209–212.CrossRefGoogle ScholarPubMed
Knapper, JM, Heath, A, Fletcher, JM, Morgan, LM & Marks, V (1995) GIP and GLP-1(7–36)amide secretion in response to intraduodenal infusions of nutrients in pigs. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 111, 445–450.CrossRefGoogle ScholarPubMed
Kok, NN, Morgan, LM, Williams, CM, Roberfroid, MB, Thissen, JP & Delzenne, NM (1998a) Insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide and insulin-like growth factor I as putative mediators of the hypolipidemic effect of oligofructose in rats. J Nutr 128, 1099–1103.CrossRefGoogle ScholarPubMed
Kok, NN, Taper, HS & Delzenne, NM (1998b) Oligofructose modulates lipid metabolism alterations induced by a fat-rich diet in rats. J Appl Toxicol 18, 47–53.3.0.CO;2-S>CrossRefGoogle ScholarPubMed
Kolligs, F, Fehmann, HC, Goke, R & Goke, B (1995) Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9–39) amide. Diabetes 44, 16–19.CrossRefGoogle ScholarPubMed
Komatsu, R, Matsuyama, T & Namba, M (1989) Glucagonostatic and insulinotropic action of glucagon like peptide-1-(7–36)-amide. Diabetes 38, 902–905.CrossRefGoogle Scholar
Kreymann, B, Williams, G, Ghatei, MA & Bloom, SR (1987) Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet 2, 1300–1304.CrossRefGoogle ScholarPubMed
Kreymann, B, Ghatei, MA, Burnet, P, Williams, G, Kanse, S, Diani, AR & Bloom, SR (1989) Characterization of glucagon-like peptide-1-(7–36)amide in the hypothalamus. Brain Res 502, 325–331.CrossRefGoogle ScholarPubMed
Mattson, MP, Perry, T & Greig, N (2003) Learning from the gut. Nat Med 9, 1113–1114.CrossRefGoogle ScholarPubMed
Miyawaki, K, Yamada, Y & Yano, H (1999) Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA 96, 14843–14847.CrossRefGoogle Scholar
Mojsov, S, Weir, GC & Habener, JF (1987) Insulinotropin: glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 79, 616–619.CrossRefGoogle ScholarPubMed
Moody, A, Thim, L & Valverde, I (1984) The isolation and sequencing of human gastric inhibitory polypeptide (GIP). FEBS Lett 172, 142–148.CrossRefGoogle Scholar
Moore, B, Edie, E & Abram, J (1906) On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J 1, 28–38.CrossRefGoogle Scholar
Moore, MC & Cherrington, AD (1996) The nerves, the liver, and the route of feeding: an integrated response to nutrient delivery. Nutrition 12, 282–284.CrossRefGoogle ScholarPubMed
Moore, MC, Rossetti, L, Pagliassotti, MJ, Monahan, M, Venable, C, Neal, D & Cherrington, AD (1996) Neural and pancreatic influences on net hepatic glucose uptake and glycogen synthesis. Am J Physiol 271, E215–E222.Google ScholarPubMed
Nakabayashi, H, Nishizawa, M, Nakagawa, A, Takeda, R & Niijima, A (1996) Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1. Am J Physiol 271, E808–E813.Google ScholarPubMed
Nathan, D, Schreiber, E, Fogel, H, Mojsov, S & Habener, J (1991) Insulinotropic action of glucagon like peptide-1-(7–37) in diabetic and non diabetic subjects. Diabetes Care 15, 270–275.CrossRefGoogle Scholar
Nauck, M (1996) Therapeutic potential of glucagon-like peptide 1 in type 2 diabetes. Diabet Med 13, S39–S43.Google ScholarPubMed
Nauck, MA (1998) Glucagon like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective. Acta Diabetol 35, 117–129.CrossRefGoogle ScholarPubMed
Nauck, MA, Bartels, E, Orskov, C, Ebert, R & Creutzfeldt, W (1993a) Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7–36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 76, 912–917.Google ScholarPubMed
Nauck, MA, Heimesaat, MM, Orskov, C, Holst, JJ, Ebert, R & Creutzfeldt, W (1993b) Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91, 301–307.CrossRefGoogle Scholar
Nauck, MA, Kleine, N, Orskov, C, Holst, JJ, Willms, B & Creutzfeldt, W (1993c) Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36, 741–744.CrossRefGoogle ScholarPubMed
Nauck, MA, Siemsgluss, J, Orskov, C & Holst, JJ (1996) Release of glucagon-like peptide 1 (GLP-1 [7–36 amide]), gastric inhibitory polypeptide (GIP) and insulin in response to oral glucose after upper and lower intestinal resections. Z Gastroenterol 34, 159–166.Google ScholarPubMed
Niijima, A (1969) Afferent impulse discharges from glucoreceptors in the liver of the guinea pig. Ann NY Acad Sci 157, 690–700.CrossRefGoogle ScholarPubMed
Niijima, A (1985) Blood glucose levels modulate efferent activity in the vagal supply to the rat liver. J Physiol 364, 105–112.CrossRefGoogle Scholar
Nordt, TK, Besenthal, I, Eggstein, M & Jakober, B (1991) Influence of breakfasts with different nutrient contents on glucose, C peptide, insulin, glucagon, triglycerides, and GIP in non-insulin-dependent diabetics. Am J Clin Nutr 53, 155–160.CrossRefGoogle ScholarPubMed
Oomura, Y (1981) Chemosensitive neuron in the hypothalamus related to food intake behavior. Jpn J Pharmacol 31, 1P–12P.CrossRefGoogle ScholarPubMed
Oomura, Y, Ono, T, Ooyama, H & Wayner, MJ (1969) Glucose and osmosensitive neurones of the rat hypothalamus. Nature 222, 282–284.CrossRefGoogle ScholarPubMed
Oomura, Y, Ooyama, H, Sugimori, M, Nakamura, T & Yamada, Y (1974) Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus. Nature 247, 284–286.CrossRefGoogle ScholarPubMed
Orskov, C, Holst, JJ, Poulsen, SS & Kirkegaard, P (1987) Pancreatic and intestinal processing of proglucagon in man. Diabetologia 30, 874–881.CrossRefGoogle ScholarPubMed
Orskov, C, Holst, JJ & Nielsen, OV (1988) Effect of truncated glucagon-like peptide-1, proglucagon-(78–107) amide, on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 123, 2009–2013.CrossRefGoogle ScholarPubMed
Orskov, C, Rabenhoj, L, Wettergren, A, Kofod, H & Holst, JJ (1994) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43, 535–539.CrossRefGoogle ScholarPubMed
Orskov, C, Wettergren, A & Holst, JJ (1996) Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. Scand J Gastroenterol 31, 665–670.CrossRefGoogle ScholarPubMed
Pagliassotti, MJ, Myers, SR, Moore, MC, Neal, DW & Cherrington, AD (1991) Magnitude of negative arterial–portal glucose gradient alters net hepatic glucose balance in conscious dogs. Diabetes 40, 1659–1668.CrossRefGoogle ScholarPubMed
Pagliassotti, MJ, Holste, LC, Moore, MC, Neal, DW & Cherrington, AD (1996) Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog. J Clin Invest 97, 81–91.CrossRefGoogle ScholarPubMed
Perley, M & Kpnis, D (1967) Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 46, 1954–1962.CrossRefGoogle Scholar
Plaisancie, P, Dumoulin, V, Chayvialle, JA & Cuber, JC (1995) Luminal glucagon-like peptide-1(7–36) amide-releasing factors in the isolated vascularly perfused rat colon. J Endocrinol 145, 521–526.CrossRefGoogle ScholarPubMed
Plant, TM & Durrant, AR (1997) Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey ( Macaca mulatta ). Endocrinology 138, 4505–4508.CrossRefGoogle Scholar
Qualmann, C, Nauck, MA, Holst, JJ, Orskov, C & Creutzfeldt, W (1995) Insulinotropic actions of intravenous glucagon-like peptide-1 (GLP-1) [7–36 amide] in the fasting state in healthy subjects. Acta Diabetol 32, 13–16.CrossRefGoogle ScholarPubMed
Reimer, RA & McBurney, MI (1996) Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats. Endocrinology 137, 3948–3956.CrossRefGoogle ScholarPubMed
Ritzel, U, Fromme, A, Ottleben, M, Leonhardt, U & Ramadori, G (1997) Release of glucagon-like peptide-1 (GLP-1) by carbohydrates in the perfused rat ileum. Acta Diabetol 34, 18–21.CrossRefGoogle ScholarPubMed
Rizza, R, Cryer, P & Gerich, J (1979) Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation: effects of somatostatin and combined alpha and beta adrenergic blockade on plasma glucose recovery and glucose flux rates following insulin-induced hypoglycemia. J Clin Invest 64, 62–71.CrossRefGoogle Scholar
Roberge, J, Gronau, K & Brubaker, P (1996) Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut. Endocrinology 137, 2383–2388.CrossRefGoogle ScholarPubMed
Rocca, AS & Brubaker, PL (1995) Stereospecific effects of fatty acids on proglucagon-derived peptide secretion in fetal rat intestinal cultures. Endocrinology 136, 5593–5599.CrossRefGoogle ScholarPubMed
Rocca, AS & Brubaker, PL (1999) Role of vagus nerve in mediating proximal nutrient induced glucagon like peptide-1 secretion. Endocrinology 140, 1687–1694.CrossRefGoogle ScholarPubMed
Rodriquez, de, Fonseca, F, Navarro, M & Alvarez, E (2000) Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 49, 709–717.Google Scholar
Rouille, Y, Westermark, G, Martin, SK & Steiner, DF (1994) Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. Proc Natl Acad Sci USA 91, 3242–3246.CrossRefGoogle ScholarPubMed
Rouille, Y, Martin, S & Steiner, DF (1995) Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. J Biol Chem 270, 26488–26496.CrossRefGoogle ScholarPubMed
Schirra, J, Katschinski, M, Weidmann, C, Schafer, T, Wank, U, Arnold, R & Goke, B (1996) Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 97, 92–103.CrossRefGoogle ScholarPubMed
Schmitt, M (1973) Influence of hepatic portal receptors on hypothalamic feeding and satiety centers. Am J Physiol 225, 1089–1095.Google ScholarPubMed
Scrocchi, LA, Brown, TJ, MaClusky, N, Brubaker, PL, Auerbach, AB, Joyner, AL & Drucker, DJ (1996) Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med 2, 1254–1258.CrossRefGoogle Scholar
Shima, K, Hirota, M & Ohboshi, C (1988) Effect of glucagon-like peptide-1 on insulin secretion. Regul Pept 22, 245–252.CrossRefGoogle ScholarPubMed
Shimizu, I, Hirota, M, Ohboshi, C & Shima, K (1987) Identification and localization of glucagon-like peptide-1 and its receptor in rat brain. Endocrinology 121, 1076–1082.CrossRefGoogle ScholarPubMed
Shimizu, N, Oomura, Y, Novin, D, Grijalva, CV & Cooper, PH (1983) Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose-sensitive units in rat. Brain Res 265, 49–54.CrossRefGoogle ScholarPubMed
Stumpel, F & Jungermann, K (1997) Sensing by intrahepatic muscarinic nerves of a portal–arterial glucose concentration gradient as a signal for insulin-dependent glucose uptake in the perfused rat liver. FEBS Lett 406, 119–122.CrossRefGoogle ScholarPubMed
Takeda, J, Seino, Y & Tanaka, K (1987) Sequence of an intestinal cDNA encoding human gastric inhibitory polypeptide precursor. Proc Natl Acad Sci USA 84, 7005–7008.CrossRefGoogle ScholarPubMed
Tanizawa, Y, Riggs, AC, Elbein, SC, Whelan, A, Donis-Keller, H & Permutt, MA (1994) Human glucagon-like peptide-1 receptor gene in NIDDM. Identification and use of simple sequence repeat polymorphisms in genetic analysis. Diabetes 43, 752–757.CrossRefGoogle ScholarPubMed
Thiele, TE, Van Dijk, G, Campfield, LA, Smith, FJ, Burn, P, Woods, SC, Bernstein, IL & Seeley, RJ (1997) Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats. Am J Physiol 272, R726–R730.Google Scholar
Thorens, B & Waeber, G (1993) Glucagon-like peptide-I and the control of insulin secretion in the normal state and in NIDDM. Diabetes 42, 1219–1225.CrossRefGoogle ScholarPubMed
Thorens, B, Porret, A, Buhler, L, Deng, SP, Morel, P & Widmann, C (1993) Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9–39) an antagonist of the receptor. Diabetes 42, 1678–1682.CrossRefGoogle ScholarPubMed
Tseng, CC, Zhang, XY & Wolfe, MM (1999) Effect of GIP and GLP-1 antagonists on insulin release in the rat. Am J Physiol 276, E1049–E1054.Google ScholarPubMed
Turton, MD, O'Shea, D & Gunn, I (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72.CrossRefGoogle ScholarPubMed
Uttenthal, LO, Toledano, A & Blazquez, E (1992) Autoradiographic localization of receptors for glucagon-like peptide-1 (7–36) amide in rat brain. Neuropeptides 21, 143–146.CrossRefGoogle ScholarPubMed
Vaag, AA, Holst, JJ, Volund, A, Beck-Nielsen, HB (1996) Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM) – evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol 135, 425–432.CrossRefGoogle ScholarPubMed
van Dijk, G & Thiele, TE (1999) Glucagon-like peptide-1 (7–36) amide: a central regulator of satiety and interoceptive stress. Neuropeptides 33, 406–414.CrossRefGoogle ScholarPubMed
van Eyll, B, Lankat-Buttgereit, B, Bode, HP, Goke, R & Goke, B (1994) Signal transduction of the GLP-1-receptor cloned from a human insulinoma. FEBS Lett 348, 7–13.CrossRefGoogle ScholarPubMed
Volz, A, Goke, R, Lankat-Buttgereit, B, Fehmann, HC, Bode, HP & Goke, B (1995) Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS Lett 373, 23–29.CrossRefGoogle ScholarPubMed
Wang, Z, Wang, RM, Owji, AA, Smith, DM, Ghatei, MA & Bloom, SR (1995) Glucagon-like peptide-1 is a physiological incretin in rat. J Clin Invest 95, 417–421.CrossRefGoogle ScholarPubMed
Wei, Y & Mojsov, S (1995) Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett 358, 219–224.CrossRefGoogle ScholarPubMed
Wettergren, A, Wojdemann, M, Meisner, S, Stadil, F & Holst, JJ (1997) The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7–36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut 40, 597–601.CrossRefGoogle Scholar
Widmann, C, Burki, E, Dolci, W & Thorens, B (1994) Signal transduction by the cloned glucagon-like peptide-1 receptor: comparison with signaling by the endogenous receptors of beta cell lines. Mol Pharmacol 45, 1029–1035.Google ScholarPubMed
Willms, B, Werner, J, Holst, JJ, Orskov, C, Creutzfeldt, W & Nauck, MA (1996) Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 81, 327–332.Google Scholar
Yoshimoto, S, Hirota, M, Ohboshi, C & Shima, K (1989) Identification of glucagon-like peptide-1(7–36) amide in rat brain. Ann Clin Biochem 26, 169–171.CrossRefGoogle ScholarPubMed
Young, AA, Gedulin, BR & Rink, TJ (1996) Dose–responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7–36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. Metabolism 45, 1–3.CrossRefGoogle Scholar
Zawalich, WS & Zawalich, KC (1996) Glucagon-like peptide-1 stimulates insulin secretion but not phosphoinositide hydrolysis from islets desensitized by prior exposure to high glucose or the muscarinic agonist carbachol. Metabolism 45, 273–278.CrossRefGoogle ScholarPubMed
Zawalich, WS, Zawalich, KC & Rasmussen, H (1993) Influence of glucagon-like peptide-1 on beta cell responsiveness. Regul Pept 44, 277–283.CrossRefGoogle ScholarPubMed
Zhang, Y, Cook, JT, Hattersley, AT, Firth, R, Saker, PJ, Warren-Perry, M, Stoffel, M & Turner, RC (1994) Non-linkage of the glucagon-like peptide 1 receptor gene with maturity onset diabetes of the young. Diabetologia 37, 721–724.CrossRefGoogle ScholarPubMed