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Horm Metab Res 2004; 36(11/12): 747-754
DOI: 10.1055/s-2004-826158
Review
© Georg Thieme Verlag KG Stuttgart · New York

On the Physiology of GIP and GLP-1

J.  J.  Holst1
  • 1Department of Medical Physiology, University of Copenhagen, Denmark
Further Information

Publication History

Received 11 August 2004

Accepted after revision 18 August 2004

Publication Date:
18 January 2005 (online)

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Abstract

Recent studies have indicated that GIP and GLP-1 are about as important as each other in the incretin effect, being released rapidly after meals and being active already at fasting glucose levels. Although the density of GLP-1 producing cells is higher distally, GlP-1 is normally secreted by jejunal L-cells, explaining the rapid onset of secretion. Moreover, many endocrine cells in the small intestine appear to produce both GIP and GLP-1. Both are metabolized rapidly by the dipeptidyl peptidase IV enzyme, but unlike GIP, about 90 % of GLP-1 is degraded before it reaches the systemic circulation. Apparently, before it is degraded, GLP-1 activates sensory afferents in the gastrointestinal mucosa with cell bodies in the nodose ganglion, signaling onwards to the brain stem and the hypothalamus. A similar mechanism seems to be involved in GLP-1’s effect on gastrointestinal motility and secretion, and perhaps its actions on appetite and food intake, all of which may be even more physiologically important than its effects on the beta cells. Cardiovascular and neuroprotective actions of GLP-1 have also recently been reported. Regarding GIP, several lines of evidence suggest that GIP, in addition to its incretin effects, may affect lipid metabolism and promote lipid storage.

Key words

Incretins sensory afferent neurons - Appetite regulation - Ileal brake - Obesity

References

  • 1 Dupre J, Ross S A, Watson D, Brown J C. Stimulation of insulin secretion by gastric inhibitory polypeptide in man.  J Clin Endocrinol Metab. 1973;  37 826-828
    CrossrefPubMedGoogle Scholar
  • 2 Takeda J, Seino Y, Tanaka K, Fukumoto H, Kayano T, Takahashi H, Mitani T, Kurono M, Suzuki T, Tobe T. Sequence of an intestinal cDNA encoding human gastric inhibitory polypeptide precursor.  Proc Natl Acad Sci USA. 1987;  84 7005-7008
    PubMedGoogle Scholar
  • 3 Mayo K E, Miller L J, Bataille D, Dalle S, Goke B, Thorens B, Drucker D J. International Union of Pharmacology. XXXV. The Glucagon Receptor Family.  Pharmacol Rev. 2003;  55 167-194
    CrossrefPubMedGoogle Scholar
  • 4 Mortensen K, Christensen L L, Holst J J, Orskov C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine.  Regul Pept. 2003;  114 189-196
    CrossrefPubMedGoogle Scholar
  • 5 Ding W G, Gromada J. Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide.  Diabetes. 1997;  46 615-621
    CrossrefPubMedGoogle Scholar
  • 6 Wheeler M B, Gelling R W, McIntosh C H, Georgiou J, Brown J C, Pederson R A. Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide receptor: ligand binding and intracellular signaling properties.  Endocrinology. 1995;  136 4629-4639
    CrossrefPubMedGoogle Scholar
  • 7 Ehses J A, Pelech S L, Pederson R A, McIntosh C H. Glucose-dependent insulinotropic polypeptide activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMP-dependent protein kinase/Rap1-mediated pathway.  J Biol Chem. 2002;  277 37088-37097
    CrossrefPubMedGoogle Scholar
  • 8 Ehses J A, Lee S S, Pederson R A, McIntosh C H. A new pathway fpr glucose-dependent insulinotropic polypeptiude (GIP) receptor signaling: evidence for the involvement of phospholipase A2 in the GIP stimulated insulin secretion.  J Biol Chem. 2003;  276 23667-23673
    PubMedGoogle Scholar
  • 9 Trumper A, Trumper K, Trusheim H, Arnold R, Goke B, Horsch D. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling.  Mol Endocrinol. 2001;  15 1559-1570
    CrossrefPubMedGoogle Scholar
  • 10 Ebert R, Creutzfeldt W. Influence of gastric inhibitory polypeptide antiserum on glucose-induced insulin secretion in rats.  Endocrinology. 1982;  111 1601-1606
    PubMedGoogle Scholar
  • 11 Lauritsen K B, Holst J J, Moody A J. Depression of Insulin Release by Anti-GIP Serum after Oral Glucose in Rats.  Scand J Gastroenterol. 1981;  16 417-420
    PubMedGoogle Scholar
  • 12 Tseng C C, Kieffer T J, Jarboe L A, Usdin T B, Wolfe M M. Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat.  J Clin Invest. 1996;  98 2440-2445
    PubMedGoogle Scholar
  • 13 Lewis J T, Dayanandan B, Habener J F, Kieffer T J. Glucose-dependent insulinotropic polypeptide confers early phase insulin release to oral glucose in rats: demonstration by a receptor antagonist.  Endocrinology. 2000;  141 3710-3716
    CrossrefPubMedGoogle Scholar
  • 14 Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A, Tsuda K, Hashimoto H, Yamashita T, Jomori T, Tashiro F, Miyazaki J, Seino Y. Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice.  Proc Natl Acad Sci U S A. 1999;  96 14 843-14 847
    PubMedGoogle Scholar
  • 15 Gault V A, O’Harte F P, Harriott P, Flatt P R. Characterization of the cellular and metabolic effects of a novel enzyme-resistant antagonist of glucose-dependent insulinotropic polypeptide.  Biochem Biophys Res Commun. 2002;  290 1420-1426
    CrossrefPubMedGoogle Scholar
  • 16 Nauck M, Schmidt W E, Ebert R, Strietzel J, Cantor P, Hoffmann G, Creutzfeldt W. Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8.  J Clin Endocrinol Metab. 1989;  69 654-662
    CrossrefPubMedGoogle Scholar
  • 17 Ebert R, Unger H, Creutzfeldt W. Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption.  Diabetologia. 1983;  24 449-454
    PubMedGoogle Scholar
  • 18 Lauritsen K B, Moody A J, Christensen K C, Lindkaer J S. Gastric inhibitory polypeptide (GIP) and insulin release after small- bowel resection in man.  Scand J Gastroenterol. 1980;  15 833-840
    PubMedGoogle Scholar
  • 19 Mojsov S, Heinrich G, Wilson I B, Ravazzola M, Orci L, Habener J F. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing.  J Biol Chem. 1986;  261 11 880-11 889
    PubMedGoogle Scholar
  • 20 Orskov C, Holst J J, Knuhtsen S, Baldissera F G, Poulsen S S, Nielsen O V. Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas.  Endocrinology. 1986;  119 1467-1475
    PubMedGoogle Scholar
  • 21 Ugleholdt R, Zhu X, Deacon C F, Orskov C, Steiner D F, Holst J J. Impaired Intestinal Proglucagon Processing In Mice Lacking Prohormone Convertase 1.  Endocrinology. 2004;  145 1349-1355
    PubMedGoogle Scholar
  • 22 Baldissera F G, Holst J J, Knuhtsen S, Hilsted L, Nielsen O V. Oxyntomodulin (glicentin- (33 - 69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs.  Regul Pept. 1988;  21 151-166
    CrossrefPubMedGoogle Scholar
  • 23 Holst J J. Molecular heterogeneity of glucagon in normal subjects and in patients with glucagon-producing tumours.  Diabetologia. 1983;  24 359-365
    PubMedGoogle Scholar
  • 24 Cohen M A, Ellis S M, Le Roux C W, Batterham R L, Park A, Patterson M, Frost G S, Ghatei M A, Bloom S R. Oxyntomodulin suppresses appetite and reduces food intake in humans.  J Clin Endocrinol Metab. 2003;  88 4696-4701
    CrossrefPubMedGoogle Scholar
  • 25 Layer P, Holst J J, Grandt D, Goebell H. Ileal release of glucagon-like peptide-1 (GLP-1). Association with inhibition of gastric acid secretion in humans.  Dig Dis Sci. 1995;  40 1074-1082
    PubMedGoogle Scholar
  • 26 Miholic J, Orskov C, Holst J J, Kotzerke J, Meyer H J. Emptying of the gastric substitute, glucagon-like peptide-1 (GLP- 1), and reactive hypoglycemia after total gastrectomy.  Dig Dis Sci. 1991;  36 1361-1370
    CrossrefPubMedGoogle Scholar
  • 27 Hansen L. , Lampert S., Mineo H, Holst JJ. Neural regulation of glucagon-like peptide-1 secretion in pigs.  Am J Physiol Endocrinol Metab. 2004;  287 E 939-947
    PubMedGoogle Scholar
  • 28 Orskov C, Wettergren A, Holst J J. 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. 1996;  31 665-670
    PubMedGoogle Scholar
  • 29 Fehmann H C, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon- like peptide-I and glucose-dependent insulin releasing polypeptide.  Endocr Rev. 1995;  16 390-410
    CrossrefPubMedGoogle Scholar
  • 30 Kreymann B, Williams G, Ghatei M A, Bloom S R. Glucagon-like peptide-17-36: a physiological incretin in man.  Lancet. 1987;  2 1300-1304
    PubMedGoogle Scholar
  • 31 Kolligs F, Fehmann H C, Goke R, Goke B. Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9 - 39) amide.  Diabetes. 1995;  44 16-19
    PubMedGoogle Scholar
  • 32 Wang Z, Wang R M, Owji A A, Smith D M, Ghatei M A, Bloom S R. Glucagon-like peptide-1 is a physiological incretin in rat [see comments].  J Clin Invest. 1995;  95 417-421
    CrossrefPubMedGoogle Scholar
  • 33 Edwards C M, Todd J F, Mahmoudi M, Wang Z, Wang R M, Ghatei M A, Bloom S R. Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39 [In Process Citation].  Diabetes. 1999;  48 86-93
    CrossrefPubMedGoogle Scholar
  • 34 Scrocchi L A, Brown T J, MaClusky N, Brubaker P L, Auerbach A B, Joyner A L, Drucker D J. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.  Nat Med. 1996;  2 1254-1258
    CrossrefPubMedGoogle Scholar
  • 35 Holz G G, Kuhtreiber W M, Habener J F. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1 (7-37).  Nature. 1993;  361 362-365
    CrossrefPubMedGoogle Scholar
  • 36 Flamez D, Van Breusegem A, Scrocchi L A, Quartier E, Pipeleers D, Drucker D J, Schuit F. Mouse pancreatic beta-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene.  Diabetes. 1998;  47 646-652
    PubMedGoogle Scholar
  • 37 Nauck M A, Heimesaat M M, Orskov C, Holst J J, Ebert R, Creutzfeldt W. 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. 1993;  91 301-307
    CrossrefPubMedGoogle Scholar
  • 38 Vilsboll T, Krarup T, Madsbad S, Holst J J. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects.  Regul Pept. 2003;  114 115-V
    CrossrefPubMedGoogle Scholar
  • 39 Nauck M A, Bartels E, Orskov C, Ebert R, Creutzfeldt W. 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. 1993;  76 912-917
    CrossrefPubMedGoogle Scholar
  • 40 Hansotia T, Baggio L L, Delmeire D, Hinke S A, Yamada Y, Tsukiyama K, Seino Y, Holst J J, Schuit F, Drucker D J. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors.  Diabetes. 2004;  53 1326-1335
    PubMedGoogle Scholar
  • 41 Preitner F, Ibberson M, Franklin I, Binnert C, Pende M, Gjinovci A, Hansotia T, Drucker D J, Wollheim C, Burcelin R, Thorens B. Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors.  J Clin Invest. 2004;  113 635-645
    CrossrefPubMedGoogle Scholar
  • 42 Qualmann C, Nauck M A, Holst J J, Orskov C, Creutzfeldt W. Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha- glucosidase inhibition (acarbose).  Scand J Gastroenterol. 1995;  30 892-896
    CrossrefPubMedGoogle Scholar
  • 43 Deacon C F, Johnsen A H, Holst J J. 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. 1995;  80 952-957
    CrossrefPubMedGoogle Scholar
  • 44 Kieffer T J, McIntosh C H, Pederson R A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.  Endocrinology. 1995;  136 3585-3596
    CrossrefPubMedGoogle Scholar
  • 45 Deacon C F, Nauck M A, Meier J, Hucking K, Holst J J. Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide.  J Clin Endocrinol Metab. 2000;  85 3575-3581
    CrossrefPubMedGoogle Scholar
  • 46 Knudsen L B, Pridal L. Glucagon-like peptide-1- (9-36) amide is a major metabolite of glucagon-like peptide-1- (7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor.  Eur J Pharmacol. 1996;  318 429-435
    CrossrefPubMedGoogle Scholar
  • 47 Gault V A, Parker J C, Harriott P, Flatt P R, O’Harte F P. Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP (3-42), is a GIP receptor antagonist in vivo.  J Endocrinol. 2002;  175 525-533
    CrossrefPubMedGoogle Scholar
  • 48 Mentlein R. Dipeptidyl-peptidase IV (CD26) - role in the inactivation of regulatory peptides.  Regul Pept. 1999;  85 9-24
    CrossrefPubMedGoogle Scholar
  • 49 Deacon C F, Nauck M A, Toft-Nielsen M, Pridal L, Willms B, Holst J J. 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. 1995;  44 1126-1131
    CrossrefPubMedGoogle Scholar
  • 50 Vilsboll T, Agerso H, Krarup T, Holst J J. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects.  J Clin Endocrinol Metab. 2003;  88 220-224
    CrossrefPubMedGoogle Scholar
  • 51 Deacon C F, Pridal L, Klarskov L, Olesen M, Holst J J. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig.  Am J Physiol. 1996;  271 E458-E464
    PubMedGoogle Scholar
  • 52 Vilsboll T, Krarup T, Deacon C F, Madsbad S, Holst J J. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients.  Diabetes. 2001;  50 609-613
    PubMedGoogle Scholar
  • 53 Vilsboll T, Krarup T, Sonne J, Madsbad S, Volund A, Juul A G, Holst J J. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.  J Clin Endocrinol Metab. 2003;  88 2706-2713
    CrossrefPubMedGoogle Scholar
  • 54 Meier J J, Nauck M A, Kranz D, Holst J J, Deacon C F, Gaeckler D, Schmidt W E, Gallwitz B. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects.  Diabetes. 2004;  53 654-662
    CrossrefPubMedGoogle Scholar
  • 55 Deacon C F, Danielsen P, Klarskov L, Olesen M, Holst J J. Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs.  Diabetes. 2001;  50 1588-1597
    PubMedGoogle Scholar
  • 56 Hansen L, Deacon C F, Orskov C, Holst J J. Glucagon-like peptide-1- (7-36)amide is transformed to glucagon-like peptide-1- (9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine [In Process Citation].  Endocrinology. 1999;  140 5356-5363
    CrossrefPubMedGoogle Scholar
  • 57 Hansen L, Hartmann B, Bisgaard T, Mineo H, Jørgensen P N, Holst J J. Somatostatin restrains the secretion of glucagon-like peptide-1 and 2 from isolated perfused porcine ileum.  Am J Physiol. 2000;  278 E1010-E1018
    PubMedGoogle Scholar
  • 58 Nakagawa A, Satake H, Nakabayashi H, Nishizawa M, Furuya K, Nakano S, Kigoshi T, Nakayama K, Uchida K. Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells.  Auton Neurosci. 2004;  110 36-43
    PubMedGoogle Scholar
  • 59 Nishizawa M, Nakabayashi H, Uchida K, Nakagawa A, Niijima A. The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose-dependent insulinotropic polypeptide, in the portal vein.  J Auton Nerv Syst. 1996;  61 149-154
    CrossrefPubMedGoogle Scholar
  • 60 Nakabayashi H, Nishizawa M, Nakagawa A, Takeda R, Niijima A. Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1.  Am J Physiol. 1996;  271 E808-E813
    PubMedGoogle Scholar
  • 61 Balkan B, Li X. Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms.  Am J Physiol Regul Integr Comp Physiol. 2000;  279 R1449-R1454
    PubMedGoogle Scholar
  • 62 Read N, French S, Cunningham K. The Role of the Gut in Regulation Food Intake in Man.  Nutrition Reviews. 1994;  52 1-10
    PubMedGoogle Scholar
  • 63 Holst J J. Enteroglucagon.  Annu Rev Physiol. 1997;  59 257-271
    CrossrefPubMedGoogle Scholar
  • 64 Groger G, Unger A, Holst J J, Goebell H, Layer P. Ileal carbohydrates inhibit cholinergically stimulated exocrine pancreatic secretion in humans.  Int J Pancreatol. 1997;  22 23-29
    PubMedGoogle Scholar
  • 65 Wettergren A, Schjoldager B, Mortensen P E, Myhre J, Christiansen J, Holst J J. Truncated GLP-1 (proglucagon 78 - 107-amide) inhibits gastric and pancreatic functions in man.  Dig Dis Sci. 1993;  38 665-673
    CrossrefPubMedGoogle Scholar
  • 66 Nauck M A, Niedereichholz U, Ettler R, Holst J J, Orskov C, Ritzel R, Schmiegel W H. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans.  Am J Physiol. 1997;  273 E981-E988
    PubMedGoogle Scholar
  • 67 Imeryuz N, Yegen B C, Bozkurt A, Coskun T, Villanueva-Penacarrillo M L, Ulusoy N B. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms.  Am J Physiol. 1997;  273 G920-G927
    PubMedGoogle Scholar
  • 68 Wettergren A, Wojdemann M, Holst J J. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow.  Am J Physiol. 1998;  275 G984-G992
    PubMedGoogle Scholar
  • 69 Wettergren A, Wojdemann M, Meisner S, Stadil F, Holst J J. 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. 1997;  40 597-601
    PubMedGoogle Scholar
  • 70 Wettergren A, Petersen H, Orskov C, Christiansen J, Sheikh S P, Holst J J. Glucagon-like peptide-1 7-36 amide and peptide YY from the L- cell of the ileal mucosa are potent inhibitors of vagally induced gastric acid secretion in man.  Scand J Gastroenterol. 1994;  29 501-505
    PubMedGoogle Scholar
  • 71 Flint A, Raben A, Astrup A, Holst J J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans.  J Clin Invest. 1998;  101 515-520
    CrossrefPubMedGoogle Scholar
  • 72 Verdich C, Flint A, Gutzwiller J P, Naslund E, Beglinger C, Hellstrom P M, Long S J, Morgan L M, Holst J J, Astrup A. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans.  J Clin Endocrinol Metab. 2001;  86 4382-4389
    CrossrefPubMedGoogle Scholar
  • 73 Naslund E, Barkeling B, King N, Gutniak M, Blundell J E, Holst J J, Rossner S, Hellstrom P M. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men.  Int J Obes Relat Metab Disord. 1999;  23 304-311
    CrossrefPubMedGoogle Scholar
  • 74 Gutzwiller J P, Drewe J, Goke B, Schmidt H, Rohrer B, Lareida J, Beglinger C. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2.  Am J Physiol. 1999;  276 R1541-R1544
    PubMedGoogle Scholar
  • 75 Zander M, Madsbad S, Madsen J L, Holst J J. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study.  Lancet. 2002;  359 824-830
    CrossrefPubMedGoogle Scholar
  • 76 Turton M D, O’Shea D, Gunn I, Beak S A, Edwards C M, Meeran K, Choi S J, Taylor G M, Heath M M, Lambert P D, Wilding J P, Smith D M, Ghatei M A, Herbert J, Bloom S R. A role for glucagon-like peptide-1 in the central regulation of feeding [see comments].  Nature. 1996;  379 69-72
    CrossrefPubMedGoogle Scholar
  • 77 Tang-Christensen M, Larsen P J, Goke R, Fink-Jensen A, Jessop D S, Moller M, Sheikh S P. Central administration of GLP-1- (7-36) amide inhibits food and water intake in rats.  Am J Physiol. 1996;  271 R848-R856
    PubMedGoogle Scholar
  • 78 Goke R, Larsen P J, Mikkelsen J D, Sheikh S P. Identification of specific binding sites for glucagon-like peptide-1 on the posterior lobe of the rat pituitary.  Neuroendocrinology. 1995;  62 130-134
    PubMedGoogle Scholar
  • 79 Larsen P J, Tang-Christensen M, Holst J J, Orskov C. Distribution of glucagon-like peptide-1 and other preproglucagon- derived peptides in the rat hypothalamus and brainstem.  Neuroscience. 1997;  77 257-270
    CrossrefPubMedGoogle Scholar
  • 80 Rinaman L. Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus.  Am J Physiol. 1999;  277 R582-R590
    PubMedGoogle Scholar
  • 81 Rinaman L. A functional role for central glucagon-like peptide-1 receptors in lithium chloride-induced anorexia.  Am J Physiol. 1999;  277 R1537-R1540
    PubMedGoogle Scholar
  • 82 Vrang N, Phifer C B, Corkern M M, Berthoud H R. Gastric distension induces c-Fos in medullary GLP-1/2-containing neurons.  Am J Physiol Regul Integr Comp Physiol. 2003;  285 R470-R478
    PubMedGoogle Scholar
  • 83 Gutzwiller J P, Goke B, Drewe J, Hildebrand P, Ketterer S, Handschin D, Winterhalder R, Conen D, Beglinger C. Glucagon-like peptide-1: a potent regulator of food intake in humans.  Gut. 1999;  44 81-86
    CrossrefPubMedGoogle Scholar
  • 84 Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Prolonged efficacy of LAF237 in patients with type 2 diabetes (T2DM) inadequately treated with metformin.  Diabetes Care,. in press; 
    PubMedGoogle Scholar
  • 85 Orskov C, Poulsen S S, Moller M, Holst J J. Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I.  Diabetes. 1996;  45 832-835
    CrossrefPubMedGoogle Scholar
  • 86 Hiles R, Carpenter T, Serota D, Schafer K, Ross P, Nelsen D, Rebelatto M. Exenatide does not cause pancreatic tumours or malignancies in rats and mice following a 2-year period of exposure (Abstract).  Diabetes. 2004;  53 (Supplement 2) A 380
    PubMedGoogle Scholar
  • 87 Bullock B P, Heller R S, Habener J F. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor.  Endocrinology. 1996;  137 2968-2978
    CrossrefPubMedGoogle Scholar
  • 88 Gros R, You X, Baggio L L, Kabir M G, Sadi A M, Mungrue I N, Parker T G, Huang Q, Drucker D J, Husain M. Cardiac function in mice lacking the glucagon-like peptide-1 receptor.  Endocrinology. 2003;  144 2242-2252
    CrossrefPubMedGoogle Scholar
  • 89 Bose A K, Mocanu M M, Mensah K N, Brand C L, Carr R D, Yellon D M. GLP-1 protects schemic and reperfused myocardium via PI3Kinase and p42/p44 MAPK signalling pathways (Abstract).  Diabetes. 2004;  53 Supplement 2 A 1
    PubMedGoogle Scholar
  • 90 Nikolaidis L A, Mankad S, Sokos G G, Miske G, Shah A, Elahi D, Shannon R P. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.  Circulation. 2004;  109 962-965
    CrossrefPubMedGoogle Scholar
  • 91 Yamamoto H, Lee C E, Marcus J N, Williams T D, Overton J M, Lopez M E, Hollenberg A N, Baggio L, Saper C B, Drucker D J, Elmquist J K. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons.  J Clin Invest. 2002;  110 43-52
    CrossrefPubMedGoogle Scholar
  • 92 Yamamoto H, Kishi T, Lee C E, Choi B J, Fang H, Hollenberg A N, Drucker D J, Elmquist J K. Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites.  J Neurosci. 2003;  23 2939-2946
    PubMedGoogle Scholar
  • 93 Perry T, Haughey N J, Mattson M P, Egan J M, Greig N H. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4.  J Pharmacol Exp Ther. 2002;  302 881-888
    CrossrefPubMedGoogle Scholar
  • 94 During M J, Cao L, Zuzga D S, Francis J S, Fitzsimons H L, Jiao X, Bland R J, Klugmann M, Banks W A, Drucker D J, Haile C N. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.  Nat Med. 2003;  9 1173-1179
    PubMedGoogle Scholar
  • 95 Perry T A, Greig N H. A new Alzheimer’s disease interventive strategy: GLP-1.  Curr Drug Targets. 2004;  5 565-571
    CrossrefPubMedGoogle Scholar
  • 96 Meier J J, Gallwitz B, Siepmann N, Holst J J, Deacon C F, Schmidt W E, Nauck M A. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia.  Diabetologia. 2003;  46 798-801
    CrossrefPubMedGoogle Scholar
  • 97 Meier J J, Goetze O, Anstipp J, Hagemann D, Holst J J, Schmidt W E, Gallwitz B, Nauck M A. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans.  Am J Physiol Endocrinol Metab. 2004;  286 E621-E625
    CrossrefPubMedGoogle Scholar
  • 98 Maxwell V, Shulkes A, Brown J C, Solomon T E, Walsh J H, Grossman M I. Effect of gastric inhibitory polypeptide on pentagastrin-stimulated acid secretion in man.  Dig Dis Sci. 1980;  25 113-116
    CrossrefPubMedGoogle Scholar
  • 99 Usdin T B, Mezey E, Button D C, Brownstein M J, Bonner T I. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain.  Endocrinology. 1993;  133 2861-2870
    CrossrefPubMedGoogle Scholar
  • 100 Marks V. GIP - the obesity hormone. In: Current Approaches: Obesity. James WPT, Parker SW (eds.) Southampton; Duphar Medical Relations 1988: 13-19
    Google Scholar
  • 101 Yip R G, Wolfe M M. GIP biology and fat metabolism.  Life Sci. 2000;  66 91-103
    PubMedGoogle Scholar
  • 102 Elliott R M, Morgan L M, Tredger J A, Deacon S, Wright J, Marks V. Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns.  J Endocrinol. 1993;  138 159-166
    PubMedGoogle Scholar
  • 103 Yip R G, Boylan M O, Kieffer T J, Wolfe M M. Functional GIP receptors are present on adipocytes.  Endocrinology. 1998;  139 4004-4007
    CrossrefPubMedGoogle Scholar
  • 104 Wasada T, McCorkle K, Harris V, Kawai K, Howard B, Unger R H. Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs.  J Clin Invest. 1981;  68 1106-1107
    PubMedGoogle Scholar
  • 105 Ebert R, Nauck M, Creutzfeldt W. Effect of exogenous or endogenous gastric inhibitory polypeptide (GIP) on plasma triglyceride responses in rats.  Horm Metab Res. 1991;  23 517-521
    PubMedGoogle Scholar
  • 106 Starich G H, Bar R S, Mazzaferri E L. GIP increases insulin receptor affinity and cellular sensitivity in adipocytes.  Am J Physiol. 1985;  249 E603-E607
    PubMedGoogle Scholar
  • 107 Beck B, Max J P. Gastric inhibitory polypeptide enhancement of the insulin effect on fatty acid incorporation into adipose tissue in the rat.  Regul Pept. 1983;  7 3-8
    CrossrefPubMedGoogle Scholar
  • 108 Oben J, Morgan L, Fletcher J, Marks V. Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1 (7-36) amide, on fatty acid synthesis in explants of rat adipose tissue.  J Endocrinol. 1991;  130 267-272
    PubMedGoogle Scholar
  • 109 Baba A S, Harper J M, Buttery P J. Effects of gastric inhibitory polypeptide, somatostatin and epidermal growth factor on lipogenesis in ovine adipose explants.  Comp Biochem Physiol B Biochem Mol Biol. 2000;  127 173-182
    PubMedGoogle Scholar
  • 110 Knapper J M, Puddicombe S M, Morgan L M, Fletcher J M. Investigations into the actions of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (7-36)amide on lipoprotein lipase activity in explants of rat adipose tissue.  J Nutr. 1995;  125 183-188
    PubMedGoogle Scholar
  • 111 Dawson J M, Greathead H M, Sessions V A, Tye F M, Buttery P J. Effect of gastric inhibitory polypeptide on bovine fat metabolism.  Comp Biochem Physiol B Biochem Mol Biol. 1999;  123 79-88
    PubMedGoogle Scholar
  • 112 Ranganath L R, Beety J M, Morgan L M. Inhibition of insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion by octreotide has no effect on post-heparin plasma lipoprotein lipase activity.  Horm Metab Res. 1999;  31 262-266
    PubMedGoogle Scholar
  • 113 Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Fushiki T, Mizunoya W, Fushiki T, Holst J J, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y. Inhibition of GIP signal prevents obesity.  Nature Medicine. 2002;  8 738-742
    CrossrefPubMedGoogle Scholar

J. J. Holst, M. D. Professor of Medical Physiology 

Department of Medical Physiology, University of Copenhagen, Panum Institute

2200 Copenhagen N · Denmark

Phone: +45 3532 7518

Fax: +45 3532 7537 ·

Email: holst@mfi.ku.dk

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