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Horm Metab Res 2004; 36(11/12): 842-845
DOI: 10.1055/s-2004-826173
DOI: 10.1055/s-2004-826173
Review
© Georg Thieme Verlag KG Stuttgart · New YorkGLP-1 and Extra-islet Effects
Further Information
Publication History
Received 9 July 2004
Accepted after revision 17 August 2004
Publication Date:
18 January 2005 (online)
Abstract
The main target of action of glucagon-like peptide-1 (GLP-1) is the islet, where the hormone stimulates insulin secretion, promotes beta cell proliferation and neogenesis, and inhibits glucagon secretion. However, GLP-1 receptors are also expressed outside the islets, increasing the likelihood that GLP-1 also plays a role in other organs. These functions are mainly the inhibition of gastric emptying, gastric acid secretion and exocrine pancreatic secretion, indicating that the hormone acts as an enterogastrone - a hormone released from the distal portion of the small intestine that inhibits proximal gastrointestinal events. Another important action of GLP-1 is to induce satiety. Other effects of the hormone include cardioprotection, neuroprotection, induction of learning and memory, stimulation of afferent, sensory nerves, stimulation of surfactant production in the lung, dilatation of pulmonary vessels, induction of diuresis, and also under some conditions, induction of antidiabetic actions unrelated to islet function. Thus, GLP-1 clearly has several manifestations of activity. The physiological relevance of these actions and their contribution to the overall antidiabetic action of GLP-1 when used in treatment of type 2 diabetes remains to be established.
Key words
GLP-1 - Extra-islet - Gastric emptying - gastric acid secretion - Pancreatic secretion - Cardiac function - Sensory nerves
References
- 1 Holz G G. Beta cell signaling of GLP-1. Horm Metab Res. 2004; 36 786-794
- 2 Perfetti R, Hui H. The role of GLP-1 in the life and death of pancreatic beta cells. Horm Metab Res. 2004; 36 822-829
- 3 Rorsman P, Gromada J. GLP-1 and alpha-cell effects. Horm Metab Res. 2004; in press
- 4 Brubaker P L, Drucker D J. Structure - function of the glucagon receptor family of G protein-cupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Receptors Channels. 2002; 8 179-188
- 5 Larsen P J, Tang-Christensen M, Holst J J, Ørskov C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience. 1997; 77 257-370
- 6 Shimizu I, Hirota M, Ohjboshi C, Shima K. Identification and localization of glucagon-like peptide 1 and its receptor in rat brain. Endocrinology. 1987; 121 1076-1082
- 7 Uttenthal L O, Toledano A, Blasquez E. Autoradiographuc localization of receptors for glucagon-like peptide-1 (7 - 36)amide in rat brain. Neuropeptides. 1992; 21 143-146
- 8 Fehmann H C, Göke R, Göke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulin releasing polypeptide. Endocr Rev. 1995; 16 390-4010
- 9 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
- 10 Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide 1: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 1995; 358 219-224
- 11 Alvarez E, Roncero J, Chowen J A, Thorens B, Blazquez E. Expression of the glucagon-like peptide-1 receptor gene in rat brain. J Neurochem. 1996; 66 920-927
- 12 Merchenthaler I, Lane M, Shughrue P. Distribution of the preproglucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol. 1999; 403 261-280
- 13 Valverde I, Morales M, Clemente F, Lopez-Delgado M I, Delgado E, Perea A, Villanueva-Penacarrillo M L. Glucagon-like peptide 1: a potent glycogenic hormone. FEBS Lett. 1994; 349 313-316
- 14 Villanueva-Penacarillo M L, Alcanatara A I, Clemente F, Delgado E, Valverde I. Potent glycogenic effect of GLP-1(7 - 36) amide in rat skeletal muscle. Diabetologia. 1994; 37 1163-1166
- 15 Galera C, Clemente F, Alcanatara A, Trapote M A, Perea A, Lopez-Delgado M I, Villanyeva-Penecarrillo M L, Valverde I. Inositolphosphoglycans and diacylglycerol are possible mediators in the glycogenic effect of GLP-1(7 - 36)amide in BC3H-1 myocytes. Cell Biochem Funct. 1996; 14 43-48
- 16 Montrose-Rafizadeh C, Yang H, Wang Y, Roth J, Montrose M H, Adams L G. Novel signal transduction and peptide specificity of glucagon-like peptide receptors in 3T3-LI adipocytes. J Cell Physiol. 1997; 172 275-283
- 17 Wheeler M B, Lu M, Dillon J S, Leng X H, Chen C, Boyd III A E. Functional expression of the rat glucagon-like peptide-1 receptor, evidence for coupling to both adenylyl cyclase and phospholipase C. Endocrinology. 1993; 133 57-62
- 18 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
- 19 Nishizawa M, Nakabayashi H, Kawai K, Ito T, Kawakami S, Nakagawa A, Niijima A, Uchida K. The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor. J Autonom Nerv Syst. 2000; 80 14-21
- 20 Dhillo W S, Bloom S R. Gastrointestinal hormones and regulation of food intake. Horm Metab Res. 2004; 36 846-851
- 21 Rizza R A. Extrapancreatic effects of GIP and GLP-1. Horm Metab Res. 2004; 36 830-836
- 22 Kosaka T, Lim R KS. Demonstration of the humoral agent in fat inhibition on gastric secretion. Proc Soc Exp Biol Med. 1930; 27 890-891
- 23 Näslund E, King N, Mansten S, Adner N, Holst J J, Gutniak M, Hellström P M. Prandial subcutaneous injections of glucagon-like peptide-I cause weight loss in obese human subjects. Br J. Nutr. 2004; 91 439-446
- 24 Nauck M A, Niedereichholz U, Ettler R, Holst J J, Ørskov 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
- 25 Gutniak M K, Svartberg J, Hellström P M, Holst J J, Adner N, Ahrén B. Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes. Int J Med. 2001; 250 81-87
- 26 Wettergren A, Wøjdemann M, Holst J J. Glucagon-like peptide-1 (GLP-1) inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol. 1998; 275 G984-G992
- 27 Wettergren A, Wøjdemann 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
- 28 Näslund E, Gutniak M, Skogar S, Rössner S, Hellström P M. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998; 68 525-530
- 29 Flint A, Raben A, Ersbøll A K, Holst J J, Astrup A. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes. 2001; 25 781-792
- 30 Kolterman O G, Buse J B, Fineman M S, Gaines E, Heintz S, Bicsak T, Taylor K, Kim D, Aisporna M, Wang Y, Baron A D. Synthetic edenxin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003; 88 3082-3089
- 31 Holst J J. Enteroglucagon. Ann Rev Physiol. 1997; 59 257-271
- 32 Barragan J M, Rodriguez R E, Blazguez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7 - 36) amide in rats. Am J Physiol. 1994; 266 E459-E466
- 33 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, Brucker 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
- 34 Barragan J M, Rodriguez R E, Eng J, Blazquez E. Interactions of exendin-(9 - 39) with the effects of glucagon-like peptide-1-(7 - 36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regul Pept. 1996; 67 63-68
- 35 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
- 36 Bose A K, Mocanu M M, Mensah K N, Brand C L, Carr R D, Yellon D M. GLP-1 protects ischemic and reperfused myocardium via PI3kinase and p42/p44-MAPK signaling pathways. Diabetes. 2004; 53 Suppl 2 A1 (2004)
- 37 Imeryoz N, Yegen B C, Bozkurt A, Coskun T, Villanueva-Penecarrillo 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
- 38 Balkan B, Li X. Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol. 2000; 279 R1449-R1454
- 39 Ahrén B. Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 (GLP-1) in mice. Am J Physiol. 2004; 286 R269-R272
- 40 Burcelin R, da Costa A, Drucker D, Thorens B. Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes. 2001; 50 1720-1728
- 41 Ahrén B, Larsson H, Holst J J. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997; 82 473-478
- 42 D'Alessio D A, Kahn S E, Leusner C R, Ensinck J W. Glucagon-like peptide I enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest. 1994; 93 2263-2266
- 43 Ørskov L, Holst J J, Moller N, Alberti K GMM, Schmitz O. GLP-1 does not acutely affect insulin in healthy men. Diabetologia. 1996; 39 1227-1232
- 44 Toft-Nielsen M, Madsbad S, Holst J J. The effect of glucagon-like peptide 1 (GLP-1) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. Diabetes. 1996; 45 552-556
- 45 Egan J M, Meneilly G S, Habener J F, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab. 2002; 87 3768-3773
- 46 Meneilly G S, McIntosh C H, Pederson R A, Habener J F, Gingerich R, Egan J M, Elahi D. Glucagon-like peptide-1 (7 - 37) augments insulin-mediated glucose uptake in elderly patients with diabetes. J Gerontol A Biol Sci Med Sci. 2001; 56 M681-M685
- 47 Zander M, Madsbad S, Lysgaard Madsen J, Holst J J. Effect of 6-week course of glucagon-like peptide 1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002; 359 824-830
- 48 Larsson H, Holst J J, Ahrén B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand. 1997; 160 413-422
- 49 Nishizawa M, Moore M, Shiota M, Gustavson S, Snead W, Neal D, Cherrington A. Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs. Am J Physiol. 2003; 284 E1027-E1036
- 50 Prigeon R L, Quddusi S, Paty B, D'Alessio D A. Suppression of endogenous glucose production by glucagon-like peptide 1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol. 2003; 285 E701-E707
- 51 Yu M, Moreno C, Hoagland K M, Dahly A, Ditter K, Mistry M, Roman R J. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hyperten. 2003; 21 1125-1135
- 52 Gutzwille J P, Tschopp S, Bock A, Zehnder C E, Huber A R, Kreuenbuehl M, Gutmann H, Drewe J, Henzen C, Göke B, Beglinger C. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004; 89(6) 3055-3061
- 53 Golpon H A, Puechner A, Welte T, Wichert P V, Feddersen C O. Vasorelaxant effect of glucagon-like peptide-(7 - 36)amide4 and amylin in the pulmonary circulation of the rat. Regul Pept. 2001; 102 81-86
- 54 Benito E, Blazquez E, Bosch M A. Glucagon-like peptide-1-(7 - 36) amide increases pulmonary surfactant secretion through a cyclic adenosine 3′,5′-monophosphate-dependent protein kinase mechanism in rat type II pneumocytes. Endocrinology. 1998; 139 2363-2368
- 55 Vara E, Arias-Diaz J, Garcia C, Balibrea J L, Blazquez E. Glucagon-like peptide-1(7 - 36)amide stimulates surfactant secretion in human type II pneumocytes. Am J Respir Crit Care Med. 2001; 163 840-846
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