Abstract
The gluco-incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) are secreted by intestinal endocrine cells and have been studied for many years because of their important effect to potentiate glucose-stimulated insulin secretion. In contrast to GIP, GLP-1 retains its insulinotropic effect in type 2 diabetic patients and a long-acting agonist of this peptide is now used for the treatment of this disease. Both peptides, however, have also long-term beneficial effect on the preservation or augmentation of the pancreatic beta-cell functional mass by stimulating beta-cell differentiation from precursors, proliferation of mature beta cells, and their protection against apoptosis. Although several studies have investigated the underlying molecular mechanisms, much remains to be learned about the mode of action of these hormones on beta cells. Here we review the current knowledge on gluco-incretin biology with a specific perspective on their beta-cell action. We also discuss the role that GLP-1 has on beta cells through indirect mechanisms, in particular through the regulation of the hepatoportal vein glucose sensors. This serves as a reminder that betacell function needs to be also studied in an integrated physiological approach where the complexity of their functional regulation can be appreciated.
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References
Holst JJ (2006) Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005. Diabetologia 49:253–260
Larsen PJ, Tang-Christansen M, Holst JJ, Orskov C (1997) Distribution of glucagonlike peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 77:257–270
Bell GI, Santerre RF, Mullenbach GT (1983) Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 302:716–718
Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC (1983) Exon duplication and divergence in the human preproglucagon gene. Nature 304:368–371
Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, Steiner DF (2002) Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99:10293–10298
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
Moody AJ, Thim L, Valverde I (1984) The isolation and sequencing of human gastric inhibitory peptide (GIP). FEBS Lett 172:142–148
Dube PE, Brubaker PL (2004) Nutrient, neural and endocrine control of glucagon-like peptide secretion. Horm Metab Res 36:755–760
Thorens B (1992) Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide I. Proc Natl Acad Sci USA 89:8641–8645
Thorens B, Porret A, Bühler L, Deng S-P, 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
Lankat-Buttgereit B, Göke R, Fehmann HC, Richter G, Göke B (1994) Molecular cloning of a cDNA encoding for the GLP-1 receptor expressed in rat lung. Exp Clin Endocrinol 102:341–347
Mayo KE, Miller LJ, Bataille D, Dalle S, Göke B, Thorens B, Drucker DJ (2003) International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 55:167–194
Göke R, Fehmann H-C, Linn T, Schmidt H, Krause M, Eng J, Göke B (1993) 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 β-cells. J Biol Chem 268:19650–19655
Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI (1993) Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 133:2861–2870
Gremlich S, Porret A, Hani E-H, Cherif D, Vionnet N, Froguel P, Thorens B (1995) Cloning, functional expression and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 44:1202–1208
Yamada Y, Hayami T, Nakamura K, Kaisaki PJ, Someya Y, Wang C-Z, Seino S, Seino Y (1995) Human gastric inhibitory polypeptide receptor: cloning of the gene (GIPR) and cDNA. Genomics 29:773–776
Boylan MO, Jepeal LI, Wolfe MM (1999) Structure of the rat glucose-dependent insulinotropic polypeptide receptor. Peptides 20:219–228
Gelling RW, Coy DH, Pederson RA, Wheeler MB, Hinke S, Kwan T, McIntosch CH (1997) GIP(6-30)amide contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro. Regul Pept 69:151–154
Tseng CC, Kieffer TJ, Jarboe LA, Usdin TB, Wolfe MM (1996) 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 98:2440–2445
Widmann C, Bürki E, Dolci W, Thorens B (1994) Signal transduction by the cloned glucagon-like peptide-1 receptor. Comparison with signalling by the endogenous receptors of β cell lines. Mol Pharmacol 45:1029–1035
Costes S, Broca C, Bertrand G, Lajoix AD, Bataille D, Bockaert J, Dalle S (2006) ERK1/2 control phosphorylation and protein level of cAMP-responsive element-binding protein: a key role in glucose-mediated pancreatic beta-cell survival. Diabetes 55:2220–2230
Gomez E, Pritchard C, Herbert TP (2002) cAMP-dependent protein kinase and Ca2+ influx through L-type voltage-gated calcium channels mediate raf-independent activation of extracellular regulated kinase in response to glucagon-like peptide-1 in pancreatic β-cells. J Biol Chem 277:48146–48151
Ehses JA, Pelech SL, Pederson RA, McIntosh CHS (2002) Glucose-dependent insulinotropic polypeptide activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMPdependent protein kinase/Rap1-mediated pathway. J Biol Chem 277:37088–37097
Arnette D, Gibson TB, Lawrence MC, January B, Khoo S, McGlynn K, Vanderbilt CA, Cobb MH (2003) Regulation of ERK1 and ERK2 by glucose and peptide hormones in pancreatic beta cells. J Biol Chem 278:32517–32525
Trumper J, Ross D, Jahr H, Brendel MD, Goke R, Horsch D (2005) The Rap-B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells. Diabetologia 48:1534–1540
Kerchner KR, Clay RL, McCleery G, Watson N, McIntire WE, Myung CS, Garrison JC (2004) Differential sensitivity of phosphatidylinositol 3-kinase p110gamma to isoforms of G protein betagamma dimers. J Biol Chem 279:44554–44562
Buteau J, Foisy S, Joly E, Prentki M (2003) Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 52:124–132
Buteau J, Foisy S, Rhodes CJ, Carpenter L, Biden TJ, Prentki M (2001) Protein kinase Czeta activation mediates glucagon-like peptide-1-induced pancreatic beta-cell proliferation. Diabetes 50:2237–2243
Ebert R, Creutzfeldt W (1987) Gastrointestinal peptides and insulin secretion. Diabetes Metab Rev 3:1–26
Unger RH, Eisentraut AM (1969) Entero-insular axis. Arch Intern Med 123:261–266
Holst JJ, Orskov C, Vagn Nielsen O, Schwartz TW (1987) Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut. FEBS Lett 211:169–174
Gromada J, Bokvist K, Ding WG, Holst JJ, Nielsen JH, Rorsman P (1998) Glucagon-like peptide 1 (7–36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes 47:57–65
Porksen N, Grofte B, Nyholm B, Holst JJ, Pincus SM, Veldhuis JD, Schmitz O, Butler PC (1998) Glucagon-like peptide 1 increases mass but not frequency or orderliness of pulsatile insulin secretion. Diabetes 47:45–49
Thorens B, Dériaz N, Bosco D, DeVos A, Pipeleers D, Schuit F, Meda P, Porret A (1996) Protein kinase A dependent phosphorylation of GLUT2 in pancreatic {beta} cells. J Biol Chem 271:8075–8081
Béguin P, Nagashima K, Nishimura M, Gonoi T, Seino S (1999) PKA-mediated phosphorylation of the human KATP channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. EMBO J 18:4722–4732
MacDonald PE, Wheeler MB (2003) Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets. Diabetologia 46:1046–1062
MacDonald PE, Wang X, Xia F, El-kholy W, Targonsky ED, Tsushima RG, Wheeler MB (2003) Antagonism of rat beta-cell voltage-dependent K+ currents by exendin 4 requires dual activation of the cAMP/protein kinase A and phosphatidylinositol 3-kinase signaling pathways. J Biol Chem 278:52446–52453
Ämmälä C, Ashcroft FM, Rorsman P (1993) Calcium-independent potentiation of insulin release by cyclic AMP in single {beta} cells. Nature 363:356–358
Ozaki N, Shibasaki T, Kashima Y, Miki T, Takahashi K, Ueno H, Sunaga Y, Yano M, Matsura Y, Iwanaga T, Takai Y, Seino S (2000) cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat Cell Biol 2:805–811
Woodford TA, Correll LA, McKnight GS, Corbin JD (1989) Expression and characterization of mutant forms of the type I regulatory subunit of cAMP-dependent protein kinase. The effect of defective cAMP binding on holoenzyme activation. J Biol Chem 264:13321–13328
Holz GG, Leech CA, Heller RS, Castonguay M, Habener JF (1999) cAMP-dependent mobilization of intracellular Ca2+ stores by activation of ryanodine receptors in pancreatic β-cells. J Biol Chem 274:14147–14156
Zhou J, Wang X, Pineyro MA, Egan JM (1999) Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon-and insulin-producing cells. Diabetes 48:2358–2366
Zhou J, Pineyro MA, Wang X, Doyle ME, Egan JM (2002) Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. J Cell Physiol 192:304–314
Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF (2002) Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology 143:3152–3161
Hui H, Wright C, Perfetti R (2001) Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes 50:785–796
Kodama S, Toyonaga T, Kondo T, Matsumoto K, Tsuruzoe K, Kawashima J, Goto H, Kume K, Kume S, Sakakida M, Araki E (2005) Enhanced expression of PDX-1 and Ngn3 by exendin-4 during beta cell regeneration in STZ-treated mice. Biochem Biophys Res Commun 327:1170–1178
Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270–227
Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Bonner-Weir S, Habener JF, Egan JM (2000) Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49:741–748
Tourrel C, Bailbe D, Meile MJ, Kergoat M, Portha B (2001) Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 50: 1562–1570
Tourrel C, Bailbe D, Lacorne M, Meile M-J, Kergoat M, Portha B (2002) Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the β-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 51:1443–1452
Stoffers DA, Desai BM, DeLeon DD, Simmons RA (2003) Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes 52: 734–740
Buteau J, Roduit R, Susini S, Prentki M (1999) Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia 42:856–864
Wang Q, Brubaker PL (2002) Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia 45:1263–1273
Donath MY, Storling J, Maedler K, Mandrup-Poulsen T (2003) Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 81:455–470
Mandrup-Poulsen T (1996) The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 39:1005–1029
Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860
Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, Gueripel X, Ellingsgaard H, Schneider MK, Biollaz G, Fontana A, Reinecke M, Homo-Delarche F, Donath MY (2007) Increased number of islet associated macrophages in type 2 diabetes. Diabetes: 56:2356–2370
Prentki M, Nolan CJ (2006) Islet beta cell failure in type 2 diabetes. J Clin Invest 116:1802–1812
Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC, Kaufman RJ (2005) Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat Med 11:757–764
Wang J, Takeuchi T, Tanaka S, Kubo S-K, Kayo T, Lu D, Takata K, Koizumi A, Izumi T (1999) A mutation in the insulin 2 gene induces diabetes with severe pancreatic β-cell dysfunction in the Mody mouse. J Clin Invest 103:27–37
Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ (2003) Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 278:471–478
Li L, El-Kholy W, Rhodes CJ, Brubaker PL (2005) Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B. Diabetologia 48:1339–1349
Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L, Joly E, Prentki M (2004) Glucagonlike peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 47:806–815
Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, Li H, Pipeleers D, Ling Z, Drucker DJ (2006) GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab 4:391–406
Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, Perfetti R (2002) Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 143:4397–4408
Hui H, Nourparvar A, Zhao X, Perfetti R (2003) Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphatedependent protein kinase A-and a phosphatidylinositol 3-kinase-dependent pathway. Endocrinology 144:1444–1455
Jhala US, Canettieri G, Screaton RA, Kulkarni RN, Krajewski S, Reed J, Walker J, Lin X, White M, Montminy M (2003) cAMP promotes pancreatic beta-cells survival via CREB-mediated induction of IRS2. Gene Dev 17:1575–1580
Withers DJ, Sanchez Gutierrez J, Towery H, Burks DJ, Ren, J-M, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904
Park S, Dong X, Fisher TL, Dunn S, Omer AK, Weir G, White MF (2006) Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem 281:1159–1168
Inada A, Hamamoto Y, Tsuura Y, Miyazaki J, Toyokuni S, Ihara Y, Nagai K, Yamada Y, Bonner-Weir S, Seino Y (2004) Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic beta cells. Mol Cell Biol 24:2831–2841
Li Y, Cao X, Li LX, Brubaker PL, Edlund H, Drucker DJ (2005) beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes 54:482–491
Buteau J, Spatz ML, Accili D (2006) Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass. Diabetes 55:1190–1196
Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs WH, Wright CVE, White MF, Arden KC, Accili D (2002) The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth. J Clin Invest 110:1839–1847
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
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-I, Seino Y (1999) Glucose intolerance caused by a defect in the enteroinsular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA 96:14843–14847
Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W, Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y (2002) Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8:738–742
Preitner F, Ibberson M, Franklin I, Binnert C, Pende M, Gjinovici A, Hansotia T, Drucker DJ, Wollheim CB, Burcelin R, Thorens B (2004) Gluco-incretin control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest 113:635–645
Hansotia T, Baggio LL, Delmeire D, Hinke SA, Yamada Y, Tsukiyama K, Seino Y, Holst JJ, Schuit F, Drucker DJ (2004) Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 53:1326–1335
Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M, Knudsen LB (2002) The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab 283:E745–E752
Egan JM, Bulotta A, Hui H, Perfetti R (2003) GLP-1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells. Diabetes Metab Res Rev 19:115–123
Movassat J, Beattie GM, Lopez AD, Hayek A (2002) Exendin 4 up-regulates expression of PDX 1 and hastens differentiation and maturation of human fetal pancreatic cells. J Clin Endocrinol Metab 87:4775–4781
De Leon DD, Deng S, Madani R, Ahima RS, Drucker DJ, Stoffers DA (2003) Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes 52:365–371
Burcelin R, Crivelli V, Perrin C, Da Costa A, Mu J, Kahn BB, Birnbaum MJ, Kahn CR, Vollenweider P, Thorens B (2003) GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor-stimulated muscle glucose utilization. J Clin Invest 111:1555–1562
Thorens B (2004) The hepatoportal glucose sensor. Mechanisms of glucose sensing and signal transduction. In: Matschinski FM, Magnuson MA (eds) Glucokinase and glycemic disease: from basics to novel therapeutics. Karger, Basel, pp 327–338
Niijima A (1969) Afferent impulse discharges from glucoreceptors in the liver of the guinea pig. Ann N Y Acad Sci 157:690–700
Niijima A (1982) Glucose-sensitive afferent nerve fibres in the hepatic branch of the vagus nerve in the guinea-pig. J Physiol 332:315–323
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
Nishizawa M, Nakabayashi H, Uchida K, Nakagawa A, Niijima A (1996) 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 61:149–154
Balkan B, Li X (2000) Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol Regul Integr Comp Physiol 279:R1449–R1454
Burcelin R, DaCosta A, Drucker D, Thorens B (2001) Glucose competence of the hepatoporal vein sensor requires the presence of an activated GLP-1 receptor. Diabetes 50:1720–1728
Flamez D, Van Breusegem A, Scrocchi LA, Quartier E, Pipeleers D, Drucker DJ, Schuit F (1998) Mouse pancreatic β-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene. Diabetes 47: 646–652
Ahren 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
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Klinger, S., Thorens, B. (2008). Molecular Biology of Gluco-Incretin Function. In: Seino, S., Bell, G.I. (eds) Pancreatic Beta Cell in Health and Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-75452-7_16
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DOI: https://doi.org/10.1007/978-4-431-75452-7_16
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