CC BY-NC-ND 4.0 · Diabetologie und Stoffwechsel 2023; 18(06): 475-487
DOI: 10.1055/a-2102-2436
Übersicht

GIP und GLP-1-Rezeptoragonismus in der Therapie des Typ 2 Diabetes mit Fokus auf Tirzepatid

GIP and GLP-1 receptor agonism in the therapy of type 2 diabetes with a focus on tirzepatide
Michael A. Nauck
1   Diabetologie, St. Josef-Hospital (Ruhr-University Bochum), Bochum, Germany
,
Matthias Blüher
2   Department of Endocrinology, University Medical Center Leipzig, Leipzig, Germany
,
Sebastian M. Meyhöfer
3   Institut für Endokrinologie & Diabetes, Universität zu Lübeck, Lübeck, Germany (Ringgold ID: RIN9191)
,
Elke Heitmann
4   Medizinische Abteilung - Diabetes, Lilly Deutschland GmbH, Bad Homburg, Germany (Ringgold ID: RIN35059)
,
Sven W Görgens
4   Medizinische Abteilung - Diabetes, Lilly Deutschland GmbH, Bad Homburg, Germany (Ringgold ID: RIN35059)
› Author Affiliations
Supported by: Eli Lilly and Company

Zusammenfassung

Die Wirkung von Inkretinen trägt wesentlich zur Aufrechterhaltung einer normalen oralen Glukosetoleranz bei gesunden Personen bei. Diese wird größtenteils durch zwei Darmhormone vermittelt: das Glukose-abhängige insulinotrope Polypeptid (GIP) und das Glukagon-ähnliche Peptid 1 (Glucagon-like peptide-1, GLP-1). Dieser Mechanismus ist bei Patienten/Patientinnen mit Typ-2-Diabetes deutlich reduziert. Inkretin-basierte Therapien wie GLP-1-Rezeptoragonisten und Dipeptidylpeptidase-4 (DPP-4)-Inhibitoren sind heute etablierte Substanzklassen in der Therapie des Typ-2-Diabetes. Neue Forschungsergebnisse, insbesondere mit Agonisten, die sowohl an GIP- als auch GLP-1-Rezeptoren wirken, steigerten das Interesse an GIP in der Therapie des Typ-2-Diabetes. In der Bauchspeicheldrüse verstärken beide Inkretine die Glukose-abhängige Insulinsekretion. GLP-1 unterdrückt glukose-abhängig die Glukagon-Sekretion, während GIP die Glukagon-Sekretion besonders bei niedrigen Plasmaglukosekonzentrationen stimuliert. Im Fettgewebe fördert GIP die Durchblutung, erhöht die Glukoseaufnahme und Triglyzerid-Speicherung und kann bei hohen Glukosespiegeln und niedrigen Plasmainsulinspiegeln eine direkte lipolytische Wirkung haben. Tierexperimentelle Studien deuten darauf hin, dass GIP wie auch GLP-1 einen Effekt auf die Sättigungsregulation im Gehirn haben kann.

Tirzepatid wurde so entwickelt, dass es das physiologische Inkretin-Gleichgewicht nachahmt, indem es sowohl an GIP- als auch GLP-1-Rezeptoren wirkt. Jüngste Daten aus dem SURPASS-Programm klinischer Phase-3-Studien mit Tirzepatid weisen darauf hin, dass sich der neuartige Wirkstoff besonders stark auf die Blutzuckersenkung und die Körpergewichtsreduktion auswirkt. Die Effekte übertreffen bezüglich glykämischer Kontrolle, Insulinsekretion, Glukagon-Suppression, Insulinsensitivität und Körpergewichtsreduktion sowohl die Wirkung potenter GLP-1-Rezeptoragonisten als auch von Basalinsulinen, sodass der Einfluss von GIP neu bewertet werden muss. Der vorliegende Übersichtsartikel fasst die physiologischen Effekte von GIP und GLP-1 zusammen. Um den genauen Wirkmechanismus von Tirzepatid und anderen GIP- und GLP-1-Rezeptoragonisten vollständig zu verstehen, bedarf es weiterer Forschung.

Abstract

The incretin effect is a major contributor to maintaining normal oral glucose tolerance in healthy individuals. The incretin effect is largely mediated by two gut-derived hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). This mechanism is substantially reduced in patients with type 2 diabetes. Incretin-based therapies such as GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are now established in the therapy of type 2 diabetes. New research results, especially with agonists acting on both GIP and GLP-1 receptors, increased the interest in GIP in the therapy of type 2 diabetes. In the pancreas, both incretins enhance glucose-dependent insulin secretion. GLP-1 suppresses glucose-dependent glucagon secretion, while GIP stimulates glucagon secretion especially at low plasma glucose concentrations. In adipose tissue, GIP promotes blood flow, increases glucose uptake and triglyceride storage, and may have a direct lipolytic effect when glucose levels are high and plasma insulin levels are low. Animal studies suggest that GIP as well as GLP-1 has an effect on the satiation regulation in the brain.

Tirzepatide acts on both GIP and GLP-1 receptors. Recent data from the SURPASS series of Phase 3 clinical trials with tirzepatide indicate that this novel agent has especially strong effects on lowering of glycated haemoglobin and body weight reduction. The effects exceed those of potent GLP-1 receptor agonists in terms of glycaemic control, insulin secretion, glucagon suppression, insulin sensitivity and body weight reduction, as well as of basal insulin preparations, so that the influence of GIP has to be reassessed. The present review summarises the physiological effects of GIP and GLP-1. More research is necessary to fully understand the exact mechanism of action of tirzepatide and other agonists of both the GIP and GLP-1 receptor.



Publication History

Received: 01 February 2023

Accepted after revision: 09 May 2023

Article published online:
24 July 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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  • Literatur

  • 1 Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004; 287: E199-206 DOI: 10.1152/ajpendo.00545.2003. (PMID: 15271645)
  • 2 Holst JJ, Gasbjerg LS, Rosenkilde MM. The Role of Incretins on Insulin Function and Glucose Homeostasis. Endocrinology 2021; 162 DOI: 10.1210/endocr/bqab065. (PMID: 33782700)
  • 3 Edie ES. Further Observations on the Treatment of Diabetes Mellitus by Acid Extract of Duodenal Mucous Membrane. Biochem J 1906; 1: 446-454 DOI: 10.1042/bj0010446. (PMID: 16742042)
  • 4 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-223 DOI: 10.1152/ajpendo.1979.237.3.E214. (PMID: 382871)
  • 5 Elrick H, Stimmler L, Hlad Jr CJ. et al. Plasma Insulin Response to Oral and Intravenous Glucose Administration. J Clin Endocrinol Metab 1964; 24: 1076-1082 DOI: 10.1210/jcem-24-10-1076. (PMID: 14228531)
  • 6 Bell GI, Sanchez-Pescador R, Laybourn PJ. et al. Exon duplication and divergence in the human preproglucagon gene. Nature 1983; 304: 368-371 DOI: 10.1038/304368a0. (PMID: 6877358)
  • 7 Brown JC, Dryburgh JR. A gastric inhibitory polypeptide. II. The complete amino acid sequence. Can J Biochem 1971; 49: 867-872 DOI: 10.1139/o71-122. (PMID: 5120249)
  • 8 Buse JB, Wexler DJ, Tsapas A. et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020; 63: 221-228 DOI: 10.1007/s00125-019-05039-w. (PMID: 31853556)
  • 9 Deane AM, Nguyen NQ, Stevens JE. et al. Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia. J Clin Endocrinol Metab 2010; 95: 215-221 DOI: 10.1210/jc.2009-1503. (PMID: 19892837)
  • 10 Plamboeck A, Veedfald S, Deacon CF. et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol 2013; 304: G1117-1127
  • 11 Salehi M, Vahl TP, D’Alessio DA. Regulation of islet hormone release and gastric emptying by endogenous glucagon-like peptide 1 after glucose ingestion. J Clin Endocrinol Metab 2008; 93: 4909-4916 DOI: 10.1210/jc.2008-0605. (PMID: 18827000)
  • 12 Krarup T, Saurbrey N, Moody AJ. et al. Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus. Metabolism 1987; 36: 677-682 DOI: 10.1016/0026-0495(87)90153-3. (PMID: 3298936)
  • 13 Nauck MA, Heimesaat MM, Orskov C. et al. 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
  • 14 Miyawaki K, Yamada Y, Ban N. et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 2002; 8: 738-742 DOI: 10.1038/nm727. (PMID: 12068290)
  • 15 Christensen M, Vedtofte L, Holst JJ. et al. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 2011; 60: 3103-3109 DOI: 10.2337/db11-0979. (PMID: 21984584)
  • 16 Irwin N, Flatt PR. Therapeutic potential for GIP receptor agonists and antagonists. Best Pract Res Clin Endocrinol Metab 2009; 23: 499-512 DOI: 10.1016/j.beem.2009.03.001. (PMID: 19748067)
  • 17 Meier JJ, Gallwitz B, Siepmann N. et al. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia 2003; 46: 798-801 DOI: 10.1007/s00125-003-1103-y. (PMID: 12764578)
  • 18 Bokvist K, Brown R, Coskun T. et al. LY3298176, a novel long-actingGIP/GLP-1 coagonist, shows enhanced activity on weight loss and energy utilization whilst maintaining its efficacy for glycaemic control. Diabetologia 2017; 60 (Suppl. 01) S399
  • 19 Finan B, Ma T, Ottaway N. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med 2013; 5: 209ra151 DOI: 10.1126/scitranslmed.3007218. (PMID: 24174327)
  • 20 Tschöp MH, Finan B, Clemmensen C. et al. Unimolecular Polypharmacy for Treatment of Diabetes and Obesity. Cell Metab 2016; 24: 51-62 DOI: 10.1016/j.cmet.2016.06.021. (PMID: 27411008)
  • 21 Nauck MA, Bartels E, Orskov C. et al. 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 DOI: 10.1210/jcem.76.4.8473405. (PMID: 8473405)
  • 22 Mentis N, Vardarli I, Kothe LD. et al. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 2011; 60: 1270-1276
  • 23 Coskun T, Sloop KW, Loghin C. et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab 2018; 18: 3-14
  • 24 Dahl D, Onishi Y, Norwood P. et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA 2021; 327: 534-545
  • 25 Del Prato S, Kahn SE, Pavo I. et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021; 398: 1811-1824 DOI: 10.1016/S0140-6736(21)02188-7. (PMID: 34672967)
  • 26 Frias JP, Davies MJ, Rosenstock J. et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med 2021; 385: 503-515
  • 27 Ludvik B, Giorgino F, Jodar E. et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet 2021; 398: 583-598 DOI: 10.1016/S0140-6736(21)01443-4. (PMID: 34370970)
  • 28 Rosenstock J, Wysham C, Frias JP. et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 2021; 398: 143-155
  • 29 Frias JP, Nauck MA, Van J. et al. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metab 2020; 22: 938-946
  • 30 Muller TD, Bluher M, Tschop MH. et al. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2022; 21: 201-223 DOI: 10.1038/s41573-021-00337-8. (PMID: 34815532)
  • 31 Nauck MA, D’Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol 2022; 21: 169 DOI: 10.1186/s12933-022-01604-7. (PMID: 36050763)
  • 32 Nauck M, Stockmann F, Ebert R. et al. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29: 46-52 DOI: 10.1007/BF02427280. (PMID: 3514343)
  • 33 Knop FK, Aaboe K, Vilsboll T. et al. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab 2012; 14: 500-510 DOI: 10.1111/j.1463-1326.2011.01549.x. (PMID: 22171657)
  • 34 Shuster LT, Go VL, Rizza RA. et al. Incretin effect due to increased secretion and decreased clearance of insulin in normal humans. Diabetes 1988; 37: 200-203 DOI: 10.2337/diab.37.2.200. (PMID: 3292314)
  • 35 Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia 1985; 28: 565-573 DOI: 10.1007/BF00281990. (PMID: 3902545)
  • 36 Nauck MA, Homberger E, Siegel EG. et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986; 63: 492-498
  • 37 Bagger JI, Knop FK, Lund A. et al. Impaired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 737-745
  • 38 Nauck MA, Meier JJ. GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family. Diabetes 2019; 68: 897-900 DOI: 10.2337/dbi19-0005. (PMID: 31010881)
  • 39 Holst JJ, Knop FK, Vilsboll T. et al. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 2011; 34: S251-257 DOI: 10.2337/dc11-s227. (PMID: 21525464)
  • 40 Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function?. Diabetes 2010; 59: 1117-1125
  • 41 Buchan AM, Polak JM, Capella C. et al. Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry 1978; 56: 37-44 DOI: 10.1007/BF00492251. (PMID: 350814)
  • 42 Deacon CF, Nauck MA, Meier J. et al. 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 DOI: 10.1210/jcem.85.10.6855. (PMID: 11061504)
  • 43 Ding WG, Gromada J. Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. Diabetes 1997; 46: 615-621 DOI: 10.2337/diab.46.4.615. (PMID: 9075801)
  • 44 Gromada J, Bokvist K, Ding WG. et al. 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 1998; 47: 57-65
  • 45 Alvarez E, Martinez MD, Roncero I. et al. The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem 2005; 92: 798-806 DOI: 10.1111/j.1471-4159.2004.02914.x. (PMID: 15686481)
  • 46 Pyke C, Heller RS, Kirk RK. et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 2014; 155: 1280-1290
  • 47 Wei Y, Mojsov S. 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 1995; 358: 219-224 DOI: 10.1016/0014-5793(94)01430-9. (PMID: 7843404)
  • 48 Orskov C, Wettergren A, Holst JJ. 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 DOI: 10.3109/00365529609009147. (PMID: 8819215)
  • 49 Vahl TP, Paty BW, Fuller BD. et al. Effects of GLP-1-(7–36)NH2, GLP-1-(7–37), and GLP-1- (9–36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab 2003; 88: 1772-1779 DOI: 10.1210/jc.2002-021479. (PMID: 12679472)
  • 50 Vilsboll T, Agerso H, Krarup T. et al. 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 DOI: 10.1210/jc.2002-021053. (PMID: 12519856)
  • 51 Flint A, Raben A, Astrup A. et al. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998; 101: 515-520 DOI: 10.1172/JCI990. (PMID: 9449682)
  • 52 Nauck MA, Niedereichholz U, Ettler R. et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997; 273: E981-988 DOI: 10.1152/ajpendo.1997.273.5.E981. (PMID: 9374685)
  • 53 Schirra J, Nicolaus M, Roggel R. et al. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut 2006; 55: 243-251 DOI: 10.1136/gut.2004.059741. (PMID: 15985560)
  • 54 Schjoldager BT, Mortensen PE, Christiansen J. et al. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig Dis Sci 1989; 34: 703-708 DOI: 10.1007/BF01540341. (PMID: 2714145)
  • 55 Verdich C, Flint A, Gutzwiller JP. et al. 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 DOI: 10.1210/jcem.86.9.7877. (PMID: 11549680)
  • 56 Wettergren A, Schjoldager B, Mortensen PE. et al. Truncated GLP-1 (proglucagon 78–107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993; 38: 665-673 DOI: 10.1007/BF01316798. (PMID: 8462365)
  • 57 Nauck MA, Quast DR, Wefers J. et al. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab 2021; 23: 5-29 DOI: 10.1111/dom.14496. (PMID: 34310013)
  • 58 Samms RJ, Coghlan MP, Sloop KW. How May GIP Enhance the Therapeutic Efficacy of GLP-1?. Trends Endocrinol Metab 2020; 31: 410-421 DOI: 10.1016/j.tem.2020.02.006. (PMID: 32396843)
  • 59 Bailey CJ. Tirzepatide: a new low for bodyweight and blood glucose. Lancet Diabetes Endocrinol 2021; 9: 646-648 DOI: 10.1016/S2213-8587(21)00217-5. (PMID: 34419226)
  • 60 Gromada J, Holst JJ, Rorsman P. Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflugers Arch 1998; 435: 583-594 DOI: 10.1007/s004240050558. (PMID: 9479010)
  • 61 Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab 2018; 20: 5-21 DOI: 10.1111/dom.13129. (PMID: 29364588)
  • 62 Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev 2013; 9: 25-53 (PMID: 22974359)
  • 63 Orskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78–107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 1988; 123: 2009-2013 DOI: 10.1210/endo-123-4-2009. (PMID: 2901341)
  • 64 Nauck MA, Heimesaat MM, Behle K. et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87: 1239-1246
  • 65 Kjems LL, Holst JJ, Volund A. et al. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003; 52: 380-386 DOI: 10.2337/diabetes.52.2.380. (PMID: 12540611)
  • 66 Choe SS, Huh JY, Hwang IJ. et al. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front Endocrinol (Lausanne) 2016; 7: 30 DOI: 10.3389/fendo.2016.00030. (PMID: 27148161)
  • 67 Asmar M, Simonsen L, Madsbad S. et al. Glucose-dependent insulinotropic polypeptide may enhance fatty acid re-esterification in subcutaneous abdominal adipose tissue in lean humans. Diabetes 2010; 59: 2160-2163 DOI: 10.2337/db10-0098. (PMID: 20547981)
  • 68 Rudovich N, Kaiser S, Engeli S. et al. GIP receptor mRNA expression in different fat tissue depots in postmenopausal non-diabetic women. Regul Pept 2007; 142: 138-145 DOI: 10.1016/j.regpep.2007.02.006. (PMID: 17395281)
  • 69 Heimburger SMN, Nielsen CN, Calanna S. et al. Glucose-dependent insulinotropic polypeptide induces lipolysis during stable basal insulin substitution and hyperglycaemia in men with type 1 diabetes: A randomized, double-blind, placebo-controlled, crossover clinical trial. Diabetes Obes Metab 2022; 24: 142-147
  • 70 Kim SJ, Nian C, Karunakaran S. et al. GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. PLoS One 2012; 7: e40156 DOI: 10.1371/journal.pone.0040156. (PMID: 22802954)
  • 71 Campbell JE, Beaudry JL, Svendsen B. et al. GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue. Diabetes 2022; 71: 1115-1127
  • 72 Kim KS, Seeley RJ, Sandoval DA. Signalling from the periphery to the brain that regulates energy homeostasis. Nat Rev Neurosci 2018; 19: 185-196
  • 73 Meier JJ, Gallwitz B, Salmen S. et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 2719-2725
  • 74 Schirra J, Wank U, Arnold R. et al. Effects of glucagon-like peptide-1(7–36)amide on motility and sensation of the proximal stomach in humans. Gut 2002; 50: 341-348 DOI: 10.1136/gut.50.3.341. (PMID: 11839712)
  • 75 Zhang Q, Delessa CT, Augustin R. et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab 2021; 33: 833-844 e835 DOI: 10.1016/j.cmet.2021.01.015. (PMID: 33571454)
  • 76 Samms RJ, Christe ME, Collins KA. et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest 2021; 131 DOI: 10.1172/JCI146353. (PMID: 34003802)
  • 77 Adriaenssens AE, Biggs EK, Darwish T. et al. Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake. Cell Metab 2019; 30: 987-996 e986 DOI: 10.1016/j.cmet.2019.07.013. (PMID: 31447324)
  • 78 NamKoong C, Kim MS, Jang BT. et al. Central administration of GLP-1 and GIP decreases feeding in mice. Biochem Biophys Res Commun 2017; 490: 247-252 DOI: 10.1016/j.bbrc.2017.06.031. (PMID: 28610922)
  • 79 Borner T, Geisler CE, Fortin SM. et al. GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models. Diabetes 2021; 70: 2545-2553 DOI: 10.2337/db21-0459. (PMID: 34380697)
  • 80 Costa A, Ai M, Nunn N. et al. Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation. Mol Metab 2022; 55: 101407 DOI: 10.1016/j.molmet.2021.101407. (PMID: 34844019)
  • 81 Bergmann NC, Gasbjerg LS, Heimburger SM. et al. No Acute Effects of Exogenous Glucose-Dependent Insulinotropic Polypeptide on Energy Intake, Appetite, or Energy Expenditure When Added to Treatment With a Long-Acting Glucagon-Like Peptide 1 Receptor Agonist in Men With Type 2 Diabetes. Diabetes Care 2020; 43: 588-596 DOI: 10.2337/dc19-0578. (PMID: 31949084)
  • 82 Stensen S, Gasbjerg LS, Krogh LL. et al. Effects of endogenous GIP in patients with type 2 diabetes. Eur J Endocrinol 2021; 185: 33-45
  • 83 Willms B, Werner J, Holst JJ. et al. 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 1996; 81: 327-332 DOI: 10.1210/jcem.81.1.8550773. (PMID: 8550773)
  • 84 Nauck MA, Kemmeries G, Holst JJ. et al. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 2011; 60: 1561-1565 DOI: 10.2337/db10-0474. (PMID: 21430088)
  • 85 Meier JJ, Rosenstock J, Hincelin-Mery A. et al. Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial. Diabetes Care 2015; 38: 1263-1273 DOI: 10.2337/dc14-1984. (PMID: 25887358)
  • 86 Meier JJ, Schenker N, Kahle M. et al. Impact of insulin glargine and lixisenatide on beta-cell function in patients with type 2 diabetes mellitus: A randomized open-label study. Diabetes Obes Metab 2017; 19: 1625-1629
  • 87 Meier JJ, Goetze O, Anstipp J. et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol Endocrinol Metab 2004; 286: E621-625
  • 88 Calanna S, Christensen M, Holst JJ. et al. Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: systematic review and meta-analysis of clinical studies. Diabetes Care 2013; 36: 3346-3352
  • 89 Calanna S, Christensen M, Holst JJ. et al. Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia 2013; 56: 965-972
  • 90 Nauck MA, Vardarli I, Deacon CF. et al. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down?. Diabetologia 2011; 54: 10-18
  • 91 Vilsboll T, Krarup T, Madsbad S. et al. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 2002; 45: 1111-1119 DOI: 10.1007/s00125-002-0878-6. (PMID: 12189441)
  • 92 Butler AE, Janson J, Bonner-Weir S. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102-110
  • 93 Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705 DOI: 10.1016/S0140-6736(06)69705-5. (PMID: 17098089)
  • 94 Nauck MA, Kleine N, Orskov C. et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36: 741-744 DOI: 10.1007/BF00401145. (PMID: 8405741)
  • 95 Karagiannis T, Avgerinos I, Liakos A. et al. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia 2022; 65: 1251-1261
  • 96 Heise T, Mari A, DeVries JH. et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol 2022; 10: 418-429 DOI: 10.1016/S2213-8587(22)00085-7. (PMID: 35468322)
  • 97 Thomas MK, Nikooienejad A, Bray R. et al. Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. J Clin Endocrinol Metab 2021; 106: 388-396 DOI: 10.1210/clinem/dgaa863. (PMID: 33236115)
  • 98 Lee CL. et al. Weekly dual GIP/GLP-1 receptor agonist tirzepatide monotherapy improved markers of islet cell function and insulin sensitivity in people with type 2 diabetes (SURPASS-1). Presented at EASD 2021. 2021
  • 99 Fisman EZ, Tenenbaum A. The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovasc Diabetol 2021; 20: 225 DOI: 10.1186/s12933-021-01412-5. (PMID: 34819089)