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Veränderungen der Sekretion und biologischen Wirksamkeit von Inkretinhormonen bei Typ-2-Diabetes

Changes in the secretion and efficacy of incretin hormones in type 2 diabetes

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Zusammenfassung

Die Inkretinhormone „glucose-dependent insulinotropic peptide“ (GIP) und „glucagon-like peptide 1“ (GLP-1) werden nach oraler Zufuhr von Nährstoffen von enteroendokrinen Zellen der Darmschleimhaut sezerniert und stimulieren in Abhängigkeit von der Blutzuckerkonzentration die Insulinsekretion. Bei Gesunden sind sie zusammen für etwa 63–74 % des Inkretineffekts verantwortlich, wobei GIP verglichen mit GLP‑1 einen fast doppelt so hohen Anteil hat. Bei Menschen mit Typ-2-Diabetes ist der Inkretineffekt trotz einer insgesamt unveränderten Sekretion beider Hormone reduziert. Bei ihnen ist GIP weitgehend unwirksam, während die Wirksamkeit von GLP‑1 zur Senkung der Blutzuckerkonzentration, Stimulation der Insulin- und Hemmung der Glukagonsekretion deutlich besser erhalten ist. Die Ursachen für diese Unterschiede sind immer noch nicht abschließend geklärt, diskutiert werden eine verminderte Expression des GIP-Rezeptors bei Diabetes mellitus oder ein allgemein reduziertes Ansprechen funktionsgestörter β‑Zellen. Der weitgehende Wirkverlust von GIP beim Typ-2-Diabetes in Kurzzeitexperimenten zur Stimulation der Insulinsekretion ist nicht ohne Weiteres kompatibel mit der besonders hohen Effektivität von GIP-/GLP-1-Rezeptor-Koagonisten wie Tirzepatid in der Therapie des Typ-2-Diabetes, welcher zu einer stärkeren Senkung des HbA1c (Glykohämoglobin) und einer ausgeprägteren Gewichtsreduktion führt, als dies mit selektiven GLP-1-Rezeptor-Agonisten möglich ist. Das wachsende Verständnis der Sekretion und der biologischen Wirksamkeit von Inkretinhormonen im Kontext der pathophysiologischen Veränderungen beim Typ-2-Diabetes wird dazu beitragen, inkretinbasierte Medikamente zur Therapie des Typ-2-Diabetes und der Adipositas weiter zu optimieren.

Abstract

The incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide‑1 (GLP-1) are secreted by specialized intestinal cells after oral intake of nutrients and, in a glucose-dependent manner, stimulate insulin secretion. In healthy individuals, they contribute about 63–74% to the incretin effect, with GIP playing a larger role than GLP‑1. Despite no overall change in hormone secretion, the incretin effect is diminished, and GIP is largely ineffective in type 2 diabetes, whereas the effects of GLP‑1 remain relatively unchanged. While the reasons for this difference remain to be clarified, alterations in GIP receptor expression or general β‑cell functional defects may provide a potential explanation. The ineffectiveness of GIP contrasts with the prominent effects on glycated hemoglobin (HbA1c) and body weight of GIP/GLP‑1 co-agonists like tirzepatide in type 2 diabetes treatment, as compared to selective GLP‑1 receptor agonists. The growing understanding of the secretion and biological efficacy of incretin hormones will help optimize the effectiveness of incretin-based therapeutics for treating type 2 diabetes and obesity.

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Literatur

  1. Adriaenssens AE, Biggs EK, Darwish T et al (2019) Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab 30:987–996 e986

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Bergmann NC, Gasbjerg LS, Heimbürger SM et al (2020) 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 43:588–596

    CAS  PubMed  Google Scholar 

  3. Bergmann NC, Lund A, Gasbjerg LS et al (2019) Effects of combined GIP and GLP‑1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia 62:665–675

    CAS  PubMed  Google Scholar 

  4. Brown JC (1982) Gastric Inhibitory Polypeptide. Springer, Heidelberg

    Google Scholar 

  5. Calanna S, Christensen M, Holst JJ et al (2013) Secretion of glucagon-like peptide‑1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia 56:965–972

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Calanna S, Christensen M, Holst JJ et al (2013) Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: systematic review and meta-analysis of clinical studies. Diabetes Care 36:3346–3352

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Chia CW, Carlson OD, Kim W et al (2009) Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 58:1342–1349

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Creutzfeldt W (1979) The incretin concept today. Diabetologia 16:75–85

    CAS  PubMed  Google Scholar 

  9. Dupré J, Ross SA, Watson D et al (1973) Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 37:826–828

    PubMed  Google Scholar 

  10. Færch K, Torekov SS, Vistisen D et al (2015) GLP‑1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: The ADDITION-PRO Study. Diabetes 64:2513–2525

    PubMed  Google Scholar 

  11. Frias JP, Davies MJ, Rosenstock J et al (2021) Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 385:503–515

    CAS  PubMed  Google Scholar 

  12. Gasbjerg LS, Bergmann NC, Stensen S et al (2020) Evaluation of the incretin effect in humans using GIP and GLP‑1 receptor antagonists. Peptides 125:170183

    CAS  PubMed  Google Scholar 

  13. Heise T, Mari A, Devries JH et al (2022) 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 10:418–429

    CAS  PubMed  Google Scholar 

  14. Højberg PV, Vilsbøll T, Rabøl R et al (2009) Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide‑1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52:199–207

    PubMed  Google Scholar 

  15. Holst JJ, Ørskov C, Nielsen OV et al (1987) Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. Febs Lett 211:169–174

    CAS  PubMed  Google Scholar 

  16. Jones IR, Owens DR, Luzio S et al (1989) The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 32:668–677

    CAS  PubMed  Google Scholar 

  17. Killion EA, Lu SC, Fort M et al (2020) Glucose-dependent insulinotropic polypeptide receptor therapies for the treatment of obesity, do agonists = antagonists? Endocr Rev 41:

  18. Kjems LL, Holst JJ, Vølund A et al (2003) The influence of GLP‑1 on glucose-stimulated insulin secretion: Effects on β‑cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52:380–386

    CAS  PubMed  Google Scholar 

  19. Krarup T, Saurbrey N, Moody AJ et al (1987) Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus. Metabolism 36:677–682

    CAS  PubMed  Google Scholar 

  20. Kreymann B, Williams G, Ghatei MA et al (1987) Glucagon-like peptide‑1 7–36: a physiological incretin in man. Lancet 2:1300–1304

    CAS  PubMed  Google Scholar 

  21. Mclean BA, Wong CK, Campbell JE et al (2021) Revisiting the complexity of GLP‑1 action from sites of synthesis to receptor activation. Endocr Rev 42:101–132

    PubMed  Google Scholar 

  22. Meier JJ, Nauck MA, Kranz D et al (2004) Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 53:654–662

    CAS  PubMed  Google Scholar 

  23. Mentis N, Vardarli I, Köthe LD et al (2011) GIP does not potentiate the antidiabetic effects of GLP‑1 in hyperglycemic patients with type 2 diabetes. Diabetes 60:1270–1276

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Miyawaki K, Yamada Y, Ban N et al (2002) Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8:738–742

    CAS  PubMed  Google Scholar 

  25. Mojsov S, Weir GC, Habener JF (1987) Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 79:616–619

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Moon JS, Hong JH, Jung YJ et al (2022) SGLT-2 inhibitors and GLP‑1 receptor agonists in metabolic dysfunction-associated fatty liver disease. Trends Endocrinol Metab 33:424–442

    CAS  PubMed  Google Scholar 

  27. Müller TD, Finan B, Bloom SR et al (2019) Glucagon-like peptide 1 (GLP-1). Mol Metab 30:72–130

    PubMed Central  PubMed  Google Scholar 

  28. Nauck M, Stöckmann F, Ebert R et al (1986) Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29:46–52

    CAS  PubMed  Google Scholar 

  29. Nauck MA, D’alessio DA (2022) Tirzepatide, a dual GIP/GLP‑1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regarding glycaemic control and body weight reduction. Cardiovasc Diabetol 21:169

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Nauck MA, El-Ouaghlidi A, Gabrys B et al (2004) Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes. Regul Pept 122:209–217

    CAS  PubMed  Google Scholar 

  31. Nauck MA, Heimesaat MM, Ørskov C et al (1993) Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type‑2 diabetes mellitus. J Clin Invest 91:301–307

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Nauck MA, Kleine N, Ørskov C et al (1993) Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36:741–744

    CAS  PubMed  Google Scholar 

  33. Nauck MA, Meier JJ (2016) The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol 4:525–536

    CAS  PubMed  Google Scholar 

  34. Nauck MA, Müller TD (2023) Incretin hormones and type 2 diabetes. Diabetologia 66:1780–1795

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Nauck MA, Quast DR, Wefers J et al (2021) The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab 23(Suppl 3):5–29

    CAS  PubMed  Google Scholar 

  36. Nauck MA, Sauerwald A, Ritzel R et al (1998) Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure. Diabetes Care 21:1925–1931

    CAS  PubMed  Google Scholar 

  37. Oduori OS, Murao N, Shimomura K et al (2020) Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes. J Clin Invest 130:6639–6655

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Pamir N, Lynn FC, Buchan AM et al (2003) Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis. Am J Physiol 284:E 931–E939

    CAS  Google Scholar 

  39. Pederson RA, Satkunaraja M, Mcintosh CH et al (1998) Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor −/− mice. Diabetes 47:1046–1052

    CAS  PubMed  Google Scholar 

  40. Suzuki S, Kawai K, Ohashi S et al (1990) Reduced insulinotropic effects of glucagonlike peptide I‑(7–36)-amide and gastric inhibitory polypeptide in isolated perfused diabetic rat pancreas. Diabetes 39:1320–1325

    CAS  PubMed  Google Scholar 

  41. Toft-Nielsen M‑B, Damholt MB, Madsbad S et al (2001) Determinants of the impaired secretion of glucagon-like peptide‑1 in type 2 diabetic patients. J Clin Endocrinol Metab 86:3717–3723

    CAS  PubMed  Google Scholar 

  42. Vardarli I, Arndt E, Deacon CF et al (2014) Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and “isoglycemic” intravenous glucose. Diabetes 63:663–674

    CAS  PubMed  Google Scholar 

  43. Vilsbøll T, Krarup T, Deacon CF et al (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609–613

    PubMed  Google Scholar 

  44. Vilsbøll T, Krarup T, Madsbad S et al (2002) Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 45:1111–1119

    PubMed  Google Scholar 

  45. Vollmer K, Holst JJ, Baller B et al (2008) Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance. Diabetes 57:678–687

    CAS  PubMed  Google Scholar 

  46. Xu G, Kaneto H, Laybutt DR et al (2007) Downregulation of GLP‑1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes 56:1551–1558

    CAS  PubMed  Google Scholar 

  47. Zhang Q, Delessa CT, Augustin R et al (2021) The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab 33:833–844 e835

    CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sektion Diabetologie, Endokrinologie und Stoffwechsel, Medizinische Klinik I, St. Josef-Hospital Bochum, Klinikum der Ruhr-Universität Bochum, Gudrunstr. 56, 44791, Bochum, Deutschland

    Daniel R. Quast &  Michael A. Nauck

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  1. Daniel R. Quast
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  2. Michael A. Nauck
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Correspondence to Daniel R. Quast or Michael A. Nauck.

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Interessenkonflikt

D.R. Quast erhielt eine Forschungsauszeichnung, die von Sanofi gesponsert wurde, sowie Honorare für Vorträge, Präsentationen und Fortbildungsveranstaltungen von Eli Lilly & Co. und Novo Nordisk und Unterstützung für die Teilnahme an Tagungen und/oder Fortbildungen von Eli Lilly & Co. und Cook Medical. M.A. Nauck war oder ist Mitglied in „advisory boards“ oder führte Beratungstätigkeiten für Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, Novo Nordisk, Pfizer, Regor, Sun Pharma und Structure Therapeutics (ShouTi, Gasherbrum) durch. Er erhielt Fördermittel von Merck, Sharp & Dohme. Darüber hinaus war er im Referentennetzwerk von Eli Lilly & Co., Menarini/Berlin Chemie, Merck, Sharp & Dohme, Medscape, Medical Learning Institute und Novo Nordisk tätig.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Quast, D.R., Nauck, M.A. Veränderungen der Sekretion und biologischen Wirksamkeit von Inkretinhormonen bei Typ-2-Diabetes. Diabetologie 20, 201–211 (2024). https://doi.org/10.1007/s11428-023-01146-w

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