Download PDF
Diabetologie und Stoffwechsel 2009; 4(5): 295-300
DOI: 10.1055/s-0029-1224610
Übersicht

© Georg Thieme Verlag Stuttgart ˙ New York

Die Bedeutung der Inkretinhormone GIP und GLP-1 für die Pathogenese des Typ-2-Diabetes[∗]

The Role of the Incretin Hormones GIP and GLP-1 in the Pathogenesis of Type 2 DiabetesJ. J. Meier1
  • 1Medizinische Klinik I, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum
Further Information

Publication History

Publication Date:
12 October 2009 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Der Inkretineffekt, d. h. die postprandiale Verstärkung der Insulinsekretion durch gastrointestinale Hormone, ist bei stoffwechselgesunden Personen für ca. 50–70 % der Insulinanstiege nach Mahlzeiten verantwortlich. Bei Patienten mit Typ-2-Diabetes fehlt die Inkretinstimulation hingegen nahezu vollständig. Ursächlich basiert die Störung des Inkretineffektes beim Typ-2-Diabetes im Wesentlichen auf einer Einschränkung der insulinotropen Wirkung von GIP, wohingegen die Wirkung von GLP-1 weitestgehend erhalten ist. Zudem wurde diskutiert, ob Störungen der GLP-1 Sekretion eine Bedeutung für die mangelnde Inkretinstimulation beim Typ-2-Diabetes haben könnten. Allerdings konnte eine solche Verminderung der GLP-1 Freisetzung in der Mehrzahl der Studien bei Patienten mit Typ-2-Diabetes nicht bestätigt werden. In diesem Artikel wird die Freisetzung und Wirkung der Inkretinhor­mone GLP-1 und GIP bei Patienten mit Typ-2-Diabetes und gesunden Personen gegenübergestellt. Ferner werden die Störungen im Bereich der ­entero-insulären Achse hinsichtlich ihrer Bedeutung für die Pathogenese des Typ-2-Diabetes diskutiert.

1 anlässlich der Verleihung des Werner Creutzfeldt Preises 2009 der Deutschen Diabetes Gesellschaft

Literatur

  • 1 Creutzfeldt W. The incretin concept today.  Diabetologia. 1979;  16 75-85
    CrossrefSearch in Google Scholar
  • 2 Perley M J, Kipnis D M. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects.  J Clin Invest. 1967;  46 1954-1962
    CrossrefSearch in Google Scholar
  • 3 Nauck M, Stöckmann F, Ebert R et al. Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes.  Diabetologia. 1986;  29 46-54
    CrossrefPubMedSearch in Google Scholar
  • 4 Creutzfeldt W, Nauck M. Gut hormones and diabetes mellitus.  Diabetes / Metab Rev. 1992;  8 149-177
    Search in Google Scholar
  • 5 Nauck M A, Homberger E, Siegel E G 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
    CrossrefSearch in Google Scholar
  • 6 Mortensen K, Christensen L L, Holst J J et al. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine.  Regul Pept. 2003;  114 189-196
    CrossrefSearch in Google Scholar
  • 7 Meier J J, Nauck M A. Clinical endocrinology and metabolism. Glucose-dependent insulinotropic polypeptide / gastric inhibitory polypeptide.  Best Pract Res Clin Endocrinol Metab. 2004;  18 587-606
    CrossrefSearch in Google Scholar
  • 8 Meier J J, Nauck M A, Schmidt W E et al. Gastric inhibitory polypeptide: the neglected incretin revisited.  Regul Pept. 2002;  107 1-13
    CrossrefSearch in Google Scholar
  • 9 Vilsbøll T, Krarup T, Deacon C F et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients.  Diabetes. 2001;  50 609-613
    CrossrefPubMedSearch in Google Scholar
  • 10 Vollmer K, Holst J J, Baller B et al. Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance.  Diabetes. 2008;  57 678-687
    CrossrefSearch in Google Scholar
  • 11 Crockett S E, Mazzaferri E L, Cataland S. Gastric inhibitory peptide (GIP) in maturity-onset diabetes mellitus.  Diabetes. 1976;  25 931-935
    CrossrefSearch in Google Scholar
  • 12 Ross S A, Brown J C, Dupré J. Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus.  Diabetes. 1977;  26 525-529
    CrossrefSearch in Google Scholar
  • 13 Ebert R, Creutzfeldt W. Hypo- and hypersecretion of GIP in maturity-onset diabetics.  Diabetologia. 1980;  19 271-272
    Search in Google Scholar
  • 14 Theodorakis M J, Carlson O, Muller D C et al. Elevated plasma glucose-dependent insulinotropic polypeptide associates with hyperinsulinemia in impaired glucose tolerance.  Diabetes Care. 2004;  27 1692-1698
    CrossrefSearch in Google Scholar
  • 15 Meier J J, Nauck M A. Incretins and the development of type 2 diabetes.  Curr Diab Rep. 2006;  6 194-201
    CrossrefSearch in Google Scholar
  • 16 Ørskov 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
    CrossrefSearch in Google Scholar
  • 17 Toft-Nielsen M B, Damholt M B, Madsbad S et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.  J Clin Endocrinol Metab. 2001;  86 3717-3723
    CrossrefSearch in Google Scholar
  • 18 Ryskjaer J, Deacon C F, Carr R D et al. Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake.  Eur J Endocrinol. 2006;  155 485-493
    CrossrefPubMedSearch in Google Scholar
  • 19 Ørskov C, Jeppesen J, Madsbad S et al. Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine.  J Clin Invest. 1991;  87 415-423
    CrossrefSearch in Google Scholar
  • 20 Fukase N, Manaka H, Sugiyama K et al. Response of truncated glucagon-like peptide-1 and gastric inhibitory polypeptide to glucose ingestion in non-insulin dependent diabetes mellitus. Effect of sulfonylurea therapy.  Acta Diabetol. 1995;  32 165-169
    CrossrefSearch in Google Scholar
  • 21 Theodorakis M J, Carlson O, Michopoulos S et al. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP.  Am J Physiol Endocrinol Metab. 2006;  290 E550-E559
    Search in Google Scholar
  • 22 Knop F K, Vilsboll T, Hojberg P V et al. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state?.  Diabetes. 2007;  56 1951-1959
    CrossrefSearch in Google Scholar
  • 23 Muscelli E, Mari A, Casolaro A et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients.  Diabetes. 2008;  57 1340-1348
    CrossrefSearch in Google Scholar
  • 24 Meier J J, Gallwitz B, Askenas M et al. Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes.  Diabetologia. 2005;  48 1872-1881
    CrossrefSearch in Google Scholar
  • 25 Nauck M A, El-Ouaghlidi A, Gabrys B et al. 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. 2004;  122 209-217
    CrossrefSearch in Google Scholar
  • 26 Vollmer K, Gardiwal H, Menge B A et al. Hyperglycemia acutely lowers the postprandial excursions of glucagon-like Peptide-1 and gastric inhibitory polypeptide in humans.  J Clin Endocrinol Metab. 2009;  94 1379-1385
    CrossrefSearch in Google Scholar
  • 27 Nauck M A, Bartels E, Ørskov 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
    CrossrefSearch in Google Scholar
  • 28 Nauck M A, Heimesaat M M, Ørskov 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
    CrossrefPubMedSearch in Google Scholar
  • 29 Meier J J, Hücking K, Holst J J et al. Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes.  Diabetes. 2001;  50 2497-2504
    CrossrefSearch in Google Scholar
  • 30 Meier J J, Gallwitz B, Kask B et al. Stimulation of insulin secretion by intravenous bolus injection and continuous infusion of gastric inhibitory polypeptide in patients with type 2 diabetes and healthy control subjects.  Diabetes. 2004;  53 Suppl 3 220-224
    CrossrefSearch in Google Scholar
  • 31 Meier J J, Nauck M A, Siepmann N et al. Similar insulin secretory response to a gastric inhibitory polypeptide bolus injection at euglycemia in first-degree relatives of patients with type 2 diabetes and control subjects.  Metabolism. 2003;  52 1579-1585
    CrossrefSearch in Google Scholar
  • 32 Nauck M A, Baller B, Meier J J. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes.  Diabetes. 2004;  53 Suppl 3 190-196
    Search in Google Scholar
  • 33 Lynn F C, Pamir N, Ng E H et al. Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats.  Diabetes. 2001;  50 1004-1011
    CrossrefSearch in Google Scholar
  • 34 Lynn F C, Thompson S A, Pospisilik J A et al. A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells.  Faseb J. 2003;  17 91-93
    Search in Google Scholar
  • 35 Xu G, Kaneto H, Laybutt D R et al. Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes.  Diabetes. 2007;  56 1551-1558
    CrossrefSearch in Google Scholar
  • 36 Butler A E, 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
    CrossrefPubMedSearch in Google Scholar
  • 37 Ward W K, Bolgiano D C, McKnight B et al. Diminished B cell secretory capacity in patients with non-insulin-dependent diabetes mellitus.  J Clin Invest. 1984;  74 1318-1328
    CrossrefSearch in Google Scholar
  • 38 Polonsky K S, Given B D, Hirsch L J et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus.  N Engl J Med. 1988;  318 1231-1239
    CrossrefSearch in Google Scholar
  • 39 Meier J J. Beta cell mass in diabetes: a realistic therapeutic target?.  Diabetologia. 2008;  51 703-713
    CrossrefSearch in Google Scholar
  • 40 Meier J J, 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
    CrossrefSearch in Google Scholar
  • 41 Meier J J, Nauck M A. Glucagon-like peptide 1 (GLP-1) in biology and pathology.  Diabetes Metab Res Rev. 2005;  21 91-117
    CrossrefPubMedSearch in Google Scholar
  • 42 Meier J J, Gallwitz B, Nauck M A. Glucagon-like peptide 1 and gastric inhibitory polypeptide: potential applications in type 2 diabetes mellitus.  BioDrugs. 2003;  17 93-102
    CrossrefSearch in Google Scholar
  • 43 Meier J J, Nauck M A. The potential role of glucagon-like peptide 1 in diabetes.  Curr Opin Investig Drugs. 2004;  5 402-410
    Search in Google Scholar
  • 44 Kjems L L, Holst J J, Vølund 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
    CrossrefSearch in Google Scholar
  • 45 Nauck M A, Kleine N, Ørskov 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
    CrossrefSearch in Google Scholar
  • 46 Pørksen N, Grofte B, Nyholm B et al. Glucagon-like peptide 1 increases mass but not frequency or orderliness of pulsatile insulin secretion.  Diabetes. 1998;  47 45-49
    CrossrefSearch in Google Scholar
  • 47 Ritzel R, Schulte M, Porksen N et al. Glucagon-like peptide 1 increases secretory burst mass of pulsatile insulin secretion in patients with type 2 diabetes and impaired glucose tolerance.  Diabetes. 2001;  50 776-784
    CrossrefSearch in Google Scholar
  • 48 Gutzwiller J P, Drewe J, Göke B et al. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2.  Am J Physiol (Integr Regul Physiol). 1999;  276 R1541-R1544
    Search in Google Scholar
  • 49 Vilsboll T, Knop F K, Krarup T et al. The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype.  J Clin Endocrinol Metab. 2003;  88 4897-4903
    CrossrefSearch in Google Scholar
  • 50 Knop F K, Vilsboll T, Hojberg P V et al. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state?.  Diabetes. 2007;  56 1951-1959
    CrossrefSearch in Google Scholar

1 anlässlich der Verleihung des Werner Creutzfeldt Preises 2009 der Deutschen Diabetes Gesellschaft

Prof. Dr. med. J. J. MeierJuniorprofessor 

Medizinische Klinik I · St. Josef-Hospital · Klinikum der Ruhr-Universität Bochum

Gudrunstr. 56

44791 Bochum

Phone: 02 34 / 5 09 27 11

Fax: 02 34 / 5 09 23 09

Email: Juris.Meier@rub.de