Acta Diabetologica

, Volume 33, Issue 1, pp 19–24 | Cite as

Glucagon-like-peptide-1 (7–36) amide improves glucose sensitivity in beta-cells of NOD mice

  • T. Linn
  • K. Schneider
  • B. Göke
  • K. Federlin


The effect of the insulinotropic gut hormone glucagon-like-peptide-1 (GLP-1) was studied on the residual insulin capacity of prediabetic nonobese diabetic (NOD) mice, a model of insulin-dependent diabetes mellitus (type 1). This was done using isolated pancreas perfusion and dynamic islet perifusion. Prediabetes was defined by insulitis and fasting normoglycemia. Insultis occurred in 100% of NOD mice beyond the age of 12 weeks. K values in the intravenous glucose tolerance test were reduced in 20-week-old NOD mice compared with agematched non-diabetes-prone NOR (nonobese resistant) mice (2.4±1.1 vs 3.8±1.5% min−1,P<0.05). Prediabetic NOD pancreases were characterized by a complete loss of the glucose-induced first-phase insulin release. In perifused NOD islets GLP-1, at concentrations already effective in normal islets, left the insulin release unaltered. However, a significant rise of glucose-dependent insulin secretion occurred for GLP-1 concentrations>0.1 nM. This was obtained with both techniques, dynamic islet perifusion and isolated pancreas perfusion, indicating a direct effect of GLP-1 on the beta-cell. Analysis of glucose-insulin dose-response curves revealed a marked improvement of glucose sensitivity of the NOD endocrine pancreas in the presence of GLP-1 (half-maximal insulin output without GLP-1 15.2 mM and with GLP-1 9.4 mM,P<0.002). We conclude that GLP-1 can successfully reverse the glucose sensing defect of islets affected by insulitis.

Key words

Glucagon-like-peptide-1 Prediabetes NOD mouse 


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  1. 1.
    Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeld W, 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, 1993Google Scholar
  2. 2.
    Ensinck JW, D'Allessio DA, The enteroinsular axis revisited. A novel role for an incretin. N Engl J Med 326:1352–1353, 1992Google Scholar
  3. 3.
    Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S, Antidiabetogenic effect of glucagon-like-peptide 1 (7–36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326:1316–1322, 1992Google Scholar
  4. 4.
    Hermann C, Göke R, Richter G, Fehmann HC, Arnold R, Göke B, GLP-1 and GIP plasma levels in response to nutrients. Digestion, in press, 1996Google Scholar
  5. 5.
    Eyll B van, Lankat-Butgereit B, Bode HP, Göke R, Göke B, Signal transduction of the GLP-1 receptor cloned from a human insulinoma. FEBS Lett 348:7–13, 1994Google Scholar
  6. 6.
    Lankat-Buttgereit B, Göke R, Stöckmann F, Fehmann HC, Göke B, Detection of the human GLP-1 receptor on insulinoma cell membranes. Digestion 55:29–33, 1994Google Scholar
  7. 7.
    Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widman C, 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 1993Google Scholar
  8. 8.
    Göke B (ed), International Symposium on Glucagon-like-peptide-1, Copenhagen, Denmark, May 17–19, Abstracts. Digestion 54:339–397, 1993Google Scholar
  9. 9.
    Strandell E, Sandler S, Boitard C, Eizirik DL, Role of infiltrating T-cells for impaired glucose metabolism in pancreatic islets isolated from non-obese diabetic mice. Diabetologia 35:924–931, 1992Google Scholar
  10. 10.
    Kano Y, Kanatsuna T, Nakamura N, Kitigawa Y, Mori H, Kajiyama S, Nakano K, Kondo M, Defect of the first phase insulin secretion to glucose stimulation in the perfused pancreas of the nonobese diabetic (NOD) mouse. Diabetes 35:486–490, 1986Google Scholar
  11. 11.
    Göke R, Fehmann HC, Göke B, Glucagon-like-peptide (7–36) amide is a new incretin enterogastrone candidate. Eur J Clin Invest 21:135–144, 1991Google Scholar
  12. 12.
    Linn T, Loewk E, Schneider K, Federlin K, Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice. Diabetologia 36:1245–1251, 1993Google Scholar
  13. 13.
    Nagakawa S, Nakayama H, Sasaki T, Yoshino K, Yu YY, Shinozaki K, Aoki S, Mashimo K, A simple method for the determination of serum free insulin levels in insulin treated patients. Diabetes 22:590–600, 1973Google Scholar
  14. 14.
    Creutzfeldt W, Ebert R, New developments in the incretin concept. Diabetologia 28:565–573, 1985Google Scholar
  15. 15.
    Elahi D, McAloon-Dyke M, Fukagawa N, Meneilly GS. Sclater AL, Minaker KL, Habener JF, Anderson DK, The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects. Regul Pept 51:63–74, 1994Google Scholar
  16. 16.
    Göke R, Wagner B, Fehmann HC, Göke B, Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7–36) amide on the rat pancreas. Res Exp Med 193:97–103, 1993Google Scholar
  17. 17.
    Kawai K, Suzuki S, Ohashi S, Mukai H, Ohmori H, Murayama Y, Yamashita K, Comparison of the effects of glucagon-like peptide-1-(7–37) and-(7–37) and glucagon on islet hormone release from isolated perfused canine and rat pancreases. Endocrinology 124:1768–1773, 1989Google Scholar
  18. 18.
    Hendrick GK, Gjinovci A, Baxter LA, Mojsov S, Wollheim CB, Habener JF, Weir GC, Glucagon-like-peptide-I-(7–37) suppresses hyperglycemia in rats. Metabolism 42:1–6, 1993Google Scholar
  19. 19.
    Weir GC, Mojsov S, Hendrick GK, Habener JF, Glucagonlike peptide I (7–37) actions on the endocrine pancreas. Diabetes 38:338–342, 1989Google Scholar
  20. 20.
    Boitard C, Bendelac A, Richard MF, Carnaud C, Bach JF, Prevention of diabetes in nonobese diabetic mice by anti-I-A monoclonal antibodies: transfer of protection by splenic T-cells. Proc Nat Acad Sci USA 85:9719–9723, 1988Google Scholar
  21. 21.
    Eizirik DL, Welsh M, Strandell E, Welsh N, Sandler S, Interleukin-1 depletes insulin messenger ribonucleic acid and increases the heat shock protein hsp 70 in mouse pancreatic islets without impairing the glucose metabolism. Endocrinology 127: 2290–2297, 1990Google Scholar
  22. 22.
    McDonald M, Elusive proximal signals of beta cells for insulin secretion. Diabetes 39:1461–1466, 1990Google Scholar
  23. 23.
    Fehmann HC, Göke R, Bächle R, Wagner B, Arnold R, Priming effect of glucagon-like-peptide-1 (7–37) amide, glucose-dependent insulinotropic peptide, and cholecystokinin-8 at the isolated perfused rat pancreas. Biochim Biophys Acta 1091:356–363, 1991Google Scholar
  24. 24.
    Holz GG, Kuhtreiber WM, Habener JF, Pancreatic beta cells are rendered glucose competent by the insulinotropic hormone glucagon-like-peptide-1 (7–37). Nature 361:362–365, 1993Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • T. Linn
    • 1
  • K. Schneider
    • 1
  • B. Göke
    • 2
  • K. Federlin
    • 1
  1. 1.Medical Clinic III and Polyclinic, Centre of Internal MedicineJustus Liebig UniversityGiessenGermany
  2. 2.Clinical Research Unit for Gastrointestinal EndocrinologyPhilipps UniversityMarburgGermany

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