Skip to main content
SpringerLink
Log in

The imidazoline NNC77-0020 affects glucose-dependent insulin, glucagon and somatostatin secretion in mouse pancreatic islets

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The effect of the novel imidazoline compound 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-(5-methyl-2,3-dihydrobenzofuran-7-yl)-ethyl]-pyridine (NNC77-0020) on stimulus-secretion coupling and hormone secretion was investigated in mouse pancreatic islets and isolated α- and β-cells. In the presence of elevated glucose concentrations NNC77-0020 stimulated insulin secretion concentration dependently (EC50 64 nM) by 200% without affecting the whole-cell K+ current or cytoplasmic Ca2+ levels. Capacitance measurements in single mouse β-cells showed that intracellular application of NNC77-0020 via the recording pipette enhanced Ca2+-dependent exocytosis. This action was dependent on protein kinase C (PKC) and cytoplasmic phospholipase A2 (cPLA2) activity and required functional granular ClC-3 Cl− channels. In intact islets NNC77-0020 stimulated glucose-dependent somatostatin secretion, an effect that was also dependent on PKC and cPLA2 activity. NNC77-0020 also inhibited glucagon secretion. In single mouse α-cells this action was not associated with a change in spontaneous electrical activity and resulted from a reduction in the rate of Ca2+-dependent exocytosis. Inhibition of exocytosis by NNC77-0020 was pertussis toxin sensitive and mediated by activation of the protein phosphatase calcineurin. In conclusion, our data suggest that the imidazoline compound NNC77-0020 modulates pancreatic hormone secretion in a complex fashion, comprising glucose-dependent stimulation of insulin and somatostatin secretion and inhibition of glucagon release. These mechanisms of action constitute an ideal basis for the development of novel imidazoline-containing anti-diabetic compounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A, B.
Fig. 2A–D.
Fig. 3A, B.
Fig. 4A, B.
Fig. 5A–D.
Fig. 6.
Fig. 7A–D.
Fig. 8.
Fig. 9A, B.
Fig. 10A, B.

Similar content being viewed by others

References

  • Barg S, Renström E, Berggren P-O, Bertorello A, Bokvist K, Braun M, Eliasson L, Holmes WE, Köhler M, Rorsman P, Thévenod F (1999) The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic β cells is mediated by a 65-kDa mdr-like P-glucoprotein. Proc Natl Acad Sci USA 96:5539–5544

    CAS  PubMed  Google Scholar 

  • Barg S, Galvanovskis J, Göpel SO, Rorsman P, Eliasson L (2000) Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting α-cells. Diabetes 49:1500–1510

    CAS  PubMed  Google Scholar 

  • Barg S, Huang P, Eliasson L, Nelson DJ, Obermüller S, Rorsman P, Thévenod F, Renström E (2001) Priming of insulin granules for exocytosis by granular Cl− uptake and acidification. J Cell Sci 114:2145–2154

    CAS  PubMed  Google Scholar 

  • Bokvist K, Olsen HL, Høy M, Gotfredsen CF, Holmes WF, Buschard K, Rorsman P, Gromada J (1999) Characterisation of sulphonylurea and ATP-regulated K+-channels in rat pancreatic A-cells. Pflugers Arch 438:428–436

    Article  CAS  PubMed  Google Scholar 

  • DeFronzo RA (1992) Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 35:389–397

    CAS  PubMed  Google Scholar 

  • Dunne MJ, Harding EA, Jaggar JH, Squires PE, Liang R, Kane C, James RFL, London NJM (1995) Potassium channels, imidazolines, and insulin-secreting cells. Ann NY Acad Sci 763:242–261

    Google Scholar 

  • Efanov AM, Zaitsev SV, Mest HJ, Raap A, Appelskog IB, Larsson O, Berggren PO, Efendic S (2001) The novel imidazoline compound BL11282 potentiates glucose-induced insulin secretion in pancreatic β-cells in the absence of modulation of KATP channel activity. Diabetes 50:797–802

    CAS  PubMed  Google Scholar 

  • Efanova IB, Zaitsev SV, Efanov AM, Ostenson C, Raap A, Mest H, Berggren PO, Efendic S (1998) Effects of imidazoline derivative RX871024 on insulin, glucagon, and somatostatin secretion from isolated perfused rat pancreas. Biochem Biophys Res Commun 252:162–165

    Article  CAS  PubMed  Google Scholar 

  • Efendic S, Efanov AM, Breggren PO, Zaitsev SV (2002) Two generations of insulinotropic imidazoline compounds. Diabetes 51 (Suppl):S448–S454

    CAS  PubMed  Google Scholar 

  • Fuhlendorff J, Rorsman P, Kofod H, Brand CL, Rolin B, MacKay P, Shymko R, Carr RD (1998) Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes 47:345–351

    CAS  PubMed  Google Scholar 

  • Gerich JE (1977) Somatostatin; its possible role in carbohydrate disposal and absorption in diabetes mellitus. Arch Intern Med 137:659–666

    Article  CAS  PubMed  Google Scholar 

  • Göpel SO, Kanno T, Barg S, Rorsman P (2000) Patch-clamp characterization of somatostatin-secreting δ-cells in intact mouse pancreatic islets. J Physiol (Lond) 528:497–507

    Google Scholar 

  • Grynkiewicz B, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450

    PubMed  Google Scholar 

  • Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49:1751–1760

    CAS  PubMed  Google Scholar 

  • Høy M, Bokvist K, Weng XG, Hansen J, Juhl K, Berggren PO, Buschard K, Gromada J (2001) Phentolamine inhibits exocytosis of glucagon by Gi2 protein-dependent activation of calcineurin in rat pancreatic α-cells. J Biol Chem 276:924–930

    Article  PubMed  Google Scholar 

  • Høy M, Olsen HL, Andersen HS, Bokvist K, Buschard K, Hansen J, Jacobsen P, Petersen JS, Rorsman P, Gromada J (2003) Imidazoline NNC77-0074 stimulates insulin secretion and inhibits glucagon release by control of Ca2+-dependent exocytosis in pancreatic α- and β-cells. Eur J Pharmacol 466:213–221

    Article  PubMed  Google Scholar 

  • Jakobsen P, Madsen P, Andersen HS (2003) Imidazolines as efficacious glucose-dependent stimulators of insulin secretion. Eur J Med Chem 38:357–362

    Article  CAS  PubMed  Google Scholar 

  • Jonas JC, Plant TD, Henquin JC (1992) Imidazoline antagonists of α2-adrenoceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic β-cells. Br J Pharmacol 107:8–14

    CAS  PubMed  Google Scholar 

  • Juhl K, Høy M, Olsen HL, Bokvist K, Efanov AM, Hoffmann EK, Gromada J (2003) cPLA2α-evoked formation of arachidonic acid and lysophospholipids is required for exocytosis in mouse pancreatic β-cells. Am J Physiol 285: E73–E81

    CAS  Google Scholar 

  • Kameda KY, Ono SE, Koyama I, Abiko Y (1982) Insulin releasing action of 2-[2-(4,5-dihydro-1H-imadazol-2-yl)-1-phenylethyl] puridine dihydrochloride sesquihydrate (DG-5128), a new, orally effective hypoglycaemic agent. Acta Endocrinol 99:410–415

    CAS  PubMed  Google Scholar 

  • Kawazu S, Suzuki M, Watanabe T, Ishii J (1987a) Studies of midaglizole (DG-5128). A new type of oral hypoglycemic drug in healthy subjects. Diabetes 36:216–220

    CAS  PubMed  Google Scholar 

  • Kawazu S, Suzuki M, Negishi K, Ishii J, Sando H, Katagiri H, Kanazawa Y, Yamanouchi S, Akanuma Y, Kajinumma H, Suzuki K, Watanabe K, Itoh T, Kobayashi T, Kosaka K (1987b) Initial phase II clinical studies on midaglizole (DG-5128). A new hypoglycemic agent. Diabetes 36:221–226

    CAS  PubMed  Google Scholar 

  • Martell AE, Smith RM (1971) Critical stability constants, Vol. 1 Amino acids; Vol. 2 Amines. Plenum Press, New York

  • Oh J, Rhee HJ, Kim S-W, Kim SB, You H-J, Kim JH, Na DS (2000) Annexin-I inhibits PMA-induced c-fos SRE activation by suppressing cytosolic phospholipase A2 signal. FEBS Lett 477:244–248

    Article  CAS  PubMed  Google Scholar 

  • Olsen HL, Nørby PL, Høy M, Spee P, Thams P, Capito K, Petersen JS, Gromada J (2003) Imidazoline NNC77-0074 stimulates Ca2+-evoked exocytosis in INS-1E cells by a phospholipase A2-dependent mechanism. Biochem Biophys Res Commun 303:1148–1151

    Article  PubMed  Google Scholar 

  • Proks P, Ashcroft FM (1997) Phentolamine block of KATP channels is mediated by Kir 6.2. Proc Natl Acad Sci USA 94:11716–11720

    CAS  PubMed  Google Scholar 

  • Unger RH (1985) Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 28:574–578

    CAS  PubMed  Google Scholar 

  • Wahren J, Efendic S, Luft R, Hagenfeldt L, Björkman O, Felig P (1977) Influence of somatostatin on splanchnic glucose metabolism in postabsorptive and 60-hour fasted humans. J Clin Invest 59:299–307

    CAS  PubMed  Google Scholar 

  • Wang L, Chen L, Jacob TJC (2000) The role of ClC-3 in volume-activated chloride currents and volume regulation in bovine epithelial cells demonstrated by antisense inhibition. J Physiol (Lond) 524:63–75

    Google Scholar 

  • Zaitsev SV, Efanov AM, Efanova IB, Larsson O, Ostenson CG, Gold G, Berggren PO, Efendic S (1996) Imidazoline compounds stimulate insulin release by inhibition of KATP channels and interaction with the exocytotic machinery. Diabetes 45:1610–1618

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Tina Olsen and Berit Gerlach for technical assistance. MH holds a scholarship from the Academy of Technical Sciences and Novo Nordisk, Denmark. HLO holds a scholarship from the Medicon Valley Academy and Novo Nordisk, Denmark

Author information

Author notes

  1. Jesper Gromada

    Present address: Lilly Research Laboratories, Essener Strasse 93, 22419, Hamburg, Germany

  2. Krister Bokvist

    Present address: Lilly Research Laboratories, Essener Strasse 93, 22419, Hamburg, Germany

  3. Marianne Høy

    Present address: Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark

Authors and Affiliations

  1. Novo Nordisk A/S, Novo Alle, 2880, Bagsvaerd, Denmark

    Marianne Høy, Hervør L. Olsen, Krister Bokvist, Jacob S. Petersen & Jesper Gromada

Authors
  1. Marianne Høy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hervør L. Olsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Krister Bokvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacob S. Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jesper Gromada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jesper Gromada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Høy, M., Olsen, H.L., Bokvist, K. et al. The imidazoline NNC77-0020 affects glucose-dependent insulin, glucagon and somatostatin secretion in mouse pancreatic islets. Naunyn-Schmiedeberg's Arch Pharmacol 368, 284–293 (2003). https://doi.org/10.1007/s00210-003-0797-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-003-0797-1

Keywords

Search

Navigation