Skip to main content
SpringerLink
Log in

TRPM5 regulates glucose-stimulated insulin secretion

  • Integrative Physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Insulin secretion in β-pancreatic cells due to glucose stimulation requires the coordinated alteration of cellular ion concentrations and a substantial membrane depolarization to enable insulin vesicle fusion with the cellular membrane. The cornerstones of this cascade are well characterized, yet current knowledge argues for the involvement of additional ion channels in this process. TRPM5 is a cation channel expressed in β-cells and proposed to be involved in coupling intracellular Ca2+ release to electrical activity and cellular responses. Here, we report that TRPM5 acts as an indispensable regulator of insulin secretion. In vivo glucose tolerance tests showed that Trpm5 −/−-mice maintain elevated blood glucose levels for over an hour compared to wild-type littermates, while insulin sensitivity is normal in Trpm5 −/−-mice. In pancreatic islets isolated from Trpm5 −/−-mice, hyperglycemia as well as arginine-induced insulin secretion was diminished. The presented results describe a major role for TRPM5 in glucose-induced insulin secretion beyond membrane depolarization. Dysfunction of the TRPM5 protein could therefore be an important factor in the etiology of some forms of type 2 diabetes, where disruption of the normal pattern of secretion is observed.

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. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ashcroft FM, Harrison DE, Ashcroft SJ (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312:446–448

    Article  CAS  PubMed  Google Scholar 

  2. Barg S, Eliasson L, Renstrom E, Rorsman P (2002) A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes 51(Suppl 1):S74–S82

    Article  CAS  PubMed  Google Scholar 

  3. Berggren PO, Yang SN, Murakami M, Efanov AM, Uhles S, Kohler M, Moede T, Fernstrom A, Appelskog IB, Aspinwall CA, Zaitsev SV, Larsson O, de Vargas LM, Fecher-Trost C, Weissgerber P, Ludwig A, Leibiger B, Juntti-Berggren L, Barker CJ, Gromada J, Freichel M, Leibiger IB, Flockerzi V (2004) Removal of Ca2+ channel beta3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis. Cell 119:273–284

    Article  CAS  PubMed  Google Scholar 

  4. Cheng H, Beck A, Launay P, Gross SA, Stokes AJ, Kinet JP, Fleig A, Penner R (2007) TRPM4 controls insulin secretion in pancreatic beta-cells. Cell Calcium 41:51–61

    Article  CAS  PubMed  Google Scholar 

  5. Colsoul B, Schraenen A, Lemaire K, Quintens R, Van Lommel L, Segal A, Owsianik G, Talavera K, Voets T, Margolskee RF, Kokrashvili Z, Gilon P, Nilius B, Schuit FC, Vennekens R (2010) Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice. Proc Natl Acad Sci USA. doi:10.1073/pnas.0913107107

    PubMed  Google Scholar 

  6. Cook DL, Hales CN (1984) Intracellular ATP directly blocks K + channels in pancreatic B-cells. Nature 311:271–273

    Article  CAS  PubMed  Google Scholar 

  7. de Miguel R, Tamagawa T, Schmeer W, Nenquin M, Henquin JC (1988) Effects of acute sodium omission on insulin release, ionic flux and membrane potential in mouse pancreatic B-cells. Biochim Biophys Acta 969:198–207

    Article  PubMed  Google Scholar 

  8. Enklaar T, Esswein M, Oswald M, Hilbert K, Winterpacht A, Higgins M, Zabel B, Prawitt D (2000) Mtr1, a novel biallelically expressed gene in the center of the mouse distal chromosome 7 imprinting cluster, is a member of the Trp gene family. Genomics 67:179–187

    Article  CAS  PubMed  Google Scholar 

  9. Gilon P, Henquin JC (1992) Influence of membrane potential changes on cytoplasmic Ca2+ concentration in an electrically excitable cell, the insulin-secreting pancreatic B-cell. J Biol Chem 267:20713–20720

    CAS  PubMed  Google Scholar 

  10. Gopel S, Kanno T, Barg S, Galvanovskis J, Rorsman P (1999) Voltage-gated and resting membrane currents recorded from B-cells in intact mouse pancreatic islets. J Physiol 521(Pt 3):717–728

    Article  CAS  PubMed  Google Scholar 

  11. Grapengiesser E, Gylfe E, Hellman B (1988) Dual effect of glucose on cytoplasmic Ca2+ in single pancreatic beta-cells. Biochem Biophys Res Commun 150:419–425

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Henquin JC (2009) Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia 52:739–751

    Article  CAS  PubMed  Google Scholar 

  14. Henquin JC, Nenquin M, Ravier MA, Szollosi A (2009) Shortcomings of current models of glucose-induced insulin secretion. Diabetes Obes Metab 11(Suppl 4):168–179

    Article  CAS  PubMed  Google Scholar 

  15. Ikehata F, Satoh J, Nata K, Tohgo A, Nakazawa T, Kato I, Kobayashi S, Akiyama T, Takasawa S, Toyota T, Okamoto H (1998) Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin-dependent diabetes patients. J Clin Invest 102:395–401

    Article  CAS  PubMed  Google Scholar 

  16. Irminger JC, Serradas P, Rickenbach K, Lyle R, Gangnerau MN, Portha B, Halban PA (2003) Identification of differentially expressed genes in islets of diabetic GK rats, using subtractive hybridization. In: Abstract No. 444, 38th annual meeting of the EASD

  17. Kato I, Yamamoto Y, Fujimura M, Noguchi N, Takasawa S, Okamoto H (1999) CD38 disruption impairs glucose-induced increases in cyclic ADP-ribose, [Ca2+]i, and insulin secretion. J Biol Chem 274:1869–1872

    Article  CAS  PubMed  Google Scholar 

  18. Lang J (1999) Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. Eur J Biochem 259:3–17

    Article  CAS  PubMed  Google Scholar 

  19. Marigo V, Courville K, Hsu WH, Feng JM, Cheng H (2009) TRPM4 impacts on Ca(2+) signals during agonist-induced insulin secretion in pancreatic beta-cells. Mol Cell Endocrinol 299:194–203

    Article  CAS  PubMed  Google Scholar 

  20. Perez CA, Huang L, Rong M, Kozak JA, Preuss AK, Zhang H, Max M, Margolskee RF (2002) A transient receptor potential channel expressed in taste receptor cells. Nat Neurosci 5:1169–1176

    Article  CAS  PubMed  Google Scholar 

  21. Poitout V, Olson LK, Robertson RP (1996) Insulin-secreting cell lines: classification, characteristics and potential applications. Diabetes Metab 22:7–14

    CAS  PubMed  Google Scholar 

  22. Prawitt D, Monteilh-Zoller MK, Brixel L, Spangenberg C, Zabel B, Fleig A, Penner R (2003) TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i. Proc Natl Acad Sci USA 100:15166–15171

    Article  CAS  PubMed  Google Scholar 

  23. Ravier MA, Nenquin M, Miki T, Seino S, Henquin JC (2009) Glucose controls cytosolic Ca2+ and insulin secretion in mouse islets lacking adenosine triphosphate-sensitive K+ channels owing to a knockout of the pore-forming subunit Kir6.2. Endocrinology 150:33–45

    Article  CAS  PubMed  Google Scholar 

  24. Roe MW, Philipson LH, Frangakis CJ, Kuznetsov A, Mertz RJ, Lancaster ME, Spencer B, Worley JF III, Dukes ID (1994) Defective glucose-dependent endoplasmic reticulum Ca2+ sequestration in diabetic mouse islets of Langerhans. J Biol Chem 269:18279–18282

    CAS  PubMed  Google Scholar 

  25. Rorsman P, Eliasson L, Renstrom E, Gromada J, Barg S, Gopel S (2000) The cell physiology of biphasic insulin secretion. News Physiol Sci 15:72–77

    CAS  PubMed  Google Scholar 

  26. Safayhi H, Haase H, Kramer U, Bihlmayer A, Roenfeldt M, Ammon HP, Froschmayr M, Cassidy TN, Morano I, Ahlijanian MK, Striessnig J (1997) L-type calcium channels in insulin-secreting cells: biochemical characterization and phosphorylation in RINm5F cells. Mol Endocrinol 11:619–629

    Article  CAS  PubMed  Google Scholar 

  27. Shewade YM, Umrani M, Bhonde RR (1999) Large-scale isolation of islets by tissue culture of adult mouse pancreas. Transplant Proc 31:1721–1723

    Article  CAS  PubMed  Google Scholar 

  28. Srivastava S, Goren HJ (2003) Insulin constitutively secreted by beta-cells is necessary for glucose-stimulated insulin secretion. Diabetes 52:2049–2056

    Article  CAS  PubMed  Google Scholar 

  29. Vennekens R, Olausson J, Meissner M, Bloch W, Mathar I, Philipp SE, Schmitz F, Weissgerber P, Nilius B, Flockerzi V, Freichel M (2007) Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat Immunol 8:312–320

    Article  CAS  PubMed  Google Scholar 

  30. Wiser O, Trus M, Hernandez A, Renstrom E, Barg S, Rorsman P, Atlas D (1999) The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci USA 96:248–253

    Article  CAS  PubMed  Google Scholar 

  31. Yagui K, Shimada F, Mimura M, Hashimoto N, Suzuki Y, Tokuyama Y, Nata K, Tohgo A, Ikehata F, Takasawa S, Okamoto H, Makino H, Saito Y, Kanatsuka A (1998) A missense mutation in the CD38 gene, a novel factor for insulin secretion: association with Type II diabetes mellitus in Japanese subjects and evidence of abnormal function when expressed in vitro. Diabetologia 41:1024–1028

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Y, Hoon MA, Chandrashekar J, Mueller KL, Cook B, Wu D, Zuker CS, Ryba NJ (2003) Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 112:293–301

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank C. Zuker for providing the Trpm5 −/−-mice and S. Fees and C.E. Oki for the expert technical assistance. This work was supported in part by the Deutsche Forschungsgemeinschaft grant PR688/3-1 (D.P.) and National Institute of Health grant R01AI046734 (R.P.). D.P. was supported by a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft.

Author information

Authors and Affiliations

  1. Centre for Paediatrics and Adolescent Medicine, University Medical Centre of the Johannes Gutenberg—University Mainz, Obere Zahlbacher Str. 63, 55131, Mainz, Germany

    Lili R. Brixel, Claudia S. Ingenbrandt, Thorsten Enklaar & Dirk Prawitt

  2. Center for Biomedical Research, Queen’s Medical Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96813, USA

    Mahealani K. Monteilh-Zoller, Andrea Fleig & Reinhold Penner

  3. Centre for Paediatrics and Adolescent Medicine, Paediatric Genetics Section, University Medical Centre Freiburg, Mathildenstr. 1, 79106, Freiburg, Germany

    Bernhard U. Zabel

Authors
  1. Lili R. Brixel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahealani K. Monteilh-Zoller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia S. Ingenbrandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Fleig
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reinhold Penner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thorsten Enklaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernhard U. Zabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dirk Prawitt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dirk Prawitt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brixel, L.R., Monteilh-Zoller, M.K., Ingenbrandt, C.S. et al. TRPM5 regulates glucose-stimulated insulin secretion. Pflugers Arch - Eur J Physiol 460, 69–76 (2010). https://doi.org/10.1007/s00424-010-0835-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-010-0835-z

Keywords

Search

Navigation