TRPM5 regulates glucose-stimulated insulin secretion

  • Lili R. Brixel
  • Mahealani K. Monteilh-Zoller
  • Claudia S. Ingenbrandt
  • Andrea Fleig
  • Reinhold Penner
  • Thorsten Enklaar
  • Bernhard U. Zabel
  • Dirk Prawitt
Integrative Physiology

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.

Keywords

Trpm5 Insulin secretion Pancreatic beta cells TRP channels Islet cell Diabetes mellitus Arginine Ca2+-activated channels 

Notes

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.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Lili R. Brixel
    • 1
  • Mahealani K. Monteilh-Zoller
    • 2
  • Claudia S. Ingenbrandt
    • 1
  • Andrea Fleig
    • 2
  • Reinhold Penner
    • 2
  • Thorsten Enklaar
    • 1
  • Bernhard U. Zabel
    • 3
  • Dirk Prawitt
    • 1
  1. 1.Centre for Paediatrics and Adolescent MedicineUniversity Medical Centre of the Johannes Gutenberg—University MainzMainzGermany
  2. 2.Center for Biomedical Research, Queen’s Medical Center and John A. Burns School of MedicineUniversity of HawaiiHonoluluUSA
  3. 3.Centre for Paediatrics and Adolescent Medicine, Paediatric Genetics SectionUniversity Medical Centre FreiburgFreiburgGermany

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