TRPM5 regulates glucose-stimulated insulin secretion.
Insulin secretion in beta-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 beta-cells and proposed to be involved in coupling intracellular Ca(2+) 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.
Brixel
Lili R
LR
Centre for Paediatrics and Adolescent Medicine, University Medical Centre of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany.
Monteilh-Zoller
Mahealani K
MK
Ingenbrandt
Claudia S
CS
Fleig
Andrea
A
Penner
Reinhold
R
Enklaar
Thorsten
T
Zabel
Bernhard U
BU
Prawitt
Dirk
D
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D050053:TRPM Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques
D001786:Blood Glucose; D007328:Insulin; D050053:TRPM Cation Channels; C498617:Trpm5 protein, mouse; D001120:Arginine
Cell Calcium. 2007 Jan;41(1):51-61
16806463
Diabetes Obes Metab. 2009 Nov;11 Suppl 4:168-79
19817799
News Physiol Sci. 2000 Apr;15:72-77
11390882
Nat Neurosci. 2002 Nov;5(11):1169-76
12368808
Diabetes. 2002 Feb;51 Suppl 1:S74-82
11815462
Diabetes. 2000 Nov;49(11):1751-60
11078440
Biochem Biophys Res Commun. 1988 Jan 15;150(1):419-25
3276310
J Clin Invest. 1998 Jul 15;102(2):395-401
9664081
Diabetes. 2003 Aug;52(8):2049-56
12882922
J Biol Chem. 1992 Oct 15;267(29):20713-20
1400388
J Biol Chem. 1994 Jul 15;269(28):18279-82
8034570
Nature. 1984 Sep 20-26;311(5983):271-3
6090930
Mol Cell Endocrinol. 2009 Feb 27;299(2):194-203
19063936
J Biol Chem. 1999 Jan 22;274(4):1869-72
9890936
Genomics. 2000 Jul 15;67(2):179-87
10903843
Endocrinology. 2009 Jan;150(1):33-45
18787024
Transplant Proc. 1999 May;31(3):1721-3
10331051
Nat Immunol. 2007 Mar;8(3):312-20
17293867
Mol Endocrinol. 1997 May;11(5):619-29
9139805
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15166-71
14634208
J Physiol. 1999 Dec 15;521 Pt 3:717-28
10601501
Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5208-13
20194741
Cell. 2003 Feb 7;112(3):293-301
12581520
Diabetes Metab. 1996 Feb;22(1):7-14
8697299
Cell. 2004 Oct 15;119(2):273-84
15479643
Eur J Biochem. 1999 Jan;259(1-2):3-17
9914469
Diabetologia. 2009 May;52(5):739-51
19288076
Diabetologia. 1998 Sep;41(9):1024-8
9754820
Nature. 1984 Nov 29-Dec 5;312(5993):446-8
6095103
Biochim Biophys Acta. 1988 Apr 25;969(2):198-207
3281715
Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):248-53
9874804