entete
         




 REGULATION AND SENSING IN BETA CELLS

glucotox

Prolonged exposure of INS-1E ß-cells induces the
loss of glucose-induced insulin secretion


adcy8
Glucose-regulated gene expression in INS-1E ß-cells
GLUCOTOXICITY, ADCY8 AND SIGNALLING
Diabetes is characterized by elevated levels of blood glucose1. We have conducted a detailed functional analysis of glucotoxicity in pancreatic beta-cells. Prolonged exposure of ß-cells to high glucose leads to diminished insulin secretion in response to acute glucose challenge and this has been linked mainly to the altered generation of metabolism-secretion coupling factors.

We have investigated whether glucotoxicity may also alter calcium handling and late steps in secretion itself such as exocytosis. Culture of clonal INS-1E ß -cells at elevated glucose induces KATP-channel dependant increases in basal intracellular calcium [Ca2+]i, increased filling of intracellular stores and diminishes glucose induced rises in [Ca2+]i. Moreover, not only glucose, but also KCl-evoked insulin secretion was largely diminished as was the case in a permeabilized cell assay for exocytosis. This indicates a defect in the final steps of exocytosis. Measuring expression levels of 31 proteins implicated in trafficking/exocytosis of post-Golgi vesicles, we found a decreased expression of several exocytotic proteins required for calcium-induced exocytosis of secretory granules such as the SNARE proteins VAMP2 and syntaxin 1 as well as complexin. Thus our data demonstrate that glucotoxicity impedes not only generation of signals for secretion, but also diminishes the efficiency of late steps in exocytosis 2.



In continuation of this work we have embarked on detailed analysis by functional genomics. Interestingly one specific isoform of adenylate cyclase is strongly down-regulated by glucotoxicity in clonal or primary cells from rat or humans. Detailed investigation demonstrated the pivotal importance of this isoform for incretin-induced signaling via calcium, to CRE and in exocytosis 3.
More recent data indicate that this gene may also be required for normal glucose signaling 4
.


Roger, B., J. Papin, P. Vacher, M. Raoux, A. Mulot, M. Dubois, B.H. Vanderwalle, F. Pattou, G. Charpentier, J.C. Jonas, N.
Moustaid-Moussa, and J. Lang, Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells. 
Diabetologia, in press

Dubois, M., P. Vacher, B. Roger, D. Huyghe, B. Vandewalle, J. Kerr-Conte, F. Pattou, N. Moustaïd Moussa, and J. Lang, Glucotoxicity inhibits late steps of insulin exocytosis. Endocrinology, 2007. 148: p.1605-1614.

Rigalleau, V., J. Lang, and H. Gin, Etiologie et physiopathologie du diabète de type 2. Encyclopédie Médico-chirurgicale, 2007.

References:

1.     Rigalleau, V., J. Lang, and H. Gin, Etiologie et physiopathologie du diabète de type 2, in Encyclopédie Médico-chirurgicale, A. Basdevant, Editor. 2007, Masson: Paris. p. 10-20.

2.   Dubois, M., P. Vacher, B. Roger, D. Huyghe, B. Vandewalle, J. Kerr-Conte, F. Pattou, N. Moustaid-Moussa, and J. Lang, Glucotoxicity inhibits late steps of insulin exocytosis. Endocrinology, 2007. 148: 1605-14.

3.     Roger, B., J. Papin, P. Vacher, M. Raoux, A. Mulot, M. Dubois, B.H. Vanderwalle, F. Pattou, G. Charpentier, J.C. Jonas, N. Moustaid-Moussa, and J. Lang, Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells. Diabetologia, In press.

4.     Raoux, M., P. Vacher, J. Papin, B. Roger, C. Magnan, and J. Lang, Adenylate cyclase 8 is required for glucose-induced calcium signalling in pancreatic β-cells. Diabetologia, 2010. 53 S1: P565.

5.     Raoux, M., G. Bontorin, Y. Bornat, J. Lang, and S. Renaud, Bioelectronic sensing of insulin demand, in Biohybrid Systems, R. Jung, Editor. in press, Wiley-VCH.

6.     Bornat, Y., M. Raoux, Y. Boutaib, F.O. Morin, G. Charpentier, J. Lang, and S. Renaud. Detection of electrical activity of pancreatic b-cells using micro-electrode arrays. in 5th  IEEE Int. Symposium on Electronic Design, Test & Applications - DELTA 2010. 2010. Ho Chi Minh City, VietNam.

french flag ACCUEILANNUAIRENOUSRECHERCHEPUBLICATIONSEQUIPEMENTEMPLOISTHESES/STAGESENSEIGNEMENTPLAN D'ACCESLIENSPPLAN DU SITE
flag       HOMEDIRECTORYABOUT USRESEARCHPUBLICATIONSEQUIPMENTJOBSTHESISACADEMICSHOW TO REACH USLINKSSITE MAP

/div>