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Bcl-2 and Bcl-xL Suppress Glucose Signaling in Pancreatic β-Cells.
- Source :
- Diabetes; Jan2013, Vol. 62 Issue 1, p170-182, 13p, 1 Color Photograph, 7 Graphs
- Publication Year :
- 2013
-
Abstract
- B-cell lymphoma 2 (Bcl-2) family proteins are established regulators of cell survival, but their involvement in the normal function of primary cells has only recently begun to receive attention. In this study, we demonstrate that chemical and genetic loss-of-function of antiapoptotic Bcl-2 and Bcl-x<subscript>L</subscript> significantly augments glucose-dependent metabolic and Ca<superscript>2+</superscript> signals in primary pancreatic β-cells. Antagonism of Bcl-2/Bcl-x<subscript>L</subscript> by two distinct small-molecule compounds rapidly hyperpolarized b-cell mitochondria, increased cytosolic Ca<superscript>2+</superscript>, and stimulated insulin release via the ATP-dependent pathway in β-cell under substimulatory glucose conditions. Experiments with single and double Bax--Bak knockout β-cells established that this occurred independently of these proapoptotic binding partners. Pancreatic β-cells from Bcl-2<superscript>-/-</superscript> mice responded to glucose with significantly increased NAD(P)H levels and cytosolic Ca<superscript>2+</superscript> signals, as well as significantly augmented insulin secretion. Inducible deletion of Bcl-x<subscript>L</subscript> in adult mouse β-cells also increased glucose-estimulated NAD(P)H and Ca<superscript>2+</superscript> responses and resulted in an improvement of in vivo glucose tolerance in the conditional Bcl-x<subscript>L</subscript> knockout animals. Our work suggests that prosurvival Bcl proteins normally dampen the β-cell response to glucose and thus reveals these core apoptosis proteins as integrators of cell death and physiology in pancreatic β-cells. [ABSTRACT FROM AUTHOR]
- Subjects :
- PANCREATIC beta cells
B cells
LYMPHOMAS
BLOOD sugar
OBESITY
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 62
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 84430556
- Full Text :
- https://doi.org/10.2337/db11-1464