Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic β-cells.

TitleBcl-2 and Bcl-xL suppress glucose signaling in pancreatic β-cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsLuciani, DS, White, SA, Widenmaier, SB, Saran, VV, Taghizadeh, F, Hu, X, Allard, MF, Johnson, JD
Date Published2013 Jan
KeywordsAnimals, Apoptosis, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein, Calcium, Endoplasmic Reticulum, Glucose, Humans, Insulin, Insulin-Secreting Cells, KATP Channels, Mice, Proto-Oncogene Proteins c-bcl-2, Signal Transduction

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(L) significantly augments glucose-dependent metabolic and Ca(2+) signals in primary pancreatic β-cells. Antagonism of Bcl-2/Bcl-x(L) by two distinct small-molecule compounds rapidly hyperpolarized β-cell mitochondria, increased cytosolic Ca(2+), 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(-/-) mice responded to glucose with significantly increased NAD(P)H levels and cytosolic Ca(2+) signals, as well as significantly augmented insulin secretion. Inducible deletion of Bcl-x(L) in adult mouse β-cells also increased glucose-stimulated NAD(P)H and Ca(2+) responses and resulted in an improvement of in vivo glucose tolerance in the conditional Bcl-x(L) 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.

Alternate JournalDiabetes
PubMed ID22933114
PubMed Central IDPMC3526034
Grant ListMOP-119537 / / Canadian Institutes of Health Research / Canada
MOP-86559 / / Canadian Institutes of Health Research / Canada