Glucose promotes survival of rat pancreatic β cells by activating synthesis of proteins which suppress a constitutive apoptotic program

This study demonstrates that rat islet β cells constitutively express an apoptotic program which is activated when mRNA or protein synthesis is blocked. Apoptotic β cells were detectable by electron microscopy after treatment with actinomycin D or cycloheximide. With a fluorescence microscopic assay both agents were found to increase the number of apoptotic β cells dose- and time-dependently, up to 70% after 1 wk of culture; virtually no apoptotic β cells occurred in control preparations or in conditions leading to primary necrosis. Thus, survival of β cells seems dependent on synthesis of proteins which suppress an endogenous suicide program. This mechanism explains earlier observed effects of glucose on survival of cultured β cells. Glucose is known to dose-dependently increase the percentage of β cells in active biosynthesis and the percentage that survives during culture. It is now demonstrated that the glucose-induced survival of β cells cultured for 1 wk results from a dose-dependent reduction in the percentage of β cells dying in apoptosis (49% at 3 mM glucose, 40% at 6 mM, 9% at 10 mM). Thus, intercellular differences in glucose sensitivity appear responsible for the heterogeneity in β cell sensitivity to apoptotic conditions. These data indicate that glucose promotes survival of β cells by activating synthesis of proteins which suppress apoptosis. The present model allows for further investigation of the regulation of apoptosis in β cells and the identification of agents which induce or prevent β cell death.