Context-dependent effects of CCN2 on beta-cell mass expansion and indicators of cell stress in the setting of acute and chronic stress

Abstract

CCN2 is a matricellular protein that stimulates beta-cell mass expansion during situations of sub-optimal beta-cell mass such as during embryogenesis, after beta-cell ablation, and during pregnancy. It was hypothesized that cell stress is required for CCN2 to induce beta-cell proliferation and that CCN2 stimulates beta-cell proliferation by alleviating cell stress. Assays utilizing beta-cell-specific CCN2 induction and acute ER stress demonstrated that CCN2 does not fully attenuate upregulation of ER stress markers in islets after ER stress induction. Furthermore, CCN2 induction during in vivo chronic beta-cell stress conditions does not alleviate cell stress as measured by BiP and 8-OHdG. However, it was found that CCN2 induction stimulated beta-cell mass expansion during prolonged diet-induced obesity. Using another in vivo model of beta cell stress, specifically db/+ heterozygosity, it was found that CCN2 induction in beta cells was detrimental. These studies demonstrate that CCN2 does require cell stress to induce beta-cell proliferation but there may be a threshold of stress that, when crossed, promotes detrimental effects of CCN2 induction in beta cells.