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

Stimulation of functional β-cell mass expansion can be beneficial for the treatment of type 2 diabetes. Our group has previously demonstrated that the matricellular protein CCN2 can induce β-cell mass expansion during embryogenesis, and postnatally during pregnancy and after 50% β-cell injury. The mechanism by which CCN2 stimulates β-cell mass expansion is unknown. However, CCN2 does not induce β-cell proliferation in the setting of euglycemic and optimal functional β-cell mass. We thus hypothesized that β-cell stress is required for responsiveness to CCN2 treatment. In this study, a doxycycline-inducible β-cell-specific CCN2 transgenic mouse model was utilized to evaluate the effects of CCN2 on β-cell stress in the setting of acute (thapsigargin treatment ex vivo) or chronic [high-fat diet or leptin receptor haploinsufficiency (db/+) in vivo] cellular stress. CCN2 induction during 1 wk or 10 wk of high-fat diet or in db/ mice had no effect on markers of β-cell stress. However, CCN2 induction did result in a significant increase in β-cell mass over high-fat diet alone when animals were fed high-fat diet for 10 wk, a duration known to induce insulin resistance. CCN2 induction in isolated islets treated with thapsigargin ex vivo resulted in upregulation of the gene encoding the Nrf2 transcription factor, a master regulator of antioxidant genes, suggesting that CCN2 further activates this pathway in the presence of cell stress. These studies indicate that the potential of CCN2 to induce β-cell mass expansion is context-dependent and that the presence of β-cell stress does not ensure β-cell proliferation in response to CCN2. CCN2 promotes β-cell mass expansion in settings of suboptimal β-cell mass. Here, we demonstrate that the ability of CCN2 to induce β-cell mass expansion in the setting of β-cell stress is context-dependent. Our results suggest that β-cell stress is necessary but insufficient for CCN2 to increase β-cell proliferation and mass. Furthermore, we found that CCN2 promotes upregulation of a key antioxidant transcription factor, suggesting that modulation of β-cell oxidative stress contributes to the actions of CCN2.