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

Stimulation of functional b-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 beta-cell mass expansion during embryogenesis, and postnatally during pregnancy and after 50% b-cell injury. The mechanism by which CCN2 stimulates beta-cell mass expansion is unknown. However, CCN2 does not induce b-cell proliferation in the setting of euglycemic and optimal functional beta-cell mass. We thus hypothesized that b-cell stress is required for responsiveness to CCN2 treatment. In this study, a doxycycline-inducible b-cellspecific CCN2 transgenic mouse model was utilized to evaluate the effects of CCN2 on b-cell stress in the setting of acute (thapsigargin treatment ex vivo) or chronic [high-fat diet or leptin receptor haploinsufficiency (db/ thorn) in vivo] cellular stress. CCN2 induction during 1 wk or 10 wk of high-fat diet or in db/ thorn mice had no effect on markers of b-cell stress. However, CCN2 induction did result in a significant increase in b-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 b-cell mass expansion is context-dependent and that the presence of b-cell stress does not ensure b-cell proliferation in response to CCN2.