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

Abstract

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 one or ten weeks 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 ten weeks, 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.