Nova1 or Bim Deficiency in Pancreatic beta-Cells Does Not Alter Multiple Low-Dose Streptozotocin-Induced Diabetes and Diet-Induced Obesity in Mice

The loss of functional pancreatic beta-cell mass is an important hallmark of both type 1 and type 2 diabetes. The RNA-binding protein NOVA1 is expressed in human and rodent pancreatic beta-cells. Previous in vitro studies indicated that NOVA1 is necessary for glucose-stimulated insulin secretion and its deficiency-enhanced cytokine-induced apoptosis. Moreover, Bim, a proapoptotic protein, is differentially spliced and potentiates apoptosis in NOVA1-deficient beta-cells in culture. We generated two novel mouse models by Cre-Lox technology lacking Nova1 (beta Nova1(-/-) or Bim (beta Bim(-/-)) in beta-cells. To test the impact of Nova1 or Bim deletion on beta-cell function, mice were subjected to multiple low-dose streptozotocin (MLD-STZ)-induced diabetes or high-fat diet-induced insulin resistance. beta-cell-specific Nova1 or Bim deficiency failed to affect diabetes development in response to MLD-STZ-induced beta-cell dysfunction and death evidenced by unaltered blood glucose levels and pancreatic insulin content. In addition, body composition, glucose and insulin tolerance test, and pancreatic insulin content were indistinguishable between control and beta Nova1(-/-) or beta Bim(-/-) mice on a high fat diet. Thus, Nova1 or Bim deletion in beta-cells does not impact on glucose homeostasis or diabetes development in mice. Together, these data argue against an in vivo role for the Nova1-Bim axis in beta-cells.