AAV Delivery of gp91‐shRNA Stimulates Synthesis and Release of Insulin and Attenuates Blood Glucose Level in Type 2 Diabetes

Abstract

Hypothesis. RNAi inhibition of gp91 improves insulin resistance and decreases blood glucose level.Methods and Results. Doubled stranded shRNA for gp91phox was synthesized and packaged into the AAV to generate AAV.gp91‐shRNA. Two groups of db/bb mice and 2 groups of lean mice were used. One group of db/db mice and 1 group of lean mice received IV injection of AAV.gp91‐shRNA (1×1011 particles) while the other 2 groups received the same doses of AAV.Control‐shRNA served as controls. Blood glucose levels were elevated in db/db mice treated with AAV.Control‐shRNA. AAV.gp91‐shRNA significantly decreased blood glucose level. Contradictory to our hypothesis, AAV.gp91‐shRNA failed to improve insulin resistance in db/db mice. Interestingly, AAV.gp91‐shRNA increased plasma insulin level significantly (by 2 folds). Immunohistochemical (IHC) data showed that RNAi inhibition of gp91phox significantly increased insulin staining in islet cells, indicating increased insulin synthesis. These data suggest that RNAi inhibition of gp91phox decreased blood glucose level by increasing insulin release.Conclusions. AAV delivery of gp91‐shRNA may serve as new approach for improving blood glucose level in type 2 diabetes. NADPH oxidase is not involved in insulin resistance in type 2 diabetes.