Pancreatic Specific Deletion of NOS1AP Lowered Islet Mass

Objective: Nitric oxide synthase associated protein (NOS1AP) is an adaptor protein regulating neuronal functions through NMDAR/nNOS-dependent pathway. We previously reported that NOS1AP SNP rs12742393 was associated with type 2 diabetes. In the present study we aimed to investigate the effect of NOS1AP on beta-cell function. Methods: Pancreatic specific deletion (CKO) of NOS1AP mice were generated from floxed nos1ap (exon 3-5) mice and pdx1-cre mice. These mice were fed with either chow or high fat diet (HFD,60% kcal fat). Results: NOS1AP was highly expression in mouse islets. Deletion of NOS1AP in pancreas had no effect on food intake and body weight in mice either fed with chow and high fat diet. However, deletion of NOS1AP impaired glucose tolerance in HFD fed mice. The blood glucose levels at 15min and 30min were higher in CKO than in its littermate control mice. The AUC of IPGTT in CKO was 20% higher than that in control mice. Insulin levels in CKO mice were lower than that in control mice after glucose load (P<0.05). Similarly, glucose stimulated insulin secretion from islets isolated from CKO was decreased compared with that from control mice. Moreover, islet mass in mice with pancreatic NOS1AP deletion decreased significantly (P<0.05). BrdU staining showed that the BrdU positive cells in islets were lower in NOS1AP CKO mice than in control mice. Overexpression of NOS1AP protected beta-cells from high levels of glucose and FFA (palmitate)-induced cell death. Conclusion: Our data demonstrate that NOS1AP plays a role in regulating beta-cell function and mass through regulation of cell proliferation and cytoprotection. Disclosure C. Wang: None. Q. Mao: None. Q. Li: None. W. Jia: None. Funding National Natural Science Foundation of China (81670707)