Urocortin-2 Gene Transfer Effectively Treats Type 1 Diabetes in Mice

Type 1 diabetes (T1D) affects 1.3 million U.S. patients. Tight glucose control reduces microvascular complications and adverse cardiovascular events. Insulin therapy is essential but has shortcomings: a) only 1 in 3 patients achieve targeted glucose control; b) aggressive insulin use increases hypoglycemia; c) 25% of T1D patients develop insulin resistance. We previously reported that urocortin-2 (UCn2) gene transfer increases insulin sensitivity and release in mouse models of type 2 diabetes. In the present study, 3m-old male Akita mice with T1D (due to Ins2 mutation) received IV saline, AAV8. Null or AAV8.UCn2 (2x10¹² gc/kg). Ten weeks after UCn2 gene transfer we saw normalization of fasting glucose, HbA1c and glucose tolerance (Table). Increased body weight and reduced water intake was seen after UCn2 gene transfer. Hyperinsulinemic euglycemic clamps showed increased insulin sensitivity and skeletal muscle glucose uptake. There was reduced nephropathy and retinopathy and increased survival (Table). Echocardiography showed improved ejection fraction (p<.001), end-systolic dimension (p<.001) and diastolic function (p<.0001). Data acquisition and analyses were blinded. The mechanisms for beneficial effects include increased insulin release and sensitivity. Thus, UCn2 gene transfer may be a viable therapy both for new onset T1D with detectable endogenous insulin, and for later stage T1D to reduce exogenous insulin needs.