The glucagon-like peptide 1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β- and α-cell function and relative volumes, islet cell apoptosis and replication in nondiabetic non-human primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an L-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated and the remnant pancreas (head-body) harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by approximately 2-fold. β-, α-, and δ-cell relative volumes in exenatide-treated baboons were significantly increased compared to saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β-, α-, and δ-cells and produces a robust increase in insulin sensitivity in non-human primates.