Marked Expansion of Exocrine and Endocrine Pancreas With Incretin Therapy in Humans With Increased Exocrine Pancreas Dysplasia and the Potential for Glucagon-Producing Neuroendocrine Tumors

Controversy exists regarding the potential regenerative influen-ces of incretin therapy on pancreatic b-cells versus possible ad-verse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an;40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P, 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P, 0.01). Pancreata in DM treated with incretin therapy were notable for a-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. b-Cell mass was reduced by;60 % in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM com