title: 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.
abstract: Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse 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 α-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. β-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 compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumors.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. aebutler@mednet.ucla.edu
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Butler
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gurlo
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000236:Adenoma / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006965:Hyperplasia; D054795:Incretins / Q000494:pharmacology / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D011719:Pyrazines; D014230:Triazoles; D000068900:Sitagliptin Phosphate