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

  1. Peter C Butler1
  1. 1Department of Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
  2. 2College of Medicine, Departments of Pathology and Pediatrics, University of Florida, Gainesville, Florida 32610-0275.
  3. 3Department of Pathology and Laboratory Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
  1. Corresponding author: Alexandra E. Butler, Email: aebutler{at}


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 (DM) treated by incretin therapy (n=8) or other therapy (n=12) and non diabetic controls (n=14) reveals a ∼40% increased pancreatic mass in DM treated with incretin therapy with both increased exocrine cell proliferation (p<0.0001) and dysplasia (increased pancreatic intraepithelia neoplasia, p<0.01). Pancreas in DM treated with incretin therapy was notable for α cell hyperplasia and glucagon expressing microadenomas (3/8) and a neuroendocrine tumor. β cell mass was reduced by approximately 60% in those with DM, yet a 6 fold increase was observed in incretin treated subjects although diabetes persists. Endocrine cells co-staining for insulin and glucagon were increased in DM compared to non diabetic controls (p<0.05) and markedly further increased by incretin therapy (p<0.05). In conclusion, in humans, incretin therapy resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia, the latter by α cell hyperplasia with the potential for evolution into neuroendocrine tumors.

  • Received December 4, 2012.
  • Accepted March 14, 2013.

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