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

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 7; pp. 2595 - 2604
• Main Authors: Butler, Alexandra E., Campbell-Thompson, Martha, Gurlo, Tatyana, Dawson, David W., Atkinson, Mark, Butler, Peter C.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.07.2013
• Subjects: Adenoma - pathology; Adolescent; Adult; Aged; Biological and medical sciences; Cell proliferation; Cell Proliferation - drug effects; Complications and side effects; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - pathology; Diabetes. Impaired glucose tolerance; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Dosage and administration; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic aspects; Humans; Hyperplasia; Hypoglycemic agents; Incretins - pharmacology; Incretins - therapeutic use; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - pathology; Male; Medical sciences; Middle Aged; Neuroendocrine Tumors - pathology; Organ Size - drug effects; Original Research; Pancreas - drug effects; Pancreas - pathology; Pancreatic beta cells; Physiological aspects; Pyrazines - pharmacology; Pyrazines - therapeutic use; Sitagliptin Phosphate; Triazoles - pharmacology; Triazoles - therapeutic use; United States; Endocrinopathy; Human; Incretin; Pancreatic hormone; Dysplasia; Glucagon; Digestive system; Diabetes mellitus; Exocrine pancreas; Peptide hormone; Neuroendocrine tumor; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db12-1686

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.