Reponse to Comments on: Butler et al. 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. Diabetes 2013;62:2595–2604

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

We would begin by thanking both Dr. Engel (1) and Dr. Heine (2), as well as their colleagues, for their interest in our recent publication (3). Both collectives of authors raise issues regarding the number of individuals studied and the age-matching of the incretin-treated versus non-incretin-treated groups of individuals with type 2 diabetes. We acknowledge that the study of pancreata from brain-dead organ donors with type 2 diabetes subject to either incretin (sitagliptin, n = 7; exenatide, n = 1) or no incretion therapy (n = 12) is small compared with the large clinical studies undertaken by drug sponsors. We also accept the critique that the matching of the two diabetic groups does not meet the standards expected for a randomized clinical study. However, to the best of our knowledge, with the exception of a single case report (4), we believe our effort represents the first evaluation of human pancreata following antecedent glucagon-like peptide 1 (GLP-1)–based therapy. We would also portend that the very random nature of obtaining human pancreata under the circumstances of brain-dead organ donors is limiting, both in terms of which individuals become obtainable and the quantity of available clinical information related to their diabetes. We fully agree that priority should be given to evaluating a larger number of pancreata, particularly given the widespread use of this class of drugs and the uncertainties with regard to their unintended actions on the pancreas.

Having mentioned the relatively small sample size, we are surprised that Heine et al. (2) would propose the use of covariate analysis to address potential confounders. To the best of our understanding, the use of covariate analysis is a statistical approach suited to large population studies rather than hypothesis testing in smaller cohorts such as the present one. With each additional covariate analyzed, a degree …

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