Incretin effects in the human pancreas
8 April 2013 (10:36 AM) - Editor's Corner
Exposure to incretin therapy has been reported to show proliferative effects on both the endocrine and exocrine pancreas in some animal models. Alex Butler and colleagues now provide the first description of human pancreas derived from donors on incretin based therapy and report increased pancreatic weight with evidence of duct proliferation and marked expansion of the numbers of cells staining for glucagon and insulin
In a ground-breaking study, investigators report on 8 human pancreases obtained from donors on incretin therapies (1 exenatide, 7 sitagliptin). Donor grade pancreas was also obtained from 12 people with diabetes who did not use incretins , all obtained via the JDRF pancreas donor scheme (nPOD); there were 14 non-diabetic controls.
The incretin-treated pancreases were on average 40% heavier, with evidence of increased ductal proliferation and dysplasia. Beta cell mass was reduced by around 60% in diabetic individuals not treated with incretins, as against a 6-fold increase in those taking incretins. This was due to an expansion of islet cells staining either for insulin, glucagon or both (the latter is normally seen only in fetal tissue). The expanded mass of insulin-staining cells had evidently not reversed diabetes in the donors, and the inference is that these new islet cells are immature and unable to secrete insulin or glucagon effectively.
Further concern was engendered by the observation that alpha cell proliferation had resulted in the formation of microadenomas in 3 donors, with the additional formation of a neuroendocrine tumour in one.
This study provides further evidence that interaction of GLP-1 (or potentially other peptides such GIP, which is also enhanced by DPP4 therapy) has pro-proliferative effects. Furthermore, there is other evidence to suggest that alpha-cell proliferation may be an unwanted effect of glucagon inhibition. These findings, especially when linked to new evidence of acute pancreatitis, are likely to stimulate a searching reappraisal of the role of incretin-based therapies, and the FDA has announced an investigation based on these new findings.
^ Butler AE 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 March 22nd [Epub before print]