Journal
CELL METABOLISM
Volume 25, Issue 1, Pages 152-165Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2016.10.007
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Funding
- Canadian Institutes of Health Research [142395, 123391]
- Canadian Diabetes Association
- Canadian Institutes of Health Research
- Alberta Innovates-Health Solutions
- Banting and Best Diabetes Centre, University of Toronto
- Canada Research Chair in Regulatory Peptides
- Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology
- Novo Nordisk
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Pharmacological inhibition of the dipeptidyl peptidase- 4 (DPP4) enzyme potentiates incretin action and is widely used to treat type 2 diabetes. Nevertheless, the precise cells and tissues critical for incretin degradation and glucose homeostasis remain unknown. Here, we use mouse genetics and pharmacologic DPP4 inhibition to identify DPP4(+) cell types essential for incretin action. Although enterocyte DPP4 accounted for substantial intestinal DPP4 activity, ablation of enterocyte DPP4 in Dpp4(Gut-/-) mice did not produce alterations in plasma DPP4 activity, incretin hormone levels, and glucose tolerance. In contrast, endothelial cell (EC)-derived DPP4 contributed substantially to levels of soluble plasma DPP4 activity, incretin degradation, and glucose control. Surprisingly, DPP4(+) cells of bone marrow origin mediated the selective degradation of fasting GIP, but not GLP-1. Collectively, these findings identify distinct roles for DPP4 in the EC versus the bone marrow compartment for selective incretin degradation and DPP4i-mediated glucoregulation.
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