Cellular Sites and Mechanisms Linking Reduction of Dipeptidyl Peptidase-4 Activity to Control of Incretin Hormone Action and Glucose Homeostasis

Cell Metab. 2017 Jan 10;25(1):152-165. doi: 10.1016/j.cmet.2016.10.007. Epub 2016 Nov 10.

Abstract

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 Dpp4Gut-/- 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.

Keywords: dipeptidyl peptidase-4; endothelial cells; enterocytes; glucagon; glucagon-like peptide-1; glucose metabolism; glucose-dependent insulinotropic polypeptide; gut; hematopoietic cells; incretin; insulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Diet, High-Fat
  • Dipeptidyl Peptidase 4 / blood
  • Dipeptidyl Peptidase 4 / metabolism*
  • Enteral Nutrition
  • Feeding Behavior / drug effects
  • Gastric Inhibitory Polypeptide / metabolism*
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Homeostasis* / drug effects
  • Incretins / metabolism*
  • Insulin Resistance
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / enzymology
  • Male
  • Mice
  • Models, Biological
  • Sitagliptin Phosphate / pharmacology

Substances

  • Incretins
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Dipeptidyl Peptidase 4
  • Glucose
  • Sitagliptin Phosphate