Combination Therapy with a Dipeptidyl Peptidase-4 Inhibitor and a Proton Pump Inhibitor Induces β-Cell Neogenesis from Adult Human Pancreatic Duct Cells Implanted in Immunodeficient Mice

Abstract

Combination therapy with a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a proton pump inhibitor (PPI) raises endogenous levels of GLP-1 and gastrin, respectively, and restores pancreatic β-cell mass and normoglycemia in nonobese diabetic (NOD) mice with autoimmune diabetes. The aim of this study was to determine whether a DPP-4i and PPI combination could increase β-cell mass in the adult human pancreas. Pancreatic cells from adult human pancreas donors were implanted in NOD-severe combined immunodeficient (NOD-scid) mice and the mice were treated with a DPP-4i and a PPI for 16 weeks. Human grafts were examined for insulin content and insulin-stained cells. Graft β-cell function was assessed by intravenous glucose tolerance tests (IVGTT) and by glucose control in human cell-engrafted mice treated with streptozotocin (STZ) to delete mouse pancreatic β-cells. Plasma GLP-1 and gastrin levels were raised to two- to threefold in DPP-4i- and PPI-treated mice. Insulin content and insulin-stained cells in human pancreatic cell grafts were increased 9- to 13-fold in DPP-4i and PPI-treated mice and insulin-stained cells were colocalized with pancreatic exocrine duct cells. Plasma human C-peptide responses to IVGTT were significantly higher and STZ-induced hyperglycemia was more completely prevented in DPP-4i- and PPI-treated mice with grafts than in vehicle-treated mice with grafts. In conclusion, DPP-4i and PPI combination therapy raises endogenous levels of GLP-1 and gastrin and greatly expands the functional β-cell mass in adult human pancreatic cells implanted in immunodeficient mice, largely from pancreatic duct cells. This suggests that a DPP-4i and PPI combination treatment may provide a pharmacologic therapy to correct the β-cell deficit in type 1 diabetes.