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

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 Dpp4 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.

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

“…10, 31-35). The circulating Ex-4 level in our system (~4 ng/ml) was much higher than the basal plasma GLP-1 level in mice (48,49) or healthy humans (50) but close to the therapeutic concentration target for GLP-1R agonists in clinical use (36). The duration of Ex-4 infusion in our study was shorter (28 days) Table 1 for the quantification of TUNEL + β cells in PBS+saline-treated, Ex-4+saline-treated, PBS+FK506-treated, and Ex-4+FK506-treated graft samples from 3 juvenile donors.…”

“…Juvenile islets were isolated at the Institute of Cellular Therapeutics of the Allegheny Health Network (Pittsburgh, Pennsylvania, USA) as previously described (3,4,26). Islets from 12 adult donors (ages 20,21,29,30,40,43,43,48,49,53,60, and 60 years, BMI ranges 24.1-29.6) were obtained from the Integrated Islet Distribution Program (http://iidp.coh.org). Islet function (i.e., glucose-induced insulin secretion) was assessed by islet perifusion assay on the day of arrival, as previously described (57,58).…”

The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

“…In 2011, Waget et al described how inhibition of DPP-4 activity in the intestine was involved in regulating glycaemia [7]. Recently, Mulvihill et al demonstrated that glucose tolerance depended on inhibition of DPP-4 activity in haematopoietic and endothelial cells, but there was no involvement of the DPP-4 expressed by enterocytes [8]. DPP-4 activity modulates the functionality of more than 40 potential substrates, including cytokines, chemokines and growth factors, some of which are particularly relevant for gut homeostasis [9].…”

Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance

“…A recent study suggested that in obese mice, oral DPP4 inhibitors function by inhibiting gut endothelial DPP4 23 . We tested the hypothesis that oral DPP4 inhibition and hepatocyte DPP4 silencing have fundamentally different effects on adipose inflammation and glucose metabolism: we directly compared treatment with the oral DPP4 inhibitor sitagliptin with silencing of hepatocyte DPP4 in DIO mice.…”