Context: Glucagon-like peptide 1 (GLP-1) an insulinotropic peptide released into the circulation from intestinal enteroendocrine cells is considered a hormonal mediator of insulin secretion. However the physiological actions of circulating GLP-1 have long been questioned because of the short half-life of the active peptide. Moreover there is mounting evidence for localized intra-islet mediation of GLP-1 receptor (GLP-1r) signaling including a role for islet dipeptidyl-peptidase 4 (DPP4).\ Objective: To determine whether GLP-1r signaling contributes to insulin secretion in the absence of enteral stimulation and increased plasma levels and whether this is affected by DPP4.
Setting: Single-site study conducted at an academic medical center.
Participants: 20 nondiabetic subjects and 13 subjects with type 2 diabetes.
Design & Interventions: Cross-over study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on two separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60 minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline.
Main Outcome Measures: Arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg).\ Results: Plasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both - and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (p < 0.03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However a significant interaction between sitagliptin and Ex-9 suggested a greater effect of GLP-1r activation with DPP4i treatment in diabetic subjects.
Conclusions: GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic humans during -cell activation but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from -cells. This process may be affected by DPP4 inhibition.
Setting: Single-site study conducted at an academic medical center.
Participants: 20 nondiabetic subjects and 13 subjects with type 2 diabetes.
Design & Interventions: Cross-over study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on two separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60 minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline.
Main Outcome Measures: Arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg).\ Results: Plasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both - and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (p < 0.03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However a significant interaction between sitagliptin and Ex-9 suggested a greater effect of GLP-1r activation with DPP4i treatment in diabetic subjects.
Conclusions: GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic humans during -cell activation but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from -cells. This process may be affected by DPP4 inhibition.