- 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. ... [Read More]
- Total Size
- 5 files (572 KB)
- Data Citation
- D'Alessio, D., Gray, S., Hoselton, A., Krishna, R., Slentz, C. (2022). Data from: GLP-1 receptor blockade reduces stimulated insulin secretion in fasted subjects with low circulating GLP-1. Duke Research Data Repository. V2 https://doi.org/10.7924/r41n87v9d
- Publication Date
- June 16, 2022
- Related Materials
- The supplemental PDF file has been updated with a new table (Table 8) after peer-review.
- David D'Alessio, https://orcid.org/0000-0003-4155-4870, 919-684-5778
- Data from: GLP-1 receptor blockade reduces stimulated insulin secretion in fasted subjects with low circulating GLP-1
|2||10.7924/r41n87v9d||The supplemental PDF file has been updated with a new table (Table 8) after peer-review.||2022-06-16|