GLP-1 receptor blockade reduces stimulated insulin secretion in fasted subjects with low circulating GLP-1
SM Gray, AL Hoselton, R Krishna… - The Journal of …, 2022 - academic.oup.com
SM Gray, AL Hoselton, R Krishna, CA Slentz, DA D'Alessio
The Journal of Clinical Endocrinology & Metabolism, 2022•academic.oup.comContext 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 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 …
circulation from intestinal enteroendocrine cells, is considered a hormonal mediator of
insulin secretion. However, the physiological actions of circulating GLP-1 have 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 …
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 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.
Methods
Single-site study conducted at an academic medical center of 20 nondiabetic subjects and 13 subjects with type 2 diabetes. This was a crossover study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on 2 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. The main outcome measures were 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 α- and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (P < .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 more GLP-1r activation with DPP4i treatment in subjects with diabetes.
Conclusion
GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic people during α-cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from α-cells. This process may be affected by DPP4 inhibition.
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