GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1

J Clin Endocrinol Metab. 2022 Aug 18;107(9):2500-2510. doi: 10.1210/clinem/dgac396.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02683187.

Keywords: GLP-1; GLP-1 receptor; dipeptidyl peptidase 4; glucagon; incretin effect; insulin secretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / therapeutic use
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2* / drug therapy
  • Dipeptidyl Peptidase 4 / metabolism
  • Fasting
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor*
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Sitagliptin Phosphate / pharmacology
  • Sitagliptin Phosphate / therapeutic use

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Glucagon-Like Peptide 1
  • Arginine
  • Dipeptidyl Peptidase 4
  • Sitagliptin Phosphate

Associated data

  • ClinicalTrials.gov/NCT02683187