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

Area of Science:

• Endocrinology
• Metabolic Research
• Pharmacology

Background:

• Glucagon-like peptide 1 (GLP-1) is an insulinotropic peptide with a short half-life, questioning its systemic role.
• Intra-islet GLP-1 receptor (GLP-1r) signaling, potentially involving dipeptidyl-peptidase 4 (DPP4), is increasingly recognized.

Purpose of the Study:

• To investigate GLP-1r signaling's contribution to insulin secretion independent of enteral stimulation and elevated plasma GLP-1.
• To determine the effect of DPP4 inhibition on this localized GLP-1r signaling pathway.

Main Methods:

• A crossover study in nondiabetic and type 2 diabetic subjects.
• Administration of a DPP4 inhibitor (sitagliptin) or placebo, followed by intravenous arginine during GLP-1r blocker (Exendin-9) or saline infusion.
• Measurement of arginine-stimulated C-peptide and insulin secretion.

Main Results:

• Intravenous arginine stimulated alpha- and beta-cell secretion in all subjects.
• GLP-1r blockade reduced C-peptide secretion by approximately 14% in both groups.
• Sitagliptin lowered glucose but did not directly impact primary insulin secretion measures, yet indicated enhanced GLP-1r activation with DPP4 inhibition in diabetics.

Conclusions:

• GLP-1r activation contributes to beta-cell secretion during alpha-cell activation, even without increased circulating GLP-1.
• Results support paracrine regulation of beta-cells by alpha-cells, potentially modulated by DPP4 inhibition.