PeptidesJul 14, 2018

GLP-1 receptor agonists increase ANGPTL8 production by activating the PI3K/Akt pathway through GLP-1 receptors

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 1, 2026

Abstract

Among 240 patients with type 2 diabetes mellitus, treatment with exenatide significantly increased serum levels of angiopoietin-like protein 8 (ANGPTL8).

Exenatide treatment was associated with significant reductions in body weight, fasting blood glucose, and glycated hemoglobin A1c in patients with type 2 diabetes mellitus.
The increase in serum ANGPTL8 following exenatide treatment was not linked to the observed reductions in body weight or blood glucose levels.
In laboratory experiments, exendin-4 and liraglutide dose-dependently increased ANGPTL8 expression and secretion in liver cells.
The effects on ANGPTL8 production in liver cells were inhibited by a GLP-1 receptor antagonist and a specific PI3K inhibitor.
GLP-1 receptor agonists may enhance ANGPTL8 production through the PI3K/Akt signaling pathway.

Simplified

The level of serum angiopoietin-like protein 8 (ANGPTL8), a novel hepatokine, is associated with obesity and type 2 diabetes mellitus (T2DM). The aims of this study were to investigate whether serum ANGPTL8 level in patients with T2DM was affected by treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, and to determine whether and how GLP-1R agonists regulated ANGPTL8 production in hepatocytes. A multiple-center trial was conducted in China. Among 240 patients with T2DM enrolled in this trial, 195 patients adhered to a 16-week exenatide treatment and follow-up. Human liver cell line HepG2 cells were incubated for 24 h with either exendin-4 (a native form of exenatide) or liraglutide in the presence or absence of GLP-1R antagonist exendin (9-39) and PI3K inhibitor LY294002. Change of serum ANGPTL8 level in patients with T2DM and regulation of ANGPTL8 production by the GLP-1R agonists in HepG2 cells were evaluated. Results showed that compared with baseline, exenatide treatment significantly increased serum ANGPTL8 level, and lowered body weight, fasting blood glucose (FBG) and glycated hemoglobin A1c (HbA1c) in patients with T2DM (all P < 0.05). The exenatide treatment-mediated upregulation of serum ANGPTL8 level was not associated with the levels of its lowering effects on body weight, FBG and HbA1c stratified by the median. Moreover, exendin-4 or liraglutide dose-dependently upregulated the level of ANGPTL8 expression and secretion in HepG2 cells, which was eliminated by adding exendin (9-39) and LY294002. In conclusion, GLP-1R agonists enhance ANGPTL8 production in vivo and in vitro, which is mediated via the PI3K/Akt pathway in a GLP-1R-dependent manner.

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GLP-1 receptor agonists increase ANGPTL8 production by activating the PI3K/Akt pathway through GLP-1 receptors

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