Abscisic Acid Stimulates Glucagon-Like Peptide-1 Secretion from L-Cells and Its Oral Administration Increases Plasma Glucagon-Like Peptide-1 Levels in Rats

Abstract

In recent years, Abscisic Acid (ABA) has been demonstrated to be involved in the regulation of glucose homeostasis in mammals as an endogenous hormone, by stimulating both insulin release and peripheral glucose uptake. In addition, ABA is released by glucose- or GLP-1-stimulated β-pancreatic cells. Here we investigated whether ABA can stimulate GLP-1 release. The human enteroendocrine L cell line hNCI-H716 was used to explore whether ABA stimulates in vitro GLP-1 secretion and/or transcription. ABA induced GLP-1 release in hNCI-H716 cells, through a cAMP/PKA-dependent mechanism. ABA also enhanced GLP-1 transcription. In addition, oral administration of ABA significantly increased plasma GLP-1 and insulin levels in rats. In conclusion, ABA can stimulate GLP-1 release: this result and the previous observation that GLP-1 stimulates ABA release from β -cells, suggest a positive feed-back mechanism between ABA and GLP-1, regulating glucose homeostasis. Type 2 diabetes treatments targeting the GLP-1 axis by either inhibiting its rapid clearance by dipeptidyl-peptidase IV or using GLP-1 mimetics are currently used. Moreover, the development of treatments aimed at stimulating GLP-1 release from L cells has been considered as an alternative approach. Accordingly, our finding that ABA increases GLP-1 release in vitro and in vivo may suggest ABA and/or ABA analogs as potential anti-diabetic treatments.

Abscisic acid stimulates the release of insulin and of GLP‐1 in the rat perfused pancreas and intestine

“…In the present study, perfusion of the rat pancreas with ABA stimulated insulin release, but only at high micromolar ABA concentrations (10 and 100‐μM ABA, Figure ). This observation is in agreement with results obtained in another in vivo setting, where orally administered ABA (50 mg/kg) induced insulin release in fasted rats . Conversely, at 1 μg/kg ABA improved the glycemic profile without increasing insulinemia in rats and in healthy humans undergoing an oral glucose tolerance test .…”

“…A number of studies have highlighted the role of ABA in the regulation of glycemia in mammals, suggesting its possible use in the treatment of T2D. In particular, several features of ABA make it an attractive new glycemia‐lowering molecule: (1) it is active at a low dose (1 μg/kg body weight), which is not insulinotropic, thus sparing β‐cell function; (2) it stimulates glucose uptake by myocytes and adipocytes, without stimulating adipocyte differentiation and triglyceride accumulation, as conversely does insulin; and (3) it stimulates glucose‐independent GLP‐1 release in vitro and in vivo …”

“…A single oral ABA administration (50 mg/kg, ie, 190 μmol/kg) was previously shown to increase plasma GLP‐1 levels in fasted rats, indicating that luminal ABA is effective in releasing GLP‐1, either by acting directly from the lumen, or after its absorption into the bloodstream. Here, we observed that intra‐arterial administration of ABA (200 μM) to the isolated perfused rat small intestine induced GLP‐1 release, whereas luminal stimulation with the same ABA concentration did not evoke a detectable GLP‐1 release (Figure ).…”

“…Indeed, besides stimulating insulin release, ABA exerts other effects impacting on glucose homeostasis: ABA increases glucose uptake by myoblasts and adipocytes, by increasing the plasmamembrane translocation of the glucose transporter GLUT4, and stimulates the release of GLP‐1 by enteroendocrine L‐cells . The latter was observed in vitro on the human L‐cell line NCI‐H716 and in vivo in rats, where oral administration of ABA induced an increase in plasma GLP‐1 levels . Intriguingly, GLP‐1 was demonstrated to evoke ABA release from rat insulinoma cells and from human pancreatic islets, in the presence of both low and high glucose concentrations .…”

“…Impairment of the response of plasma ABA to hyperglycemia in diabetes suggests a critical role for ABA in the maintenance of glucose tolerance. Indeed, besides stimulating insulin release, ABA exerts other effects impacting on glucose homeostasis: ABA increases glucose uptake by myoblasts and adipocytes, by increasing the plasmamembrane translocation of the glucose transporter GLUT4, and stimulates the release of GLP‐1 by enteroendocrine L‐cells . The latter was observed in vitro on the human L‐cell line NCI‐H716 and in vivo in rats, where oral administration of ABA induced an increase in plasma GLP‐1 levels .…”