Matrine, as a CaSR agonist promotes intestinal GLP-1 secretion and improves insulin resistance in diabetes mellitus

Feb 26, 2021Phytomedicine : international journal of phytotherapy and phytopharmacology

Matrine boosts gut hormone release and improves insulin resistance in diabetes by activating a calcium-sensing receptor

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Abstract

Matrine significantly improved glucose metabolism and increased insulin and GLP-1 secretion in diabetic mice.

Matrine may stimulate the secretion of GLP-1, which is associated with blood glucose regulation.
The compound increased levels of trisphosphate inositol (IP3) by affecting the expression of phospholipase C β2 (PLCβ2).
Higher intracellular calcium levels in intestinal secretory cells were observed following Matrine treatment.
Knockdown of specific bitter taste receptors did not affect Matrine's ability to regulate GLP-1 secretion.
Inhibition of the calcium-sensing receptor (CaSR) significantly reduced the GLP-1 secretion induced by Matrine.
Molecular docking analysis indicated that Matrine binds to the CaSR protein, acting as an agonist.

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BACKGROUND: Matrine (Mat), a bitter tastes compounds of derived from leguminosae such as Sophora flavescens and S. subprostrata, commonly used to improve obesity and diabetes.

PURPOSE: Our study to demonstrate bitter substances can stimulate the Bitter taste receptors (TAS2Rs) or Calcium-sensing receptor (CaSR) to stimulate the secretion of GLP-1 to promote blood glucose regulation.

METHODS: The diabetic mice and intestinal secretory cell model were established to evaluate the Mat on glucose metabolism, intestinal insulin secretion and GLP-1 secretion related substances. To clarify the mechanism of Mat in regulating GLP-1 secretion by immunofluorescence, calcium labeling, siRNA, and molecular docking.

RESULTS: The results showed that Mat could significantly improve glucose metabolism and increased insulin and GLP-1 secretion in diabetic mice and increased trisphosphate inositol (IP3) levels by affecting the expression of phospholipase C β2 (PLCβ2) and promote an increase in intracellular Ca2levels in STC-1 cells to subsequently stimulate the secretion of GLP-1. Knockdown of the bitter taste receptors mTas2r108, mTas2r137, and mTas2r138 in STC-1 cells by siRNA did could not affect the role of Mat in regulating GLP-1. However, the secretion of GLP-1 by Mat could be significantly inhibited by administration of a CaSR inhibitor or siRNA CaSR. Molecular docking analysis showed that Mat could embed CaSR protein and bind to the original ligand of the egg white at the same amino acid site to play the role of an agonist. +

CONCLUSION: Matrine is a typical bitter alkaloid could be used as an agonist of CaSR to stimulate the secretion of GLP-1 in the intestine, and it may be used as a potential drug for diabetes treatment.

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Matrine, as a CaSR agonist promotes intestinal GLP-1 secretion and improves insulin resistance in diabetes mellitus

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