Multi-target antidiabetic mechanisms of mexicanolides from Swietenia humilis

Phytomedicine. 2019 May:58:152891. doi: 10.1016/j.phymed.2019.152891. Epub 2019 Mar 13.

Abstract

Background: Swietenia humilis seeds are consumed in Mexico to treat type 2 diabetes; the antihyperglycemic effect of this species was previously demonstrated and related to the presence of tetranortriterpenoids of the mexicanolide class.

Purpose and study design: The present investigation was conducted to determine the mechanism of action of selected mexicanolides, including 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), methyl-2-hydroxy-3-β-tigloyloxy-1-oxomeliac-8(30)-enate (2) and humilinolide H (3), using in vivo experiments with hyperglycemic mice, and cell-based models.

Methods: Nicotinamide-streptozotocin hyperglycemic mice (50-130 mg/kg, i.p.) were used to build antihyperglycemic drug-response curves using an oral glucose tolerance test model. In vitro studies were carried out on INSE1, H4IIE and C2C12 cells to assess insulin secretion, glucose-6-phosphatase inhibition, glucose uptake and mitochondrial bioenergetics, respectively.

Results: The combination of the decoction of S. humilis or 2-hydroxy-destigloyl-6-deoxyswietenine acetate (mexicanolide 1) with glibenclamide resulted in a reduction of the antihyperglycemic effect while a significant increase was observed when they were dosed with metformin. These effects were related to KATP SUR blockade, insulin secretion in INSE1 cells, and modulation of 5-HT2 receptors. Furthermore, mexicanolides 1-3 inhibited glucose-phosphatase in H4IIE cells, and enhanced glucose uptake and spare respiratory capacity in C2C12 myotubes.

Conclusion: S. humilis mexicanolides interact with pharmacological targets at pancreas (KATP channels), liver (glucose-6-phosphatase), and skeletal muscle (mitochondria and possibly glucose transporters) to modulate glucose homeostasis, and could be a promising resource to treat type 2 diabetes.

Keywords: Diabetes; Glucose homeostasis; Mexicanolides; Pharmacological interaction; Swietenia humilis.

MeSH terms

  • Animals
  • Cell Line
  • Diabetes Mellitus, Experimental / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Glucose Tolerance Test
  • Glyburide / pharmacology
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology*
  • Limonins / pharmacology*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Meliaceae / chemistry*
  • Metformin / pharmacology
  • Mexico
  • Mice, Inbred ICR
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Plants, Medicinal / chemistry

Substances

  • Hypoglycemic Agents
  • Limonins
  • humilinolide H
  • mexicanolide
  • Metformin
  • Glyburide