Multi-target antidiabetic mechanisms of mexicanolides from Swietenia humilis

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.

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.

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.

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 K_ATP 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.

S. humilis mexicanolides interact with pharmacological targets at pancreas (K_ATP 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.