Multi-target antidiabetic mechanisms of mexicanolides from Swietenia humilis
Por:
Ovalle-Magallanes, Berenice, Navarrete, Andres, Haddad, Pierre S., Tovar, Armando R., Noriega, Lilia G., Tovar-Palacio, Claudia, Mata, Rachel
Publicada:
1 ene 2019
Resumen:
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-ß-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 K ATP SUR blockade, insulin secretion in INSE1 cells, and modulation of 5-HT 2 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 (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. © 2019
Filiaciones:
Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México. Circuito Exterior, Ciudad Universitaria. Delegación Coyoacán, Ciudad de México, 04510, Mexico
Department of Pharmacology and Physiology, Université de Montréal, Montréal, Québec, Canada
Instituto Nacional Ciencias Médicas y Nutrición “Salvador Zubirán”, Departamento de Fisiología de la Nutrición, Ciudad de México, Mexico
Instituto Nacional Ciencias Médicas y Nutrición “Salvador Zubirán”, Departamento de Nefrología y Metabolismo Mineral, Ciudad de México, Mexico
Univ Nacl Autonoma Mexico, Dept Farm, Fac Quim, Ciudad De Mexico 04510, Mexico
Univ Montreal, Dept Pharmacol & Physiol, Montreal, PQ, Canada
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Fisiol Nutr, Ciudad De Mexico, Mexico
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nefrol & Metab Mineral, Ciudad De Mexico, Mexico
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