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-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 (50-130â¯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.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Limonins/pharmacology , Meliaceae/chemistry , Animals , Cell Line , Dose-Response Relationship, Drug , Drug Synergism , Glucose Tolerance Test , Glyburide/pharmacology , Hypoglycemic Agents/administration & dosage , Liver/drug effects , Liver/metabolism , Male , Metformin/pharmacology , Mexico , Mice, Inbred ICR , Pancreas/drug effects , Pancreas/metabolism , Plants, Medicinal/chemistryABSTRACT
Non-enzymatic glycation and the accumulation of advanced glycation end products (AGEs) are associated with various disease states, including complications of diabetes and aging. Secondary metabolites from several plant species are known to inhibit non-enzymatic glycation and the formation of AGEs, including flavonoids found in the style (silk) of Zea mays (maize). Thirteen modern maize inbreds and one land race were tested for in vitro inhibition of non-enzymatic glycation of bovine serum albumin. Many of the tested extracts exhibited inhibitory activity, in particular the newest inbreds, which were bred for resistance to gibberella ear rot (Fusarium graminearum) and common smut (Ustilago maydis). The most active maize genotype (CO441), displaying an IC50 of 9.5 microg/mL, was more effective than aminoguanidine, a known inhibitor of glycation. Zapalote chico, a land race with high maysin content, showed only moderate inhibitory activity compared with the modern maize genotypes. Antiglycation activity was highly correlated with the total phenolic content of silk extracts and mildly correlated with resistance to certain fungal infections. The results identify modern resistant and high phenolic maize inbreds as promising candidates for the development of natural AGE inhibitors for the prevention and treatment of diabetic complications and the degenerative effects of aging.