Effect of 7-Hydroxy-2-(4-Hydroxy-3-Methoxy-Phenyl)-Chroman-4-One (Swietenia Macrophylla King Seed) on Retinol Binding Protein-4 and Phosphoenolpyruvate Carboxykinase Gene Expression in Type 2 Diabetic Rats

Abstract

Background and Aims: Diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to a defect of insulin secretion, insulin action, or both. There are increasing evidence that active compounds of medicinal plants may be used to treat diabetes. The aim of this study is to investigate the effect of a 7-hydroxy-2-(4-hydroxy-3methoxy-phenyl)-chroman-4-one flavonoid compound of the Swietenia macrophylla King seed on homeostatic model assessment of insulin resistance (HOMA-IR), phosphoenolpyruvate carboxykinase (PEPCK) and retinol binding protein-4 (RBP4) gene expression in diabetic rats. Materials and Method: Thirty Wistar rats were used with 5 in each group as follows: 1) normal rats; 2) diabetic rats; 3) diabetic rats with metformin; 4), 5) and 6) diabetic rats with a 7-hydroxy-2-(4-hydroxy-3-methoxy-phenly)-chroman-4one 10, 30 and 90 mg/200 g body weight (BW) respectively. Blood glucose and insulin levels were analyzed before and after treatment. At the end of the study, the liver tissue was removed for quantitative PCR (qPCR) analyses. Results: Blood glucose levels decreased significantly (p<0.05) in diabetic rats with metformin and three different dosages of 7-hydroxy-2-(4-hydroxy-3-methoxy-phenly)-chroman-4-one. Insulin levels increased significantly (p<0.05) in diabetic rats with metformin and diabetic rats with 10 mg/200 g BW of 7-hydroxy-2-(4-hydroxy-3-methoxy-phenly)-chroman-4-one. HOMA-IR value decreased significantly (p<0.05) in diabetic rats with metformin and three different dosages of 7-hydroxy-2-(4-hydroxy-3-methoxy-phenly)-chroman-4-one. There was a significant decrease of PEPCK gene expression in the group with 90 mg/200 g BW of 7hydroxy-2-(4-hydroxy-3-methoxy-phenly)-chroman-4-one. RBP4 gene expression showed a decline, but the difference between groups was not statistically different. Conclusion: These results demonstrated that 7-hydroxy-2-(4-hydroxy-3-methoxy-phenly)-chroman-4one increased insulin and decreased blood glucose level, HOMA-IR value and PEPCK gene expression.

The Molecular Mechanisms of Hypoglycemic Properties and Safety Profiles of Swietenia Macrophylla Seeds Extract: A Review

“…Compounds acting as PPARγ ligands are an interesting focus in the development In vitro 6-O-acetyl swietenolide, diacetyl swietenolide and swietenine from S. macrophylla seeds induced GLUT4 membrane translocation in C2C12 muscle cells which led to glucose utilization [26] The SMEAF improved the cell viability and showed protection of rat's primary neuronal culture cell against oxidative stress induced by tert-butyl hydroperoxide [31] In Vivo Methanol extract of S. macrophylla seeds at dose 300 mg/kg caused a significant decreasing (59, 69%) of blood glucose in STZ-induced diabetic rats model. It also reduces cholesterol and triglyceride as well as increases glycogen contents in liver [15] The alcoholic seeds extract of S. macrophylla leads to the decreasing of blood glucose, improvement of body weight, normalize the serum insulin and liver glycogen content in STZdiabetic rats model [32] The treatment of S. macrophylla seeds petroleum ether extract for 14 days resulted in a significant enhancement of abdominal glucose utilization which leads to the reduction of blood glucose on rats after intraperitoneal glucose tolerance test [33] In vivo study on diabetic rat model documented that S. macrophylla seed saponins isolate has the strongest effect in lowering blood glucose levels [34] Saponins isolated from S. macrophylla seeds extract was able to reduce blood glucose significantly while increasing pancreatic insulin expression in STZ-induced diabetic rat model [29] Saponins isolated from S. macrophylla seeds extract has also been proven to be able to decrease HOMA-IR significantly which leads to insulin resistance improvement in a T2D rat model [35] Saponins isolated from S. macrophylla seeds extract had glucose-lowering and antioxidant effects through reducing malondialdehyde in STZ-nicotinamide induced diabetic rats model [36] 7-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-chroman-4one, flavonoids isolated from S. macrophylla seeds extract reduced blood glucose by reducing HOMA-IR level and phosphoenolpyruvate carboxykinase gene expression in a T2D rat model [37] The same flavonoids have the abilities to improve pancreatic β-cell function through inhibiting the development of oxidized low-density lipoprotein and increasing the expression of glucagon-like peptide-1 [38] of T2D treatment because it suggests the ability to improve insulin sensitivity. The PPARγ agonists increase adipocyte differentiation and promote FFA uptake and storage, hence decreasing FFA plasma level.…”

“…Oxidative stress is considered to be the major determining factor for the development of diabetes complications, including retinopathy, neuropathy, stroke, and coronary heart disease. It is strongly related to uncontrolled hyperglycemia, which causes the massive exertion of ROS [37], [64], [65], [66]. ROS is a type of free radical associated with oxidative stress, including various chemical compounds with reactive characteristic and are able to act as acceptor or donor electrons (e-) for many biological molecules [65], [67].…”

“…An in vivo study by Prasetyastuti et al (2016) showed the hypoglycemic properties of 7-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-chroman-4-one, a flavonoid substance isolated from S. macrophylla seeds extract. It reduces blood glucose levels by reducing HOMA-IR and phosphoenolpyruvate carboxykinase (PEPCK) gene expression in T2D rat's model [37]. The PEPCK is an enzyme that crucial in triggering the gluconeogenesis process [72].…”

“…The failure of GLUT4 membrane translocation due to the reducing response to insulin stimulation leads to the development of IR and T2D [134]. Moreover, 7-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-chroman-4-one, flavonoids from S. macrophylla seeds extract was able to modulate the downstream of PI3K/Akt pathway, demonstrated by its ability to downregulate PEPCK expression in a T2D rat model [37].…”

“…Apart from limonoids and flavonoids, saponins are also considered to play a major role in mediating the hypoglycemic effect of S. macrophylla. The saponins 1,4-bis-(3,4,5-trimethoxy-phenyl)-tetrahydrofuro(3,4-c)furan from S. macrophylla seeds, possesses hypoglycemic effects related to antioxidative and anti-inflammatory mechanisms through their role in modulating MDA and TNFα level [37], [118]. Supporting this finding, saponins from Momordica charantia showed potential antidiabetic effects in a T2D rat model induced by a high fat diet-STZ through suppressing stress oxidative pathways (inducing the activities of SOD and CAT enzymes while decreasing MDA levels in the liver and pancreas), modulating insulin signaling pathways (promoting the tyrosine phosphorylation of IRS-1 and Akt Ser-473 while reducing the serine phosphorylation of IRS-1), and attenuating metabolic markers (reducing non-esterified fatty acid, triglyceride, and total cholesterol) [145].…”