Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation (original) (raw)
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Drug Discoveries & Therapeutics, 2019
Chronic uncontrolled hyperglycaemia leads to increased oxidative stress and lipid peroxidation resulting in vascular complications and accelerates the progression of diabetic atherosclerosis. Though varieties of modern drugs used in the treatment of diabetes, the complications of diabetes are increasing. Naringenin (NG), has been reported to have potent antioxidant and anti-atherosclerotic properties. However, the effects of NG as vasculoprotective agent in prolonged hyperglycaemia are not well documented. Thus, this study was aimed to determine the effect of NG against vascular changes after prolonged hyperglycaemia in a diabetic rat model. Thirty adult male Sprague-Dawley rats were induced with fructose and streptozotocin to develop the diabetic rat model. After 4 weeks, the rats were randomly divided into 5 groups each group consisting of 6 animals: control, control treated with NG, non-treated diabetes mellitus (DM), DM treated with NG and metformin-treated DM. The treatment with NG (50 mg/kg) and metformin were continued for 5 weeks. The results showed that consumption of NG at 4 weeks post diabetic did not improved blood sugar, blood pressure and serum lipid profile. However, NG did significantly improve oxidative stress parameters in the aortic tissue like malondialdehyde (MDA). Analysis through light microscopy and transmission electron microscope (TEM) reverted the histological changes caused by prolonged hyperglycaemia. The findings thus demonstrated that introduction of NG after prolonged exposure to hyperglycaemia improved the vascular deterioration in diabetic group by decreasing oxidative stress evident by the reduced in the lipid peroxidation activity. Thus, this study showed the potential use of NG as adjunct in managing the diabetic condition during late presentation.
Chemico-Biological Interactions, 2014
Type 2 diabetes Molecular docking a b s t r a c t Obesity and the onset of diabetes are two closely linked medical complications prevalent globally. Postprandial hyperglycemia is one of the earliest abnormalities of glucose homeostasis associated with type 2 diabetes (T2D). Postprandial glucose levels can be regulated through a-glucosidase inhibition. The present study aims to demonstrate the potent inhibitory role of naringenin against a-glucosidase activity. The mode of inhibition of naringenin was examined by measuring enzyme activity in vitro with different concentrations of substrate using Lineweaver-Burk plot analysis. It shows competitive inhibition towards mammalian a-glucosidase thereby competing with a-limit dextrins and oligosaccharide residues for binding in the active site. Similar results have been obtained from the molecular docking analyses, where naringenin shows preferential binding for the active sites in each of the evaluated human intestinal a-glucosidase enzymes. Post-docking intramolecular hydrogen bonding analysis shows water molecule mediated hydrogen bonding for N-terminal maltase glucoamylase and N-terminal sucrase isomaltase. Naringenin's docked pose in the C-terminal maltase glucoamylase active site does not show any particular water mediated interaction similar to the co-crystallized acarbose. Further, our results suggest that naringenin (25 mg/kg) exerts significant inhibition of intestinal a-glucosidase activity in vivo thereby delaying the absorption of carbohydrates in T2D rats, thus resulting in significant lowering of postprandial blood glucose levels. Both in vitro and in vivo results were compared to the commercially available a-glucosidase inhibitor acarbose. Our findings clearly indicate that naringenin dampens postprandial glycemic response and offers a potential complementary approach in the management of T2D.
Evaluation of hypoglycaemic and anti-hyperglycaemic activities of Guduchi Ghana in Swiss albino mice
International Journal of Green Pharmacy, 2013
Background: Diabetes mellitus is a common endocrine disorder, characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action or both. Ayurvedic herbs are relatively low cost, more suitable and have negligible side-effects than synthetic oral anti-hyperglycaemic agents. Guduchi is reported as highly potent anti-diabetic herb in Ayurveda and Guduchi Ghanavati is popularly known by the Ayurvedic fraternity for its therapeutic properties on Madhumeha represented as diabetes mellitus. Aim: The aim of this study is to evaluate hypoglycaemic and anti-hyperglycaemic activities of Guduchi Ghana (GG) in Swiss albino mice. Materials and Methods: Hypoglycaemic and anti-hyperglycaemic potential of GG was evaluated in normal mice using both 18 h fasted mice model and oral glucose tolerance test. GG was suspended in distilled water and administered to animals at the dose of 130 mg/kg. Statistical Analysis: The results were statistically interpreted using Student's 't'-test for paired and unpaired data to assess the statistical significance and the significant level was set at P < 0.05. Results: GG showed mild reduction in blood sugar level (BSL) at all the time intervals in normoglycaemic mice. In anti-hyperglycaemic activity, glibenclamide at a dose of 0.65 mg/kg studied as the reference standard to compare the potency of test drug. Administration of GG prior to glucose over load resulted significant attenuation in BSL at 60 min, 90 min and 120 min in comparison to glucose control group. Conclusions: GG has mild hypoglycaemic and significant anti-hyperglycaemic activity and can be used in the treatment of diabetes mellitus as well as a supportive drug without fear of producing hypoglycaemia.
International Journal of Pharmacy and Pharmaceutical Sciences, 2015
The aim of the study was to investigate the in vitro and ex vivo (acute and sub-chronic doses) effect of Phyllanthus niruri methanol extract (PNME) on the microsomal UDP-glucuronyltransferase (UGT) enzyme activity in streptozotocin (STZ)-induced diabetic young female Sprague Dawley (SD) rats. Methods: Young female SD rats were induced type I diabetes mellitus using STZ (60 mg/kg i. v.). The in vitro study was performed on a microsomal fraction of diabetic rat livers using PNME in doses of (0.01 µg, 1 µg and 10 µg)/ml. While ex vivo studies were performed on the microsomal fraction of diabetic rats using PNME in doses of 500, 1000, 2000 and 5000 mg/kg p. o. for acute ex vivo study (one-day treatment) and 100, 500 and 2000 mg/kg/day p. o. for sub-chronic one (daily dose for two weeks). p-nitrophenol (p-NP), was used as a marker substrate for UGT enzyme activity and analyzed using the spectrophotometer to determine UGT enzyme activity. Results: The in vitro result showed that, there is no significant effect of the three concentrations of PNME versus control on UGT activity in the microsomal fraction of diabetic young female SD rat livers, while for ex vivo study, the result showed that UGT activity in the microsomal fraction of diabetic young female SD rats significantly and dose-independently increased at doses 1000, 2000 and 5000 mg/kg p. o in acute study (all p<0.05 vs control). However, no significant effect of PNME has been seen in the three doses used in the sub-chronic study. Conclusion: The three different concentrations of PNME have no significant effect as compared to control on UGT activity in the in vitro study. However, ex vivo study showed significant and dose-independent increased in UGT activity at doses 1000, 2000, and 5000 mg/kg p. o in acute study (all P<0.01 vs control), but no significant effect on sub-chronic study.
Saudi medical journal, 2009
To determine on protective role of NG-nitro-L-arginine methyl ester L-NAME, and insulin on the liver in streptozotocin STZ induced diabetic rats. This study was performed in the Department of Biochemistry, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey in 2007. Forty male Wistar albino rats were divided into 5 groups. These were untreated, diabetic control, STZ+insulin, STZ+L-NAME and STZ+insulin+L-NAME induced groups. The STZ was intraperitonally injected into 3 groups, and includes insulin, L-NAME, and their joint administrations as protective agents. The blood glucose and nitric oxide (NO) levels were determined. The tissue samples were obtained at the end of the fourth week. The liver tissue distortions were evaluated using hematoxylin and eosin staining. The serum glucose level was significantly higher in diabetic control (p=0.000), than the untreated group. Nitric oxide level was significantly lower in STZ+L-NAME (p=0.000) than the untreated group. The ...
The Journal of nutrition, 2004
Dietary antioxidant compounds such as bioflavonoids may offer some protection against the early stage of diabetes mellitus and the development of complications. We investigated the effect of citrus bioflavonoids on blood glucose level, hepatic glucose-regulating enzymes activities, hepatic glycogen concentration, and plasma insulin levels, and assessed the relations between plasma leptin and body weight, blood glucose, and plasma insulin. Male C57BL/KsJ-db/db mice (db/db mice, 5 wk old), an animal model for type 2 diabetes, were fed a nonpurified diet for 2 wk and then were fed an AIN-76 control diet or the control diet supplemented with hesperidin (0.2 g/kg diet) or naringin (0.2 g/kg diet). Hesperidin and naringin supplementation significantly reduced blood glucose compared with the control group. Hepatic glucokinase activity and glycogen concentration were both significantly elevated in the hesperidin- and the naringin-supplemented groups compared with the control group. Naringin...
Pharmacological Research, 1999
. Both control and hereditarily diabetic Goto᎐Kakizaki rats were administered twice daily for 7 days with an oral solution of carboxymethylcellulose containing, when required, Ž y1 . Ž y 1 . glibenclamide 1.0 g g body wt. or nateglinide 50.0 g g body wt. . The increase in plasma D-glucose concentration and decrease in insulinogenic index caused by the bleeding and handling of the rats prior to sacrifice was more pronounced in the hyperglycaemic and hyperinsulinemic diabetic rats than in the control animals. Eighteen hours after the last oral loading, a sizeable fall in plasma D-glucose concentration and increase in plasma insulin concentration was only observed in the glibenclamide-treated control rats, indicating a more prolonged biological effect of the hypoglycaemic sulphonylurea, as compared to the meglitinide analog. This coincided with the fact that the insulin content of the islets, their secretory response to a high concentration of D-glucose and their basal biosynthetic activity were more severely affected in glibenclamide than nateglinide-treated animals, especially in the control rats. It is proposed, therefore, that the meglitinide analog, considered as a new insulinotropic tool for the treatment of non-insulin-dependent diabetic subjects, may offer the far-from-negligible advantage of minimising the risk of a sustained decrease in both islet insulin content and glycaemia.
In enterocytes, protein RS1 (RSC1A1) mediates an increase of glucose absorption after ingestion of glucose-rich food via upregulation of Na +-D-glucose cotransporter SGLT1 in the brush-border membrane (BBM). Whereas RS1 decelerates the exocytotic pathway of vesicles containing SGLT1 at low glucose levels between meals, RS1-mediated deceleration is relieved after ingestion of glucose-rich food. Regulation of SGLT1 is mediated by RS1 domain RS1-Reg, in which Gln-Ser-Pro (QSP) is effective. In contrast to QSP and RS1-Reg, Gln-Glu-Pro (QEP) and RS1-Reg with a serine to glutamate exchange in the QSP motif downregulate the abundance of SGLT1 in the BBM at high intracellular glucose concentrations by about 50%. We investigated whether oral application of QEP improves diabetes in db/db mice and affects the induction of diabetes in New Zealand obese (NZO) mice under glucolipotoxic conditions. After 6-day administration of drinking water containing 5 mM QEP to db/db mice, fasting glucose was decreased, increase of blood glucose in the oral glucose tolerance test was blunted, and insulin sensitivity was increased. When QEP was added for several days to a high fat/high carbohydrate diet that induced diabetes in NZO mice, the increase of random plasma glucose was prevented, accompanied by lower plasma insulin levels. QEP is considered a lead compound for development of new antidiabetic drugs with more rapid cellular uptake. In contrast to SGLT1 inhibitors, QEP-based drugs may be applied in combination with insulin for the treatment of type 1 and type 2 diabetes, decreasing the required insulin amount, and thereby may reduce the risk of hypoglycemia.
Antihyperglycaemic activity of 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal in diabetic mice
Journal of Cellular and Molecular Medicine, 2012
We have recently generated lipophilic D-xylose derivatives that increase the rate of glucose uptake in cultured skeletal muscle cells in an AMP-activated protein kinase (AMPK)-dependent manner. The derivative 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal (EH-36) stimulated the rate of glucose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of cultured myotubes. The present study aimed at investigating potential antihyperglycaemic effects of EH-36 in animal models of diabetes. Two animal models were treated subcutaneously with EH-36: streptozotocin-induced diabetes in C57BL/6 mice (a model of insulin-deficient type 1 diabetes), and spontaneously diabetic KKAy mice (Kuo Kondo rats carrying the A y yellow obese gene; insulin-resistant type 2 diabetes). The in vivo biodistribution of glucose in control and treated mice was followed with the glucose analogue 2-deoxy-2-[ 18 F]-D-glucose; the rate of glucose uptake in excised soleus muscles was measured with [ 3 H]-2-deoxy-D-glucose. Pharmacokinetic parameters were determined by non-compartmental analysis of the in vivo data. The effective blood EH-36 concentration in treated animals was 2 M. It reduced significantly the blood glucose levels in both types of diabetic mice and also corrected the typical compensatory hyperinsulinaemia of KKAy mice. EH-36 markedly increased glucose transport in vivo into skeletal muscle and heart, but not to adipose tissue. This stimulatory effect was mediated by Thr 172 -phosphorylation in AMPK. Biochemical tests in treated animals and acute toxicological examinations showed that EH-36 was well tolerated and not toxic to the mice. These findings indicate that EH-36 is a promising prototype molecule for the development of novel antidiabetic drugs. Fig. 8 EH-36 reduces body weight gain in male C57BL/6 mice. Nondiabetic male (squares) and female (circles) C57BL/6 mice were treated with EH-36 (50 mg/kg body weight; black symbols) or the vehicle (3.3 ml sesame oil/kg body weight; open symbols) once a day by s.c. injection for 14 days. A recovery period lasted for additional 2 weeks. Mean Ϯ S.E.M., n ϭ 5, *P Ͻ 0.05 in comparison with the oil-treated male mice.