Abstract
In this study, the effect and mechanism of a series of ursolic acid (UA) derivatives on glucose uptake were investigated in a Caco-2 cells model. Their effect on hyperglycemia, hyperlipidemia and oxidative stress were also demonstrated in streptozocin (STZ)-induced diabetic rats. 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-glucose (2-NBDG) was used as a fluorescein in Caco-2 cells model to screen UA derivatives by glucose uptake and expression of glucose transporter protein (SGLT-1, GLUT-2). Moreover, STZ-induced diabetic rats were administered with these derivatives for 4 weeks of treatment. The fasting blood glucose (FBG), insulin levels, biochemical parameters, lipid levels, and oxidative stress markers were finally evaluated. The results of this study indicated that compounds 10 and 11 significantly inhibited 2-NBDG uptake under both Na+-dependent and Na+-independent conditions by decreasing SGLT-1 and GLUT-2 expression in the Caco-2 cells model. Further in vivo studies revealed that compound 10 significantly reduced hyperglycemia by increasing levels of serum insulin, total protein, and albumin, while the fasting blood glucose, body weight and food intake were restored much closer to those of normal rats. Compounds 10 and 11 showed hypolipidemic activity by decreasing the total amounts of cholesterol (TC) and triglycerides (TG). Furthermore, compound 10 showed antioxidant potential which was confirmed by elevation of glutathione (GSH) and superoxide dismutase (SOD) and reduction of malondialdehyde (MDA) levels in the liver and kidney of diabetic rats. It was concluded that compound 10 caused an apparent inhibition of intestinal glucose uptake in Caco-2 cells and hypoglycemia, hypolipidemia and augmented oxidative stress in STZ-induced diabetic rats. Thus, compound 10 could be developed as a potentially complementary therapeutic or prophylactic agent for diabetics mellitus and its complications.
Highlights
There are more than 347 million people worldwide that have diabetes, making diabetes mellitus (DM) one of the most serious chronic diseases in the world
The results indicate that the viability of Caco-2 cells was greater than 90%, with the exception of cells treated with compound 6, for which the cell viability was 86.12%, it is not suitable for in vivo studies
To gain insight into the effects of ursolic acid (UA) and its derivatives on glucose uptake, we studied the most important glucose transporter proteins as the major transporters are responsible for the absorption of glucose by Caco-2 cells
Summary
There are more than 347 million people worldwide that have diabetes, making diabetes mellitus (DM) one of the most serious chronic diseases in the world. Long-term diabetic patients who are treated ineffectively suffer from complications such as nephropathy, retinopathy, heart disease, peripheral neuropathy and so on [4]. The risks of acquiring cardiovascular disease, stroke, and cancer are higher in DM patients [5,6,7]. The overall risk of dying among people with DM linked complications is at least double the risk of their peers without DM [8]. Hypoglycemic agents, including insulin and other modern oral drugs, can control the blood glucose levels, but they may have limited efficacy and many other undesirable effects. It is evident that there is an urgent need for more effective therapeutic agents
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