Hesperidin improves insulin resistance via down-regulation of inflammatory responses: Biochemical analysis and in silico validation

Abstract

Leptin resistance and co-existing insulin resistance is considered as hallmark of dietinduced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.

Effect of Hesperidin on Cardiovascular Disease Risk Factors: The Role of Intestinal Microbiota on Hesperidin Bioavailability

“…Akiyama and collaborators also reported a recovery of adiponectin levels mediated by hesperidin both in T1D and T2D models [36,44]. In addition to the effects observed in diabetic models, improvement of glucose metabolism and insulin resistance were also described by our group and others in other animal models of human diseases that are associated with alterations in glucose metabolism, such as metabolic syndrome (MetS) and obesity [47][48][49][50][51].…”

“…In this sense, there are several studies demonstrating that hesperidin exerts beneficial effects on lipid accumulation and adiposity [71,72,77,78]. In animal models of obesity or MetS, a body-weight-reducing effect has been widely reported in response to hesperidin treatment [47][48][49][50][51], as well as a reduction in adipose tissue weight [25,48,50,51]. In contrast, Mosqueda-Solis et al reported no significant changes in body weight after a daily hesperidin administration (100 mg/kg body weight) for eight weeks in Western-diet-fed rats, although hesperidin treatment resulted in a decreased size of adipocytes [78].…”

Hesperidin alleviates insulin resistance by improving HG-induced oxidative stress and mitochondrial dysfunction by restoring miR-149

“…For instance, hesperidin upregulated the GLUT2, GLUT4, IRS1 and glucokinase levels and downregulated the hepatic fatty acid oxidation and carnitine palmitoyl transferase activity in type-2 diabetes to improve hyperlipidaemia and hyperglycaemia [ 34 , 35 ]. Kanwal et al also reported that hesperidin relieved insulin resistance by inhibiting inflammatory responses [ 36 ]. In this study, our study showed that HG treatment successfully exhibited a low antioxidant activity, and accompanied by mitochondrial dysfunction and insulin resistance in LO2 cells, suggesting that the diabetic model of oxidative stress was successfully established in vitro.…”

Mathematical Models of Meal Amount and Timing Variability With Implementation in the Type-1 Diabetes Patient Decision Simulator

“…In the past 15 years of type 1 diabetes (T1D) research, in-silico clinical trials (ISCTs), performed using simulators relying on mathematical models of glucose-insulin system dynamics, have accelerated the development of new treatments 1 - 4 and drugs, 5 - 7 and have facilitated the design of clinical studies. 8 - 11 ISCTs allow investigators to carry out a vast number of experiments quickly, in order to evaluate, for example, new algorithms in high-risk scenarios, and so offer considerable economic and human resource savings.…”