Glycemic control and pancreatic beta cells protective effect of a lanosteryl triterpene from Protorhus longifolia in hyperlipidemic and STZ-induced diabetic rats
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Date
2018
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University of Zululand
Abstract
Prevalence of diabetes mellitus (DM), a chronic metabolic disorder of carbohydrates and lipids that is characterized by persistent hyperglycemia, is rapidly reaching epidemic levels. Hyperglycemia-induced oxidative stress and accelerated inflammatory response may trigger various signaling pathways which further aggravates insult to insulin producing beta cells of the pancreas, thereby worsening the diabetic state. Current treatment regimen for DM comprises self-care and anti-diabetic drugs such as biguanides (metformin), thiazolidinediones and sulfonylureas. Metformin is currently the most commonly used antidiabetic drug. However, due to the lack of compliance to self-care recommendations and some undesirable side effects of metformin, there is an increasing need for alternative therapy. Drugs that cannot only decrease postprandial hyperglycemia, but also maintain pancreatic beta cells integrity for optimal function, could be vital in the management of DM. This study investigated the glycemic control and pancreatic beta cell protective effect of a lanosteryl triterpene (RA-3) from Protorhus longifolia stem bark in hyperlipidemic and streptozotocin-induced diabetic rats. RA-3 was isolated from the chloroform extract of P. longifolia using chromatographic techniques and its chemical structure was confirmed based on spectral data analysis. The glycemic control and pancreatic beta cells protective effect of RA-3 were evaluated in the high fat diet (HFD) and streptozotocin (STZ) induced diabetes in rats. The rats were divided into two main groups; rats fed on normal diet and those fed on HFD for 28 days. The animals were then injected with STZ to induce diabetes and RA-3 (100 mg/kg) was orally administered to the diabetic rats daily for 28 days. At the end of the experimental period, animals were fasted overnight and oral glucose tolerance test was performed. The animals were then euthanized and blood, muscle, liver and pancreatic tissues were collected for analysis of biochemical parameters, protein expression and histopathology. The effect of RA-3 on the pancreatic beta cell structure and function in HFD and STZ-induced diabetes in animals has been reported in Chapter Three. A significant decrease in serum levels of C-peptide and antioxidants (catalase-CAT, superoxide dismutase-SOD), accompanied by reduced glutathione (GSH), were observed in the untreated diabetic controls. Increases in serum levels of malondialdehyde (MDA), interleukin-6 (IL-v 6), fasting blood glucose and total cholesterol levels, as well as damaged beta cell structure, were also noted. However, all these parameters were significantly reversed in the diabetic groups treated with RA-3. Furthermore, the molecular mechanism through which the lanosteryl triterpene improves peripheral insulin signalling in skeletal muscle of STZ-induced diabetic animals was investigated. Treatment of the diabetic animals with the RA-3 showed marked reduction in fasting plasma glucose (67%), serum MDA and IL-6 levels, which were concomitant with the increased serum levels of antioxidants (SOD, CAT) and GSH, in comparison to the untreated diabetic group animals. An improved pancreatic beta cell structure along with increased serum C-peptide levels were also observed in the RA-3 treated diabetic animals. This was evidenced by the observed minimal histopathological changes when compared to the untreated diabetic groups in which major cell damage was evident. A decrease in IRS-1Ser307 expression along with increases in p-Akt, p-GSK-3β and GLUT 4 expression were observed in the RA-3 treated group vs untreated diabetic controls. Finally, the molecular basis of RA-3 in hyperlipidemic and STZ-induced type 2 diabetes in animals was studied. Diabetic animals treated with RA-3 effectively enhanced insulin signaling which was observed by a decrease in expression of IRS-1ser307 and higher expression levels of p-Akt, p-GSK-3β GLUT 2 and GLUT 4 in comparison to the diabetic control group. The findings obtained from the current study on RA-3 treatment were similar and highly comparable to those of the metformin treated groups. It is apparent that lanosteryl triterpene, RA-3, improved glycemic control and possesses pancreatic beta cells protective properties. It is concluded that the molecular mechanism by which RA-3 improves glycemic control is based on its enhancement of the insulin signaling pathway, leading to increased recruitment of glucose transporters and thus increased cellular glucose uptake.
Description
A dissertation submitted to the Faculty of Science and Agriculture in fulfillment of the requirements for the Degree of Master Of Science in Biochemistry in the Department of Biochemistry and Microbiology at the University Of Zululand, 2018
Keywords
glycemic control --pancras --lanosteryl triterpene --protorhus longifolia --hyperlipidemic --STZ-induced --rats