Mechanistic insights into the effects of quercetin and/or GLP-1 analogue liraglutide on high-fat diet/streptozotocin-induced type 2 diabetes in rats

Abstract

Background: The development of complementary treatment strategies that focuses on achieving a balance between adaptive and apoptotic unfolded protein response (UPR), enhancing endoplasmic reticulum (ER) homeostasis, and thus preserving β cell mass and function is particularly warranted.

Aim: This study was designed to investigate the effectiveness of the combined treatment by Quercetin (QUE) and Liraglutide (LIRA) in modulating hyperglycemia, insulin-insensitivity, UPR/ER stress markers, apoptosis, oxidative stress and inflammation using a high-fat diet/streptozotocin -induced type 2 diabetic rat model.

Methods: Sixty male albino rats were allocated into five equal groups: normal control, diabetic control, LIRA treated diabetic; QUE treated diabetic and combined treatment diabetic groups. Fasting glucose, insulin, CHOP, macrophage inflammatory protein -1 α (MIP-1α) and Bax, Bcl₂ levels were estimated by ELISA; mRNA expression levels of the spliced X-box binding protein 1 (XBP1) were estimated using quantitative real-time RT-PCR, while MDA, advanced oxidation protein products, reduced glutathione levels and protein disulfide isomerase (PDI) activity were evaluated spectrophotometrically. Pancreatic tissues were also subjected to histopathological examination.

Results: The combined treatment with both LIRA and QUE causes significant improvements in all the studied parameters; including XBP1 splicing, CHOP, MIP-1α, Bax/Bcl₂ ratio, PDI activity, as well as oxidative stress markers as compared to either treatment alone. It also attenuated pancreatic histopathological damage.

In conclusion: Our study nominates this combination to be used in T2DM to achieve adequate glycaemic control and to preserve optimal β cell function.

Keywords: Apoptosis; Diabetes mellitus; Liraglutide; Protein disulfide isomerase; Quercetin; Spliced XBP1.