Liraglutide attenuates atherosclerosis via inhibiting ER-induced macrophage derived microvesicles production in T2DM rats

Abstract

BackgroundWe investigated the effects of liraglutide on the formation and progression of atherosclerosis in type 2 diabetes mellitus (T2DM) rats.MethodsSprague–Dawley rats were divided into control group, diabetes group and liraglutide treated group. The T2DM rats model with atherosclerosis were induced by high fat diet followed small dosage streptozotocin injection. Body weight and blood glucose levels were monitored once a week for 3 months and then the rats were sacrificed.Peripheral blood and aorta tissues were collected for further biochemical and pathological estimation respectively. Moreover, immunohistochemistry staining was used to detect the infiltration of macrophages and cell apoptosis in tissue samples. The amount of microvesicles of atherosclerotic plaques was determined by ELISA. Western blot was applied to detect the protein expressions of CHOP, GRP78 and caspase-3 in tissue samples. The mRNA expressions of SREBP-1c and FAS were detected by RT-PCR.ResultsThe rat model of diabetic atherosclerosis was established successfully. Compared with the control group, glucose, triglycerides, total cholesterol, AST, ALT, BUN, fasting insulin and homeostatic model assessment insulin resistance levels in peripheral blood were significantly increased in the diabetes group. While, these indicators in the liraglutide group were significantly lower than that in the diabetes group. Moreover, the atherosclerotic plaques were observed in the rats of diabetes group but not remarkable in the liraglutide group. The ratio between aorta intima and media thickness was significantly greater in the diabetes group than that in the liraglutide group. Compared with the diabetes group, the infiltration and apoptosis of macrophages were milder in the liraglutide group. The expressions of CD68, caspase-3, CHOP and GRP78 in aorta tissue samples were significantly downregulated in the liraglutide group than that in the diabetes group. Furthermore, the microvesicles of aorta tissues in the liraglutide group were significantly decreased than that in the diabetes group. The mRNA expressions of SREBP-1c and FAS were lower in the liraglutide group than that in the diabetes group.ConclusionLiraglutide attenuates diabetic atherosclerosis by inhibition of ER stress and subsequent macrophage apoptosis and microvesicles production in T2DM rats.

Liraglutide ameliorates beta-cell function, alleviates oxidative stress and inhibits low grade inflammation in young patients with new-onset type 2 diabetes

“…Previous reports have shown that beta-cell volume decreased by 63% in obese T2DM patients due to increasing threefold beta-cell apoptosis [16], which suggested that improvement of beta-cell dysfunction may be an important therapeutic strategy for the treatment of T2DM. GLP-1 is an incretin hormone secreted by intestinal epithelial L cells that promotes glucose-dependent insulin secretion, decreases glucagon secretion, stimulates beta-cell proliferation, suppresses apoptosis, and restores the function of islet beta-cells [17–19]. It is widely recognized that T2DM in East Asians is characterized primarily by beta-cell dysfunction, which is evident immediately after ingestion of glucose or meal, and less adiposity compared to the disease in Caucasians [20].…”

A GLP-1 Analog Liraglutide Reduces Intimal Hyperplasia After Coronary Stent Implantation via Regulation of Glycemic Variability and NLRP3 Inflammasome/IL-10 Signaling in Diabetic Swine

“…Metabolic syndrome prevalence was significantly reduced (Rizzo et al, 2016). Dr. Li found that liraglutide attenuated the atherosclerotic lesion and plaque progression in aortic tissues induced by high fat diets followed by low-dose streptozotocin injection in type 2 DM rats (Li et al, 2017). Rizzo et al proposed that liraglutide exerted favorable cardiovascular effects through its direct antiatherosclerotic action, as well as its ability to prevent plaque formation and progression beyond glycemic control (Rizzo et al, 2018).…”

Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

“…As summarized in Table 1 , studies in rodents and rabbits have shown beneficial actions of GLP1As in atherosclerosis, vascular injury, and cardiac function. Liraglutide treatment in diabetic rats led to diminished atherosclerotic lesion formation and intima-media thickening through a decrease of macrophage secretion of ER-stress induced microvesicles [ 51 ]. Similarly, the expression of GLP1 by adenovirus-mediated delivery in diabetic rats reduced intima-media thickening, VSMC and monocyte migration, and inflammatory processes [ 52 ].…”