Insulin resistance (IR) is a hallmark of type 2 diabetes mellitus (T2DM). This study aimed to explore the effects of rapamycin, a specific inhibitor of kinase mammalian target of rapamycin (mTOR), on IR in T2DM rats, and to validate whether the underlying mechanism was associated with autophagy. In this study, the model of T2DM rats was established by feeding the animals with a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). Diabetic rats were randomly divided into model of T2DM control group (DM-C, n = 15), metformin group (DM-M, n = 15), rapamycin group (DM-Rapa, n = 15), 3-methyladenine (3-MA) group (DM-3-MA, n = 15), and rapamycin + 3-MA group (DM-Rapa-3-MA, n = 15). Rats in different treatment groups were given by corresponding therapy from gastric tube. Meanwhile, normal control group was established (n = 10). As expected, HFD- and STZ- induced T2DM rats exhibited significantly impaired glucose tolerance, reduced insulin sensitivity, dysglycemia and dyslipidemia, aggravated hepatic steatosis, enhanced hepatic inflammation, elevated p-mTOR, and suppressed hepatic autophagy. Importantly, rapamycin and metformin significantly ameliorated IR, relieved disorders of glucose and lipid metabolism, reduced inflammatory level, inhibited mTOR, and promoted autophagy. Importantly, the autophagy inhibitor 3-MA significantly reversed the effects exerted by rapamycin. Collectively, our study suggests that rapamycin improved IR and hepatic steatosis in T2DM rats via activation of autophagy.
Background: Kawasaki disease (KD) is a self-limiting illness with acute systematic vascular inflammation. It causes pathological changes in mostly medium and small-sized arteries, especially the arteria coronaria, which adds the risk of developing coronary heart disease in adults. Materials and methods: We detected the miR-223-3p expression in 30 KD patients combined with 12 normal controls using miRNA microarrays and RT-PCR. A KD mouse model was constructed using Candida albicans water insoluble substance (CAWS). We also checked the miR-223-3p's expression using qRT-PCR. The Luciferase reporting system was implemented to validate the correlation between miR-223-3p and Interleukin-6 receptor subunit beta (IL-6ST). TNF-α was used to stimulate human coronary artery endothelial cells (HCAECs), and miR-223-3p activator or inhibitor and KD serum were used to treat HCAECs. A Western blotting automatic quantitative analysis protein imprinting system was used to test the expression of signal transducer and the activator of transcription 3 (STAT3), phosphorylated-signal transducer and the activator of transcription 3 (pSTAT3) and NF-κB p65. Results: Clinical trials found that miR-223-3p expressions were markedly different (more than 2-fold) between the acute KD group and the control group. E-selectin and intercellular cell adhesion molecule-1 (ICAM-1) levels were also significantly higher (about 2-fold) in KD especially with coronary artery lesions. MiR-223-3p could alleviate vascular endothelial damage in KD mice, and IL-6 (Interleukin-6), E-selectin and ICAM-1 were simultaneously negative. The values of IL-6, E-selectin, and ICAM-1 mRNA expressions decreased, while the value of IL-6ST was increased between the agonist treated mice and KD mice. The RT-qPCR consequences displayed that miR-223-3p explored the highest expression on the third day in both the KD mice as well as the agonist group. MiR-223-3p can directly combine with IL-6ST 3' untranslatable regions (UTR) and held back the IL-6's expression. Overexpression of miR-223 down regulated IL6ST expression and decreased the expression of p-STAT3 and NF-κB p65, while the miR-223 inhibitor could reverse the above process. Conclusion: MiR-223-3p is an important regulatory factor of vascular endothelial damage in KD and could possibly become a potential target of KD treatment in the future.
The purposes of this study were to evaluate the expression of retinol-binding protein 4 (RBP4) in diabetic rats with atherosclerosis and to investigate the role of vitamin D intervention. Male Wistar rats were randomly divided into 4 groups, including the control group (NC), the diabetic rats (DM1), the untreated diabetic atherosclerosis rats (DM2), and the vitamin D-treated diabetic atherosclerosis rats (DM3). The levels of serum and adipose RBP4, fasting insulin (FINS), fasting plasma glucose (FPG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), 25-hydroxyvitamin D [25(OH)D], C-reactive protein (CRP), and systolic blood pressure (SBP) were measured. Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment β-cell function index (HOMA-β), and atherogenic indexes (AI) were calculated. Compared with group NC, the levels of RBP4, TG, LDL-c, FPG, FINS, CRP, AI1, AI2, SBP, and HOMA-IR increased, while the levels of HDL-c, 25(OH)D, and HOMA-β decreased in groups DM1 and DM2. After 8 weeks of vitamin D supplementation in group DM3, the levels of 25(OH)D and HOMA-β increased and the levels of LDL-c, TC, HOMA-IR, FINS, CRP, RBP4, AI1, AI2, and SBP decreased significantly when compared with group DM2 (P < 0.05); Pearson analysis showed that serum RBP4 was positively correlated with TG, FINS, HOMA-IR, SBP, CRP, and AI and negatively correlated with 25(OH)D. In addition, multivariable logistic regression analysis showed that serum RBP4, SBP, and HDL-c were predictors for the presence of diabetic atherosclerosis. These findings suggested that RBP4 could involve in the improvement of diabetic atherosclerosis; vitamin D had the ability to decrease the level of RBP4 and eventually played an important role in preventing atherosclerosis in diabetes.
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