Dapagliflozin Ameliorates STZ-Induced Cardiac Hypertrophy in Type 2 Diabetic Rats by Inhibiting the Calpain-1 Expression and Nuclear Transfer of NF-κB.

OBJECTIVE: To investigate the effect of dapagliflozin (DAPA) on cardiac hypertrophy induced by type 2 diabetes mellitus (T2DM) and its mechanism. METHODS: SD rats with T2DM were divided into a T2DM group (n = 6) and DAPA group (n = 6). They were, respectively, fed with the same amount of normal saline and 1 mg/kg DAPA. The control group (n = 6) was also fed with normal saline. The hearts were tested by the application of echocardiography and hemodynamics. Subsequently, fasting blood glucose (FBG), serum total cholesterol (TC), and triglyceride (TG) as well as interleukin- (IL-) 10, IL-6, and tumor necrosis factor (TNF)-α in serum were tested. H&E and Masson staining was performed to observe the degree of cardiac tissue lesions, and expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), calpain-1, p-IκBα, and p65 in myocardial tissue was tested by qRT-PCR and Western blot. RESULTS: Compared with the control group, rats in the T2DM group exhibited significant diabetic symptoms: FBG was significantly elevated, and the levels of TC, TG, IL-6, and TNF-α were significantly increased, while the levels of IL-10 and the calpain activity were evidently decreased. However, DAPA treatment could improve the above changes. At the same time, the damage and fibrosis of the heart tissue in the DAPA group were markedly improved. Additionally, the mRNA expression of ANP and BNP in myocardial tissue of the DAPA group was markedly increased. And DAPA could inhibit the expression of p-IκBα/IκBα in the cytoplasm and p65 in the nucleus as well as the expression of calpain-1 in myocardial tissue. CONCLUSION: DAPA treatment ameliorates the cardiac hypertrophy caused by T2DM by decreasing body blood glucose, while reducing the expression of calpain-1 in cardiomyocytes and inhibiting the nuclear translocation of NF-κB.

The Roles of IL-10 Gene Polymorphisms in Diabetes Mellitus and Their Associated Complications: A Meta-Analysis.

The roles of interleukin-10 (IL-10) gene polymorphisms in diabetes mellitus (DM) have been intensively analyzed earlier, but the results of these studies were conflicting. Hence, we performed this study to better assess the relationship between IL-10 genetic variations and DM. Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess correlations between IL-10 polymorphisms and DM. A total of 32 studies were finally included in our analyses. Significant associations with the risk of DM were detected for the rs1800871, rs1800872, and rs1800896 polymorphisms. As for complications in DM, significant association with the risk of diabetic nephropathy (DN) was detected for the rs1800871 polymorphism. In addition, we also found that the rs1800896 polymorphism was significantly associated with the risk of diabetic retinopathy (DR). Further stratified analyses on the basis of type of disease demonstrated that the positive results were predominantly driven by the T2DM subgroup. When we stratified data based on ethnicity of participants, we found that the rs1800871 polymorphism was significantly correlated with DM in Caucasians, the rs1800872 polymorphism was significantly correlated with DM in Asians, and the rs1800896 polymorphism was significantly correlated with DM in both Caucasians and Asians. Our findings indicate that rs1800871, rs1800872, and rs1800896 polymorphisms may serve as genetic biomarkers of DM. Moreover, the rs1800871 and rs1800896 polymorphisms may also contribute to the development of complications in DM.

Integrative analysis of super enhancer SNPs for type 2 diabetes.

Clinical studies in type 2 diabetes (T2D) primarily focused on the single nucleotide polymorphisms (SNPs) located in protein-coding regions. Recently, the SNPs located in noncoding regions have also been recognized to play an important role in disease susceptibility. The super enhancer is a cluster of transcriptional enhancers located in noncoding regions. It plays a critical role in cell-type specific gene expression. However, the exact mechanism of the super enhancer SNPs for T2D remains unclear. In this study, we integrated genome-wide association studies (GWASs) and T2D cell/tissue-specific histone modification ChIP-seq data to identify T2D-associated SNPs in super enhancer, followed by comprehensive bioinformatics analyses to further explore the functional importance of these SNPs. We identified several interesting T2D super enhancer SNPs. Interesting, most of them were clustered within the same or neighboring super enhancers. A number of SNPs are involved in chromatin interactive regulation and/or potentially influence the binding affinity of transcription factors. Gene Ontology (GO) analysis showed a significant enrichment in several well-known signaling pathways and regulatory process, e.g. WNT signaling pathway, which plays a key role in T2D metabolism. Our results highlighted the potential functional importance of T2D super enhancer SNPs, which may yield novel insights into the pathogenesis of T2D.

[Transforming growth factor-ß1 regulates renal α3 and ß1 integrin expressions in diabetic rats: a new insight into the renoprotective effect of irbesartan].

OBJECTIVE: To explore the association between renal transforming growth factor-ß1 (TGF-ß1) and the expressions of α3 and ß1 integrins and observe the effect of irbesartan on their expressions in diabetic rats. METHODS: Thirty 8-week-old male Wistar rats were randomly divided into normal control group (n=7), diabetic control group (n=14) and irbesartan group (n=9). Rat models of diabetes were established by a single peritoneal injection of streptozotocin (STZ), and 4 weeks later the rats received irbesartan treatment for 8 weeks. Enzyme-linked immunosorbent assay (ELISA) was used to measure the urinary albumin excretion rate, and PAS staining was utilized to observe the renal pathologies. Immunohistochemistry was performed for semi-quantitative determination of podocyte density, and real-time RT-PCR was used to detect the renal TGF-ß1 and α3/ß1 integrin mRNA expressions. RESULTS: In diabetic rats, the expression of renal TGF-ß1 mRNA was significantly increased, while α3 and ß1 integrin mRNA expressions and podocyte density significantly decreased with increased proteinuria. Irbesartan obviously improved such changes. CONCLUSION: In diabetic rats renal TGF-ß1 can regulate α3 and ß1 integrin mRNA expressions to reduce the number of podocytes, and inhibition of this pathway may be one of the mechanisms of the renal protective effect of irbesartan.

[Effect of irbesartan on ACE2 expression in diabetic rat myocardium].

OBJECTIVE: To explore the effect of irbesartan on angiotensin-converting enzyme 2 (ACE2) mRNA expression in diabetic rat myocardium. METHODS: Thirty 8-week-old male Wistar rats were randomly divided into control group (n=7), diabetic model group (n=14) and irbesartan group (n=9). Diabetes was induced by a single intraperitoneal injection of STZ (55 mg/kg), a blood glucose>16.7 mmol/L 72 h after the injection indicated successful establishment of diabetes. Four weeks after the modeling, the rats in irbesartan group were given 50 mg/kg irbesartan. ELISA was used to measure myocardial AngII content in the rats, and myocardial ACE2 mRNA expression was determined by real-time PCR. RESULTS: Myocardial AngII level in the diabetic model group was significantly higher than that in the control group (P<0.001). Irbesartan administration significantly lowered cardiac AngII levels in the diabetic rats (P<0.001). The rats in irbesartan group showed significantly increased myocardial ACE2 mRNA expression compared with those in the control and diabetic rat groups (P<0.05). CONCLUSION: Irbesartan can increase ACE2 mRNA expression in the myocardium, which might be one of the mechanisms underlying its effect in improving the cardiac function in diabetic rats.

[Dose-effect relationship of irbsartan with the changes in the renal tissue structure in diabetic rats].

OBJECTIVE: To investigate the relationship between the dosage of irbesartan and the renal tissue structure in diabetic rats. METHODS: Male Wistar rats was given a single intraperitoneal dose (mg/kg) of streptozotocin to induce diabetes. The diabetic rats were randomized into 4 groups and received 4 weeks later 25 mg/kg (n=9), 50 mg/kg (n=9), 200 mg/kg (n=9) irbesartan intragastrically, or equal volume of water (model group, n=11) on a daily basis. Seven normal rats receiving with equal volume of water served as the normal control. All the rats were sacrificed after 8 weeks and the 24-hour albumin excretion, renal mass index and the volume of the glomerulus were measured. RESULTS: The 24-hour albumin excretion, renal mass index and volume of the glomerulus in the 3 irbesartan groups were significantly decreased as compare with those in the model group; the reductions in 50 and 200 mg/kg irbesartan groups were significant greater than those in 25 mg/kg irbesartan group. CONCLUSION: Irbesartan can decrease the 24-hour urinary albumin excretion and relive glomerulopathy in diabetic rats. Within a certain dose range, irbesartan produces a dose-dependent protective effect on the renal structures in the diabetic rats.