Elevated retinol binding protein 4 levels are associated with atherosclerosis in diabetic rats via JAK2/STAT3 signaling pathway.

BACKGROUND: Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors, including diabetes, which results in an increased atherosclerotic burden, but the precise mechanisms for the occurrence and development of diabetic atherosclerosis have not been fully elucidated. AIM: To summarize the potential role of retinol binding protein 4 (RBP4) in the pathogenesis of diabetic atherosclerosis, particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. METHODS: Male Wistar rats were randomly divided into three groups, including a control group (NC group), diabetic rat group (DM group), and diabetic atherosclerotic rat group (DA group). The contents of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), fasting insulin (FINS), fasting plasma glucose, and hemoglobin A1c (HbA1c) were measured. Moreover, the adipose and serum levels of RBP4, along with the expression levels of JAK2, phosphorylated JAK2 (p-JAK2), STAT3, phosphorylated STAT3 (p-STAT3), B-cell lymphoma-2 (Bcl-2), and Cyclin D1 in aortic tissues were also measured. Besides, homeostasis model assessment of insulin resistance (HOMA-IR) and atherogenic indexes (AI) were calculated. RESULTS: Compared with the NC and DM groups, the levels LDL-c, TG, TC, FINS, HOMA-IR, RBP4, and AI were upregulated, whereas that of HDL-c was downregulated in the DA group (P < 0.05); the mRNA levels of JAK2, STAT3, Cyclin D1, and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group; P-JAK2, p-JAK2/JAK2 ratio, p-STAT3, p-STAT3/STAT3 ratio, Cyclin D1, and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group. In addition, as shown by Pearson analysis, serum RBP4 had a positive correlation with TG, TC, LDL-c, FINS, HbA1C, p-JAK2, p-STAT3, Bcl-2, Cyclin D1, AI, and HOMA-IR but a negative correlation with HDL-c. In addition, multivariable logistic regression analysis showed that serum RBP4, p-JAK2, p-STAT3, and LDL-c were predictors of the presence of diabetic atherosclerosis. CONCLUSION: RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.

Relationship between serum 25-hydroxyvitamin D and lower extremity arterial disease in type 2 diabetes mellitus patients and the analysis of the intervention of vitamin D.

The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and lower extremity arterial disease (LEAD) in type 2 diabetes mellitus (T2DM) patients and to investigate the intervention effect of vitamin D. 145 subjects were assigned to a control group (Group NC), T2DM group (Group DM1), and T2DM complicated with LEAD group (Group DM2); then Group DM2 were randomly divided into Group DM3 who received oral hypoglycemic agents and Group DM4 who received oral hypoglycemic drugs and vitamin D3 therapy. Compared to Group NC, 25(OH)D was significantly lower in Group DM2 and marginally lower in Group DM1. In contrast to baseline and Group DM3, 25(OH)D rose while low density lipoprotein (LDL), retinol binding protein 4 (RBP4), and HbA1c significantly lowered in Group DM4. Statistical analysis revealed that 25(OH)D had a negative correlation with RBP4, duration, HbA1c, homeostasis model assessment for insulin resistance (HOMA-IR), and fasting plasma glucose (FPG). LDL, systolic blood pressure (SBP), FPG, and smoking were risk factors of LEAD while high density lipoprotein (HDL) and 25(OH)D were protective ones. Therefore, we deduced that low level of 25(OH)D is significantly associated with the occurrence of T2DM complicated with LEAD.

Correlation between serum cathepsin S and insulin resistance in type 2 diabetes.

Cathepsin S (CatS), a proteolytic enzyme, which belongs to the cysteine proteinase family, is associated with atherosclerosis, coronary heart disease, cancer and other diseases. The present study aimed to explore the correlation between serum CatS and insulin resistance (IR) in patients with type 2 diabetes. A total of 51 patients with type 2 diabetes (Group DM) were recruited for this study and 49 healthy individuals were selected as normal controls (Group NC). Blood pressure and body mass index (BMI) were recorded, and serum creatinine, CatS, glycosylated hemoglobin (HbA1c), lipid and insulin levels, and fasting plasma glucose (FPG) levels were measured in all the participants. The homeostatic model assessment index of IR (HOMA-IR) was calculated according to FPG and serum insulin levels. Serum CatS, very low density lipoprotein (VLDL) and triglyceride (TG) levels in Group DM were significantly higher compared with those in Group NC (P=0.000, 0.014 and 0.020, respectively). Significantly positive correlations were identified between CatS levels and VLDL and TG levels, respectively (P<0.05 for both); however, no significant correlations were determined between CatS levels and age, course of disease, blood pressure, cholesterol, BMI, FPG, HbAc1 and HOMA-IR (P>0.05). Further stratification analysis showed that CatS had no association with IR at different HOMA-IR and HbA1c levels. The present study demonstrated that serum CatS, which was significantly increased in patients with type 2 diabetes, had no correlation with IR. This indicates that CatS and IR are independent of each other; however, the precise mechanisms require further investigation.

Hydrochloride pioglitazone decreases urinary cytokines excretion in type 2 diabetes.

OBJECTIVE: To observe the effects of hydrochloride pioglitazone on urinary cytokine excretion in type 2 diabetes and to explore its possible reno-protective mechanisms. DESIGN: Subjects and Methods. Ninety-eight patients with type 2 diabetes and a fasting blood glucose (FBG) levels between 7.0 and 13.0 mm and glycated haemoglobin A1c (HbA1c) ≥ 7.0% were assigned randomly to receive either the pioglitazone (DP group) or a sulphonylurea (DS group). Another 49 healthy individuals were chosen as normal controls (group NC). At the start of the study and after 12 weeks of treatment, urinary cytokines including monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-ß1 (TGF-ß1) and vascular endothelial growth factor were measured and were expressed as a ratio of urinary creatinine excretion. Urinary albumin/creatinine ratio, FBG and HbA1c were determined at the same time. RESULTS: The excretion of each urinary cytokine, corrected for urinary creatinine, was significantly increased in both groups of patients with diabetes, compared with normal controls, and after a 12-week treatment were significantly decreased by both therapies but the effect of pioglitazone was statistically greater than with sulphonylureas. Urinary albumin/UCr and both systolic and diastolic blood pressure were decreased significantly by pioglitazone (P < 0.01 or P < 0.05) but not by sulphonylurea treatment (P < 0.05), while there was no significant difference in FBG or HbA1c between two groups. There was a positive correlation between the excretion of cytokines and urinary albumin /UCr (all P < 0.01). CONCLUSIONS: This study indicates that pioglitazone reduces urinary albumin excretion by a mechanism that is at least partly independent of blood sugar control. The correlation of urinary albumin excretion with improvement in urinary cytokines suggests that this reno-protective effect of piogliazone in diabetes may be related to local reduction in cytokine activity within the kidney.