Comparative efficacy and safety of sodium-glucose cotransporter 2 inhibitors for renal outcomes in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis.

In this study, the summarized WMDs and RRs were calculated using a pairwise analysis and a network meta-analysis with a random effects model, to compare and rank the efficacy and safety of SGLT-2i for renal outcomes in patients with T2DM. Among 1894 identified articles, 30 trials including 50,244 patients with T2DM were evaluated. Network analysis revealed that the administration of canagliflozin was associated with a reduced risk of renal impairment (surface under the cumulative ranking: 90.8%). Further, although the administration of SGLT-2i was not associated with the risk of renal impairment (RR = 0.88, 95%CI = 0.68-1.15, p = 0.354), the administration of empagliflozin was associated with a reduced risk of renal impairment compared to that with the administration of placebo (RR = 0.74, 95%CI = 0.62-0.90, p = 0.002). Moreover, compared with the administration of a placebo, the administration of 50, 100, and 200 mg of canagliflozin was associated with lower serum creatinine levels. Furthermore, compared with the administration of a placebo, the administration of 100 mg canagliflozin, 2.5 mg dapagliflozin, and 25 mg empagliflozin was associated with a lower reduction in the estimated glomerular filtration rate. Except for 300 mg canagliflozin, all SGLT-2i were associated with greater increases in blood urea nitrogen levels (WMD = 1.39, 95%CI = 1.20-1.59, p < 0.001). Finally, the administration of all SGLT-2i significantly increased the ratio of urinary glucose to creatinine compared with the ratio upon administration of placebo (WMD = 36.21, 95%CI = 31.50-40.92, p < 0.001). Briefly, canagliflozin exerts the greatest therapeutic effect in terms of reducing the risk of renal impairment. Empagliflozin and canagliflozin may be more effective than other SGLT-2i in preventing renal impairment.

FMO1 Promotes Nonalcoholic Fatty Liver Disease Progression by Regulating PPARα Activation and Inducing Ferroptosis.

BACKGROUND: The function of flavin containing dimethylaniline monooxygenase 1 (FMO1), which is known to play a part in lipid metabolism, remains unclear in the development of nonalcoholic fatty liver disease (NAFLD). This research has the objective of examining the contributions of FMO1 in the progression of NAFLD and the associated mechanisms, particularly the peroxisome proliferator activated receptor alpha (PPARα) and ferroptosis pathways. METHODS: An in vitro NAFLD model was established by treating L02 cells with free fatty acids (FFAs). The FMO1 and ferroptosis levels were examined in the cellular NAFLD model. FMO1 was knocked down using short-interfering RNA transfection. The effects of FMO1 knockdown on lipid accumulation, PPARα expression, and ferroptosis were examined in the cellular NAFLD model. Additionally, the effects of FMO1 and/or PPARα overexpression on lipid metabolism and ferroptosis were analyzed. Furthermore, L02 cells were pre-treated with GW7647 (PPARα agonist) or RSL3 (ferroptosis activator) and stimulated with FFAs. RESULTS: The levels of FMO1 and ferroptosis were upregulated in the in vitro NAFLD model. FMO1 knockdown suppressed the FFA-induced accumulation of lipids in hepatocytes, downregulation of PPARα expression, and upregulation of ferroptosis. In contrast, FMO1 overexpression dysregulated lipid metabolism and downregulated PPARα levels. Meanwhile, PPARα overexpression mitigated the FMO1 overexpression-induced upregulation of ferroptosis and lipid accumulation. Treatment with RSL3 suppressed the effects of PPARα overexpression on lipid accumulation and FMO1 expression. CONCLUSIONS: FMO1 upregulates ferroptosis by suppressing PPARα in NAFLD, which leads to the dysregulation of lipid metabolism.

MicroRNA-17-5p Promotes Vascular Calcification by Targeting ANKH.

BACKGROUND: MicroRNAs (miRNAs) may participate in the process of vascular calcification. However, the role of microRNA-17-5p in vascular calcification has not been clarified. In this study, we showed the effects of microRNA-17-5p on vascular calcification. MATERIALS AND METHODS: Vascular smooth muscle cells (VSMCs) were transfected with miR-17-5p mimics, a miR-17-5p inhibitor or negative control (NC) using Lipofectamine 2000. Then the cells were induced by an osteogenic medium. Alkaline phosphatase (ALP) activity and mineralization were determined. Osteocalcin (OC), bone morphogenetic protein 2(BMP-2), Collagen Ia (Colla), Runx2, and ankylosis protein homolog (ANKH) gene expressions were determined by reverse transcription-polymerase chain reaction. Vascular calcification was developed using a renal failure model. RESULTS: The ALP activity was increased when miR-17-5p mimics were transfected, whereas the miR-17-5p inhibitor reduced ALP activity (p < 0.05). The number and average area of mineral nodes in the miR-17-5p mimic group was larger than those in the corresponding control and NC groups (p < 0.05). The number and average area of the mineral nodes in the miR-17-5p inhibitor group were smaller than those in the corresponding control and NC groups (p < 0.05). Bmp2, OC, Col1a and Runx2 were higher in the miR-17-5p mimics group compared to those in the control and NC groups. ANKH expression was decreased in VSMCs with the miR-17-5p mimics and increased in VSMCs with miR-17-5p inhibitor. ANKH siRNA intervention also promoted mineralization. The miR-17-5p expression was upregulated and ANKH was down-regulated in the aortic arteries with calcification. CONCLUSION: Our data showed that miR-17-5p may promote vascular calcification by inhibiting ANKH expression.

Osteoclasts May Affect Glucose Uptake-Related Insulin Resistance by Secreting Resistin.

OBJECTIVES: Bone may play a role in the modulation of insulin sensitivity. Insulin resistance can be caused by increased resistin. However, whether osteoclasts affect the insulin resistance via resistin remains unclear. In the present study, we show the expression of resistin in osteoclasts and the possible underlying role of resistin on glucose uptake-related insulin resistance in vitro. METHODS: Conditioned mediums (CM) were collected from Raw264.7 cells treated without (CCM) or with RANKL (CM3, treated with RANKL for 3 days; CM5, treated with RANKL for 5 days) and transfected with control or resistin siRNA (CMsiRNA). The osteoclast formation was examined by tartrate resistant acid phosphatase (TRAP) staining. C2C12 myoblasts were cultured with the CM or CMsiRNA. Glucose uptake was evaluated by 2-NBDG fluorescence intensity. Resistin expression was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay. Statistical analysis was performed by an independent two sample t-test or one-way ANOVA. RESULTS: The 2-NBDG fluorescence intensity was higher in C2C12 cells treated with CCM compared to those that received CM3 and CM5 (p < 0.05). Resistin mRNA and protein expressions were both increased in RAW264.7 cells treated with RANKL for 3 days and 5 days compared with those cells without RANKL administration. The 2-NBDG fluorescence intensities in C2C12 cells treated with CMsiRNA and CM5+Anti-resistin antibody were significantly higher than those cultured with CM5 (p < 0.05). CONCLUSION: Osteoclasts may promote glucose uptake-related insulin resistance by secreting resistin.

Association of Serum Melatonin Level with Mild Cognitive Impairment in Type 2 Diabetic Patients: A Cross-Sectional Study.

OBJECTIVES: Melatonin is an essential neuroendocrine hormone that participates in the regulation of sleep rhythm and cognitive function. This study aimed to determine serum melatonin levels with mild cognitive impairment (MCI) in patients with type 2 diabetes (T2DM). METHODS: A total of 247 T2DM patients were recruited in this retrospective study and divided into 75 subjects with MCI and 172 with normal cognition. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). Their blood sample was examined for the level of melatonin and other biochemical parameters. RESULTS: Melatonin concentration was decreased in MCI patients to non-MCI patients (P < 0.001). Melatonin level was negatively correlated with age (r = -0.202; P = 0.001), diabetes duration (r = -0.282; P < 0.001), serum HbA1c (r = -0.195; P = 0.002), hs-CRP (r = -0.324; P < 0.001), and TSH (r = -0.184; P = 0.004) levels and positively correlated with MoCA score, serum HDL-C (r = 0.145; P < 0.001), FT3 (r = 0.241; P < 0.001), and FT4 (r = 0.169; P = 0.008) levels. The multivariable analysis indicated that fewer years of formal education, longer diabetes duration, higher serum HbA1c, higher serum hs-CRP, and lower serum melatonin are the predisposing factors for MCI. CONCLUSION: Lower melatonin level was associated with cognitive impairment in patients with T2DM. Melatonin might serve as a potential protective molecule against cognitive dysfunction in T2DM.

Effects of Aldosterone on Chemerin Expression And Secretion in 3T3-L1 Adipocytes.

Aldosterone plays a pivotal role in the pathogenesis of metabolic syndrome and cardiovascular disease; however, the underlying mechanisms have not been clarified. Chemerin has been characterized as an adipokine with crucial roles in obesity-associated disorders and cardiovascular homeostasis. The aim of the present study was to investigate the direct effects of aldosterone on chemerin expression and secretion in 3T3-L1 adipocytes and to identify the potential signalling pathways involved. Chemerin mRNA levels were measured using real-time PCR, whereas the levels of secreted chemerin in the culture media were determined using ELISA. Treatment with aldosterone induced time- and dose-dependent increases of chemerin gene expression and protein secretion, and effect that was mediated through the mineralocorticoid receptor. Signalling studies suggested that the NF-κB pathway is involved in aldosterone-induced chemerin expression. Taken together, our data demonstrate a direct interaction between aldosterone and chemerin in adipocytes, which may be an underlying mechanism linking aldosterone-associated metabolic abnormalities and cardiovascular disease.

Hydrogen-rich saline improves non­alcoholic fatty liver disease by alleviating oxidative stress and activating hepatic PPARα and PPARγ.

Non-alcoholic fatty liver disease (NAFLD) comprises a range of liver diseases, between steatosis and non­alcoholic steatohepatitis and liver cirrhosis, which are closely associated with diabetes mellitus. Previous studies have indicated that oxidative stress is a key factor in the development of NAFLD. Molecular hydrogen (H2) may ameliorate oxidative stress injuries by selectively neutralizing peroxynitrite and hydroxyl radicals. The present study evaluated the effects of H2 on NAFLD in rats and concluded that H2­rich saline had significant therapeutic effects on NAFLD induced by hyperglycemia and hyperlipidemia, as demonstrated by hematoxylin and eosin and terminal deoxynucleotidyl-transferase­mediated dUTP nick end labeling staining. H2­rich saline improved fasting blood glucose, fasting insulin, insulin sensitivity and glucose tolerance, and lowered the expression levels of tumor necrosis factor alpha, interleukin­1 beta, 3­nitrotyrosine and 8­hydroxy­2'­deoxyguanosine in the liver. In addition, the present study revealed that H2­rich saline could significantly increase peroxisome proliferator­activated receptor (PPAR) α and PPARγ expression in hepatocytes. In conclusion, H2­rich saline may significantly improve NAFLD, possibly by reducing oxidative stress and activating hepatic PPARα and PPARγ expression.

Elevated B Cell Activation is Associated with Type 2 Diabetes Development in Obese Subjects.

BACKGROUND/AIMS: Despite strong association between obesity and the pathogenesis of type 2 diabetes (T2D), only a subset of obese individuals eventually develops T2D. We sought to determine the immunological factors behind this heterogeneity. METHODS: Peripheral blood of obese non-diabetic subjects and obese diabetic subjects were collected and the B cell responses in these subjects were analyzed. RESULTS: We found that the B cells from obese diabetic subjects had similar B cell subtype composition and secreted similar levels of low-grade pro-inflammatory cytokines to obese non-diabetic subjects, characteristic to the background chronic immune activation frequently observed in obese subjects. When examining adaptive B cell antibody responses, however, obese diabetic subjects presented much higher levels of polyclonal activation and antibody secretion, with impaired ability to response to new antigens such as seasonal influenza vaccination. CONCLUSIONS: These data demonstrated that in obese diabetic subjects, B cell adaptive response is impaired and potentially contribute to overall higher inflammation.

Dysregulation of circulating CD4+CXCR5+ T cells in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is characterized by a chronic low-grade inflammatory state. Follicular helper T cells (Tfh) play critical roles in inducing B-cell activation and producing various cytokines, whereas circulating CD4+CXCR5+ T cells (CTfh) may act as a counterpart to measure Tfh cell disorders. In this study, we investigated whether Tfh could be involved in the development of T2DM by assessing CTfh in peripheral blood. CTfh and it subtypes were determined by measuring CD3, CD4, CXCR5, CXCR3, and CCR6 in 68 T2DM patients and 60 healthy controls using flow cytometry. Results showed that proportion of CTfh in the peripheral CD4+ T cells was significantly increased in T2DM patients (8.5 ± 0.5%) than in controls (4.5 ± 0.3%) (p < 0.001). Further study revealed that the balance of CTfh subtypes was greatly dysregulated, in which percentage of Th17 subtype was significantly increased in patients. Investigating the correlation between CTfh and risk factors of T2DM demonstrated that proportion of CTfh were significantly elevated in patients with body mass index (BMI) over 24.0 (p = 0.005). Interestingly, patients with abdominal obesity had further increase in CTfh than those without abdominal obesity. This study suggests the involvement of CTfh in T2DM, especially in T2DM-related obesity.