Network pharmacology and molecular docking of endogenous active metabolites in diabetic kidney disease.

OBJECTIVES: Network pharmacology and molecular docking were used to predict endogenous active metabolites with protective effects in diabetic kidney disease (DKD). METHODS: We utilized metabolomics to screen differentially expressed metabolites in kidney tissues of mice with type 2 DKD and predicted potential targets using relevant databases. The interaction network between endogenous active metabolites and target proteins was established by integrating differentially expressed metabolites and proteins associated with DKD identified through proteomics. Gene ontology (GO) and signaling pathway enrichment analysis were performed. The biological functions of the active candidate metabolites and their effects on downstream pathways were also verified. RESULTS: Metabolomics revealed 130 differentially expressed metabolites. Through co-expression network analysis coupled with the investigation of differentially expressed proteins in proteomics, 2-hydroxyphenylpropionylglycine (2-HPG) emerged as a key regulator of DKD. 2-HPG was found to modulate the progression of DKD by regulating the conformation and activity of synaptophysin 1 (SYNJ1), with a correlation coefficient of 0.974. In vivo experiments revealed that SYNJ1 expression was significantly downregulated in the Macroalbuminuria Group compared to the Control Group and negatively correlated with proteinuria (r = -0.7137), indicating its important role in DKD progression. Immunofluorescence demonstrated that treatment with 2-HPG restores the expression of the foot process marker protein Wilms tumor-1 (WT-1) in podocytes injured by high glucose levels. Western blot and polymerase chain reaction support the involvement of SYNJ1 in this process. CONCLUSIONS: This study demonstrated the significance of the 2-HPG/SYNJ1 signaling axis in safeguarding the foot process of podocytes in DKD.

Long non­coding RNA L13Rik promotes high glucose-induced mesangial cell hypertrophy and matrix protein expression by regulating miR-2861/CDKN1B axis.

Background: Diabetic nephropathy (DN) is a frequent microvascular complication of diabetes. Glomerular mesangial cell (MC) hypertrophy occurs at the initial phase of DN and plays a critical role in the pathogenesis of DN. Given the role of long non coding RNA (lncRNA) in regulating MC hypertrophy and extracellular matrix (ECM) accumulation, our aim was to identify functional lncRNAs during MC hypertrophy. Methods: Here, an lncRNA, C920021L13Rik (L13Rik for short), was identified to be up-regulated in DN progression. The expression of L13Rik in DN patients and diabetic mice was assessed using quantitative real-time PCR (qRT-PCR), and the function of L13Rik in regulating HG-induced MC hypertrophy and ECM accumulation was assessed through flow cytometry and western blotting analysis. Results: The L13Rik levels were significantly increased while the miR-2861 levels were decreased in the peripheral blood of DN patients, the renal tissues of diabetic mice, and HG-treated MCs. Functionally, both L13Rik depletion and miR-2861 overexpression effectively reduced HG-induced cell hypertrophy and ECM accumulation. Mechanistically, L13Rik functioned as a competing endogenous RNA (ceRNA) to sponge miR-2861, resulting in the de-repression of cyclin-dependent kinase inhibitor 1B (CDKN1B), a gene known to regulate cell cycle and MC hypertrophy. Conclusions: Collectively, the current results demonstrate that up-regulated L13Rik is correlated with DN and may be a hopeful therapeutic target for DN.

The protective mechanism of Dehydromiltirone in diabetic kidney disease is revealed through network pharmacology and experimental validation.

Background: Salvia miltiorrhiza (SM) is an effective traditional Chinese medicine for treating DKD, but the exact mechanism is elusive. In this study, we aimed to investigate and confirm the method underlying the action of the active components of SM in the treatment of DKD. Methods: Renal tissue transcriptomics and network pharmacology of DKD patients was performed to identify the active components of SM and the disease targets of DKD. Next, the point of convergence among these three groups was studied. Potential candidate genes were identified and analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The component-target networks were modelled and visualized with Cytoscape. In addition, docking studies were performed to validate our potential target predictions. Lastly, in vitro and in vivo experiments were performed to understand the role of Dehydromiltirone (DHT), the active component of SM, in the phenotypic switching of mesangial cells. Results: Transcriptomics of DKD patients' renal tissues screened 4,864 differentially expressed genes. Eighty-nine active components of SM and 161 common targets were found. Functional enrichment analysis indicated that 161 genes were enriched in apoptosis, the PI3K-AKT signaling pathway, and the AGE-RAGE signaling pathway in diabetes complications. Molecular docking and molecular dynamic simulations show that DHT can bind to functional PIK3CA pockets, thereby becoming a possible inhibitor of PIK3CA. In vitro study demonstrated that DHT reduced the expression of phenotypic switching markers α-SMA, Col-I, and FN in HMCs by downregulating the over-activation of the PI3K-AKT signaling pathway through the inhibition of PIK3CA. Furthermore, the DKD mouse model confirmed that DHT could reduce proteinuria and improve glomerular hypertrophy in vivo. Conclusion: DHT was identified as the key active component of SM, and its therapeutic effect on DKD was achieved by inhibiting the phenotypic switching of mesangial cells via the PIK3CA signaling pathway.

Investigating the effect of dehydromiltirone on septic AKI using a network pharmacology method, molecular docking, and experimental validation.

Acute kidney injury (AKI) is a severe and frequent complication of sepsis that occurs in intensive care units with inflammation and rapid decline in renal function as the main pathological features. Systemic inflammation, microvascular dysfunction, and tubule injury are the main causes of sepsis-induced AKI (SI-AKI). The high prevalence and death rate from SI-AKI is a great challenge for clinical treatment worldwide. However, in addition to hemodialysis, there is no effective drug to improve renal tissue damage and alleviate the decline in kidney function. We conducted a network pharmacological analysis of Salvia miltiorrhiza (SM), a traditional Chinese medicine, which is widely used for the treatment of kidney disease. Then, we combined molecular docking and a dynamics simulation to screen for the active monomer dehydromiltirone (DHT) that has therapeutic effects on SI-AKI and investigated its potential mechanism of action through experimental validation. The components and targets of SM were obtained by searching the database, and 32 overlapping genes were screened by intersection analysis with AKI targets. GO and KEGG data showed that the functions of a common gene were closely related to oxidative stress, mitochondrial function, and apoptosis. The molecular docking results combined with molecular dynamics simulations provide evidence for a binding model between DHT and cyclooxygenase-2 (COX2), both of which are mainly driven by van der Waals interactions and a hydrophobic effect. In vivo, we found that mice pretreated with an intraperitoneal injection of DHT (20 mg/kg/d) for 3 days ameliorated CLP surgery-induced renal function loss and renal tissue damage and inhibited inflammatory mediators IL-6, IL-1ß, TNF-α, and MCP-1 production. In vitro, the DHT pretreatment decreased LPS-induced expression of COX2, inhibited cell death and oxidative stress, alleviated mitochondrial dysfunction, and restrained apoptosis in HK-2 cells. Our research indicates that the renal preventive effect of DHT is related to maintaining mitochondrial dynamic balance, restoring mitochondrial oxidative phosphorylation, and inhibiting cell apoptosis. The findings in this study provide a theoretical basis and a novel method for the clinical therapy of SI-AKI.

Breviscapine alleviates podocyte injury by inhibiting NF-κB/NLRP3-mediated pyroptosis in diabetic nephropathy.

Podocyte injury is a critical factor in the pathogenesis of diabeticnephropathy (DN). Emerging evidence has demonstrated that breviscapine (Bre) exerts a renoprotective effect on diabetic rats. However, the effects of Bre on regulating podocyte injury under high glucose (HG) conditions remain unclear. In this study, an experimental mouse model of DN was induced by intraperitoneal injections of streptozotocin (STZ) in vivo. The effects of Bre on podocyte injury were assessed using cell counting kit-8 (CCK-8) assay, TdT-mediated dUTPnick-endlabelling (TUNEL) staining, quantitative real-time PCR (qRT‒PCR) and western blot analysis. We found that renal function was significantly decreased in diabetic mice, and this effect was blocked by Bre treatment. Bre effectively increased podocyte viability and inhibited HG-induced cell apoptosis. Furthermore, Bre ameliorated HG-induced podocyte injury, as evidenced by decreased α-smooth muscle actin (α-SMA) expression and increased podocin and synaptopodin expression. Mechanistically, Bre inhibited HG-induced nuclear factorkappaB (NF-κB) signalling activation and subsequently decreased NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, resulting in a decrease in pyroptosis. Pharmacological inhibition of NLRP3 decreased HG-induced podocyte injury, whereas the NLRP3 agonist abrogated the effects of Bre on inhibiting podocyte injury. In summary, these results demonstrate that Bre alleviates HG-induced podocyte injury and improves renal function in diabetic mice, at least in part by inhibiting NF-κB/NLRP3-mediated pyroptosis.

Non-crystalline light chain proximal tubulopathy associated with monoclonal gammopathy of renal significance: A case report and review of the literature.

BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare M-proteinemia-related nephropathy. Non-crystalline LCPT is even rarer. We herein report an unusual case of renal dysfunction and proteinuria due to κ-restricted and non-crystalline LCPT in a context of monoclonal gammopathy of renal significance (MGRS) without Fanconi syndrome (FS). CASE PRESENTATION: A 67-year-old man was admitted for a 2-year history of proteinuria and renal dysfunction. Fanconi syndrome (FS) was not observed. He was noted to have IgG-κ M protein, and the previous bone marrow biopsy revealed that atypical plasma cells accounted for 1.5% of the cells, which did not meet the diagnostic criteria for multiple myeloma. A renal biopsy revealed proximal tubular injury, including increased lysosomes with irregular contours and a mottled appearance without crystalline structure and the accumulation of κ light chains. He was diagnosed with non-crystalline LCPT with MGRS. Concurrently, we reviewed the non-crystalline LCPT cases previously published in the literature. Our patient finally received chemotherapy with a bortezomib and dexamethasone regimen. The patient did not seem to achieve evident nephrological and hematological remission after chemotherapy, but he was in a stable condition. CONCLUSION: Very few similar cases are reported in the literature. It is considered crucial to enhance our knowledge about these cases to establish the definition of the non-crystalline LCPT entity and allow for early diagnosis. Chemotherapy may not be necessary for all patients to maintain good renal function. Future prospective clinical research studies are necessary.

Investigation into the effect and mechanism of dapagliflozin against renal interstitial fibrosis based on transcriptome and network pharmacology.

BACKGROUND: Renal interstitial fibrosis (RIF) is the final pathway for chronic kidney diseases (CKD) to end-stage renal disease (ESRD). Dapagliflozin, a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of renal events in non-diabetic CKD patients in the DAPA-CKD trial. However, the effect and mechanism of dapagliflozin on RIF are not very clear. Currently, we evaluate the effects of dapagliflozin on RIF and systematically explore its mechanism. METHODS AND RESULTS: Firstly, unilateral ureteral obstruction (UUO) mouse model was established to evaluate effects of dapagliflozin on RIF, and results demonstrated dapagliflozin improved renal function and RIF of UUO mice independent of blood glucose control. Subsequently, transcriptome analysis was performed to explore the potential mechanism of dapagliflozin against RIF, which exhibited the therapeutic effect of dapagliflozin on RIF may be achieved through multiple pathways regulation. Then we verified the potential mechanisms with molecular biology methods, and found that dapagliflozin treatment significantly alleviated inflammation, apoptosis, oxidative stress and mitochondrial injury in kidneys of UUO mice. Furthermore, network pharmacology analysis was used to investigate the potential targets of dapagliflozin against RIF. Moreover, we also applied molecular docking and molecular dynamics simulation to predict the specific binding sites and binding capacity of dapagliflozin and hub target. CONCLUSIONS: Dapagliflozin had therapeutic effect on RIF independent of blood glucose control, and the protective effects probably mediated by multiple pathways and targets regulation.

Single-Molecule Junction: A Reliable Platform for Monitoring Molecular Physical and Chemical Processes.

Monitoring and manipulating the physical and chemical behavior of single molecules is an important development direction of molecular electronics that aids in understanding the molecular world at the single-molecule level. The electrical detection platform based on single-molecule junctions can monitor physical and chemical processes at the single-molecule level with a high temporal resolution, stability, and signal-to-noise ratio. Recently, the combination of single-molecule junctions with different multimodal control systems has been widely used to explore significant physical and chemical phenomena because of its powerful monitoring and control capabilities. In this review, we focus on the applications of single-molecule junctions in monitoring molecular physical and chemical processes. The methods developed for characterizing single-molecule charge transfer and spin characteristics as well as revealing the corresponding intrinsic mechanisms are introduced. Dynamic detection and regulation of single-molecule conformational isomerization, intermolecular interactions, and chemical reactions are also discussed in detail. In addition to these dynamic investigations, this review discusses the open challenges of single-molecule detection in the fields of physics and chemistry and proposes some potential applications in this field.

Cross-Scale Synthesis of Organic High-k Semiconductors Based on Spiro-Gridized Nanopolymers.

High dielectric constants in organic semiconductors have been identified as a central challenge for the improvement in not only piezoelectric, pyroelectric, and ferroelectric effects but also photoelectric conversion efficiency in OPVs, carrier mobility in OFETs, and charge density in charge-trapping memories. Herein, we report an ultralong persistence length (l p ≈ 41 nm) effect of spiro-fused organic nanopolymers on dielectric properties, together with excitonic and charge carrier behaviors. The state-of-the-art nanopolymers, namely, nanopolyspirogrids (NPSGs), are synthesized via the simple cross-scale Friedel-Crafts polygridization of A2B2-type nanomonomers. The high dielectric constant (k = 8.43) of NPSG is firstly achieved by locking spiro-polygridization effect that results in the enhancement of dipole polarization. When doping into a polystyrene-based dielectric layer, such a high-k feature of NPSG increases the field-effect carrier mobility from 0.20 to 0.90 cm2 V-1 s-1 in pentacene OFET devices. Meanwhile, amorphous NPSG film exhibits an ultralow energy disorder (<50 meV) for an excellent zero-field hole mobility of 3.94 × 10-3 cm2 V-1 s-1, surpassing most of the amorphous π-conjugated polymers. Organic nanopolymers with high dielectric constants open a new way to break through the bottleneck of efficiency and multifunctionality in the blueprint of the fourth-generation semiconductors.

High-Sensitive Cardiac Troponin T for Prediction of Cardiovascular Outcomes in Stable Maintenance Hemodialysis Patients: A 3-Year Prospective Study.

BACKGROUND: Hemodialysis patients, who are often excluded from cardiovascular (CV) clinical trials, are associated with higher CV morbidity and mortality. The risk stratification scheme for these patients is lacking. Therefore, this investigation examined the independent CV prognostic value of high-sensitive cardiac troponin T (hs-cTnT) and added prognostic value over echocardiographic parameters and other clinical risk predictors in asymptomatic stable maintenance hemodialysis (MHD) patients. METHODS: 181 patients with end-stage renal disease undergoing MHD were eligible from the dialysis center of Tongren Hospital, Shanghai Jiao Tong University School of Medicine between October 2017 and September 2018. These patients were followed until September 2020 or until death. The median follow-up was 31 (IQR: 21-33) months. Outcome measures were all-cause mortality, first fatal or nonfatal CV events (CVEs), and 4-point composite major adverse CVEs (MACE). We performed multivariable Cox regression analysis using demographic, clinical, laboratory, and echocardiographic data to identify predictors of CV outcomes. We also evaluated the increased discriminative value associated with the addition of echocardiographic parameters and hs-cTnT using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: During follow-up, 37 patients died, 84 patients suffered one or more CVEs, and 78 patients developed 4-point MACE. In univariable analyses, age, dialysis vintage, diastolic blood pressure, parathyroid hormone concentrations, hs-cTnT, B-type natriuretic peptide, left ventricular mass index (LVMI), and E/E' predicted all end points. hs-cTnT remained a strong predictor for each end point in multivariate analysis, whereas LVMI and E/E' did not. The addition of hs-cTnT on top of clinical and echocardiographic variables was associated with improvements in reclassification for CVEs (NRI = 44.6% [15.9-74.3%], IDI = 15.9% [5.7-31.0%], all p < 0.001), all-cause mortality (NRI = 35.5% [10.1-50.2%], p < 0.001, IDI = 4.4% [1.3-8.5%], p = 0.005), and 4-point MACE (NRI = 47.2% [16.1-64.9%], p < 0.001, IDI = 16.9% [5.5-37.3%], p = 0.005). Adding echocardiographic variables on top of clinical variables and hs-cTnT was not associated with significant improvements in NRI and IDI (all p > 0.05). CONCLUSIONS: Our data suggest that hs-cTnT is a powerful independent predictor of CV outcome and all-cause mortality in stable MHD patients. The additional use of echocardiography for improvement of risk stratification is not supported by our results.

EA15, MIR22, LINC00472 as diagnostic markers for diabetic kidney disease.

This study aimed to investigate the molecular mechanisms of diabetic kidney disease (DKD) and to explore new potential therapeutic strategies and biomarkers for DKD. First we analyzed the differentially expressed changes between patients with DKD and the control group using the chip data in Gene Expression Omnibus (GEO) database. Then the gene chip was subjected to be annotated again, so as to screen long noncoding RNAs (lncRNAs) and study expression differences of these lncRNAs in DKD and controlled samples. At last, the function of the differential lncRNAs was analyzed. A total of 252 lncRNAs were identified, and 14 were differentially expressed. In addition, there were 1,629 differentially expressed messenger RNAs (mRNAs) genes, and proliferation and apoptosis adapter protein 15 (PEA15), MIR22, and long intergenic nonprotein coding RNA 472 ( LINC00472) were significantly differentially expressed in DKD samples. Through functional analysis of the encoding genes coexpressed by the three lncRNAs, we found these genes were mainly enriched in type 1 diabetes and autoimmune thyroid disease pathways, whereas in Gene Ontology (GO) function classification, they were also mainly enriched in the immune response, type I interferon signaling pathways, interferon-γ mediated signaling pathways, and so forth. To summary, we identified EA15, MIR22, and LINC00472 may serve as the potential diagnostic markers of DKD.

High-sensitive cardiac troponin T: a biomarker of left-ventricular diastolic dysfunction in hemodialysis patients.

OBJECTIVE: To identify the relationship between serum high-sensitive cardiac troponin T (hs-cTnT) and left ventricular diastolic dysfunction (LVDD) among maintenance hemodialysis patients and to further explore the value of hs-cTnT in evaluating and predicting LVDD in this special group of patients. METHODS: In a cross-sectional study, 152 dialysis patients with end-stage renal disease (ESRD) underwent Hs-cTnT measurement using the high sensitivity assay. Echocardiography measurements were carried out according to the American Society of Echocardiography recommendations and E/E' > 15 or E' < 7 cm/s was defined as diastolic dysfunction. Demographic, biochemical, and echocardiographic values of left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), left atrial diameter, early/late peak velocities ratio (E/A), early peak diastolic annular velocity (E') and E/E' were compared across quartiles of hs-cTnT. The association of plasma hs-cTnT concentrations with echocardiographic parameters was analyzed by Spearman's correlation. The relationship between serum hs-cTnT and LVDD parameters of E/E' and E' was analyzed using multivariate regression analysis, and the value of hs-cTnT on assessing LVDD was evaluated by receiver-operating characteristic (ROC) curves. RESULTS: The median value of hs-cTnT was 45 pg/ml (range 28-73). All patients had detectable hs-cTnT, while 88% had greater hs-cTnT than the 99th percentile of the general population (14 pg/ml). Serum hs-cTnT values showed a significantly positive correlation with E/E' (r = 0.739, p < 0.001) and LVMI (r = 0.608, p < 0.001), but showed a negative correlation with E' (r = - 0.554, p < 0.001). Serum hs-cTnT was not associated with LV systolic dysfunction. The associations of hs-cTnT with E/E' and E' persisted after multivariate adjustment for LVMI and comorbidities. In logistic multiple regression analysis, compared with the lowest quartile of hs-cTnT, the highest two quartiles were approximately 5 and 11 times more likely to have E/E' > 15 and 7 and 17 times more likely to have E' < 7 cm/s. The area under the ROC curve for hs-cTnT evaluating E/E' > 15 was 0.847 and evaluating E' < 7 cm/s was 0.799, which denoted a moderate accuracy. CONCLUSIONS: Our studies suggest that serum hs-cTnT may serve as a biomarker of LVDD in hemodialysis patients.

Specific expression network analysis of diabetic nephropathy kidney tissue revealed key methylated sites.

Diabetic nephropathy (DN) is one of the most common and serious complication in diabetes patients. However, the evidences of gene regulation mechanism and epigenetic modification with DN remain unclear. Therefore, it is necessary to search regulating genes for early diagnosis on DN. We identified tissue specific genes through mining the gene expression omnibus (GEO) public database, enriched function by gene ontology (GO), and kyoto encyclopedia of genes and genomes (KEGG) analysis, and further compared tissue-specific network. Meanwhile, combining with differentially methylated sites, we explored the association epigenetic modification with the pathogenesis of DN. Glomeruli (Glom) may be the main tissue of signal recognition and tubulointerstitium (Tub) is mainly associated with energy metabolism in the occurrence of DN. By comparing tissue-specific networks between Glom and Tub, we screened 319 genes, which played an important role in multiple tissue on kidney. Among them, ANXA2, UBE2L6, MME, IQGAP, SLC7A7, and PLG played a key role in regulating the incidence of DN. Besides, we also identified 1 up-regulated gene (PIK3C2B) and 39 down-regulated genes (POLR2G, DDB1, and ZNF230, etc.) in the methylated data of Glom specific genes. In the Tub specific expressed genes, we identified two hypo-methylated genes (PPARA and GLS). Tub mainly caused abnormal energy metabolism, and Glom caused the changes in cell connections and histone modification. By analyzing differentially methylated sites and tissue-specific expressed genes, we found the change of methylated status about the core regulating genes may be a potential factor in the pathogenesis of DN.

Circulating 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) levels are associated with hyperglycemia and ß cell dysfunction in a Chinese population.

Several recent clinical studies have suggested that the levels of circulating 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) are significantly higher in patients with gestational diabetes mellitus (GDM), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM). This study recruited a total of 516 participants. The following patient populations were enrolled: 99 newly diagnosed cases with T2DM, 219 cases with prediabetes [82 with isolated impaired glucose tolerance (I - IGT), 66 with isolated impaired fasting glucose (I - IFG) and 71 with impaired glucose tolerance and impaired fasting glucose (IGT + IFG)], and 198 cases with normal glucose tolerance [NGT, including 99 first-degree relatives of type 2 diabetes patients (FDRs) and 99 non-FDRs]. We investigated the circulating CMPF levels in subjects with different glucose metabolism statuses and examined the potential link between CMPF and ß cell function. Our results indicate that the serum CMPF levels were elevated in the prediabetes, T2DM, and FDRs groups compared to the NGT group. Additionally, the serum CMPF concentrations were independently and negatively associated with the triglyceride levels and Stumvoll first-phase insulin secretion index. Cumulatively, our findings suggest that the circulating CMPF levels can predict glycolipid metabolism disorders. Furthermore, elevated serum CMPF concentrations may determine hyperglycemia and ß cell dysfunction.

Circulating Adipocyte Fatty Acid Binding Protein (FABP4) Levels Are Associated with Irisin in the Middle-Aged General Chinese Population.

BACKGROUND: Adipocyte fatty acid binding protein (FABP4) has been recently characterized as an adipokine that is closely associated with obesity and metabolic syndrome. Irisin, a novel myokine, activates thermogenesis by increasing the transformation of white adipocytes to brown, and it has improved glucose homeostasis in animal models. In this study, we aimed to explore the relationship between serum FABP4 and irisin in middle-aged Chinese subjects. METHODS: A total of 111 normal residents (56 men and 55 women) of Fengxian District who were 40 to 60 years of age were recruited. Circulating FABP4 and irisin were determined by enzyme-linked immunosorbent assay. Anthropometric parameters, oral glucose tolerance test results, hemoglobin A1C (HbA1C), blood lipids, homeostasis model assessment of insulin resistance, homeostasis model assessment-ß and body fat composition were also determined. RESULTS: All participants were categorized by FABP4 tertiles. There were significant differences in blood pressure, body fat percentage, 2-h plasma glucose, and skeletal muscle mass among the three groups (P<0.05). Furthermore, FABP4 levels in the women were significantly higher than in the men (P<0.05). However, there was no sexual dimorphism in serum irisin (P>0.05). To exclude the effect of sex difference, partial correlations analysis showed that FABP4 was positively correlated with diastolic blood pressure (P<0.05) and body fat percentage (P<0.05) negatively correlated with skeletal muscle mass (P<0.05) and irisin (P<0.05), while irisin was positively correlated with HbA1c (P<0.05) and negatively correlated with creatinine (P<0.05). Multivariate regression analysis demonstrated that serum FABP4 was independently associated with skeletal muscle mass (P<0.001), diastolic blood pressure (P<0.05) and irisin (P<0.05) after adjustment for age, body mass index, body fat percentage, total cholesterol and HbA1C. CONCLUSIONS: Elevated FABP4 levels increase the risks of obesity-related metabolic disorders and hypertension. Serum irisin might exert antagonistic effects on FABP4 in the middle-aged Chinese population.

Circulating Betatrophin Correlates with Triglycerides and Postprandial Glucose among Different Glucose Tolerance Statuses--A Case-Control Study.

PURPOSE: Previous researches of betatrophin on glucose and lipids metabolism under insulin-resistant condition have reached controversial conclusions. To further identify the possible impact of betatrophin, we measured the circulating betatrophin levels in newly diagnosed type 2 diabetes (T2DM) patients, and in subjects with both impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) and investigated the relationship between serum betatrophin and other clinical parameters in these patients with different glucose tolerance statuses. METHODS: A total of 460 permanent residents of the Fengxian District, aged 40-60 years, were enrolled. Based on the results of a 75 g oral glucose tolerance test, we selected newly diagnosed T2DM (n = 50) patients and subjects with IGT (n = 51) and NGT (n = 50) according to their age, gender and body mass index (18-28 kg/m2). Anthropometric parameters, glycosylated haemoglobin, blood lipids and fasting insulin were measured. Serum betatrophin concentrations were determined via ELISA. RESULTS: Serum betatrophin levels in T2DM patients were increased significantly compared with IGT and NGT groups, and decreased in subjects with better islet beta cell function. Serum betatrophin was positively correlated with triglyceride, 2-hour postprandial glucose, alanine aminotransferase and aspartate transaminase after adjusting for age, sex and body mass index in all subjects. Multiple regression analysis showed that 2-hour postprandial glucose was independently associated with serum betatrophin significantly. CONCLUSIONS: Circulating betatrophin is increased in newly-diagnosed T2DM patients and positively correlated with the triglycerides and postprandial glucose levels. The results suggest that betatrophin may participate in glucose and triglycerides metabolism.

Associations of betatrophin levels with irisin in Chinese women with normal glucose tolerance.

BACKGROUND: Betatrophin may increase islet ß cell proliferation in insulin resistance and irisin may improve glucose tolerance in mice. To examine the relationship between betatrophin and irisin, we investigated it in middle-aged Chinese subjects with normal glucose tolerance (NGT) and type 2 diabetes mellitus (T2DM). METHODS: A total of 460 permanent residents of Fengxian District, aged 40-60 years and without T2DM, were enrolled. Anthropometric parameters, oral glucose tolerance test (OGTT) results, glycosylated haemoglobin levels, blood lipid levels, insulin sensitivity (homeostasis model assessment of insulin resistance, HOMA-IR), ß cell function (homeostasis model assessment-ß, HOMA-ß), estimated glomerular filtration rate (eGFR) and body fat composition were determined. Matched for age, gender and body mass index (BMI, 18-28 kg/m2), newly diagnosed T2DM (n = 50, male/female = 23/27) and NGT (n = 50, male/female = 21/29) subjects were selected based on the results of an OGTT. Serum betatrophin and irisin levels were determined by enzyme linked immune sorbent assay (ELISA). RESULTS: Males had higher levels of betatrophin compared with females in both the NGT and T2DM groups. Compared with NGT subjects, the level of betatrophin in the T2DM group was higher, and males in the T2DM group had higher betatrophin levels than males in the NGT group, but there was no significant difference in betatrophin levels in females between the T2DM and NGT groups. Spearman's correlation analysis revealed that serum betatrophin levels in females with NGT were positively correlated with irisin and negatively correlated with FINS (fasting insulin) levels ( p < 0.05), but no correlation was found between betatrophin and irisin levels in males with NGT or in males or females with T2DM. In females with T2DM, circulating betatrophin levels were positively correlated with weight, BMI and hip circumference (p < 0.05) but negatively correlated with FPG (fasting plasma glucose) and HOMA-IR (p < 0.05). CONCLUSIONS: Gender differences in the relationship between betatrophin and irisin indicate that there might be cytokine-mediated crosstalk among the liver, adipose tissue and skeletal muscle.

Circulating levels of irisin in middle-aged first-degree relatives of type 2 diabetes mellitus - correlation with pancreatic ß-cell function.

BACKGROUND: Irisin is a novel myokine secreted in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) activation through exercise. The first-degree relatives (FDRs) of type 2 diabetes mellitus (T2DM) patients bear a lifetime risk for developing T2DM, especially after 40 years old. However, the circulating irisin levels in middle-aged FDRs of T2DM is unclear. We therefore investigated the association between circulating irisin and pancreatic ß-cell function in normal-glucose-tolerance (NGT) subjects. METHODS: In this cross-sectional study, we recruited 412 supposed healthy subjects aged 40-60 who were FDRs of T2DM patients but without previous diagnosis of T2DM. Of the 412 individuals, 254 had NGT and 60 were newly diagnosed T2DM based on the results of a 75 g oral glucose tolerance test (OGTT- World Health Organization diagnostic criteria). We measured irisin in the newly diagnosed T2DM group (n = 60) and in an age- and sex-matched NGT subgroups (n = 62). Serum irisin was quantified by ELISA, and its association with metabolic parameters was analysed by Pearson's correlation and multiple linear regression analyses. RESULTS: There was no significant difference in serum irisin between middle-aged newly diagnosed T2DM patients and the NGT control group. Circulating irisin was correlated with haemoglobin A1c (r = 0.202, p = 0.026) and estimated glomerular filtration rate (r = 0.239, p = 0.010). Multiple linear regression revealed that only homeostasis model assessment-ß (HOMA-ß) was associated with irisin in NGT subjects after adjusting for confounding factors. However, similar analysis in T2DM did not reveal a significant association between circulating irisin and metabolic parameters. CONCLUSIONS: There was no significant difference in serum irisin between middle-aged newly diagnosed T2DM patients and the NGT controls. Serum irisin level was closely related to HOMA-ß in NGT, suggesting that irisin may play a crucial role in pancreatic ß-cell function.