Association of serum asprosin with metabolic dysfunction-associated fatty liver disease in older adult type 2 diabetic patients: a cross-sectional study.

BACKGROUND: To explore the association of serum asprosin levels with metabolic dysfunction-associated fatty liver disease (MAFLD) in older adults with type 2 diabetes mellitus (T2DM). METHODS: The cross-sectional study enrolled patients ≥ 65 years old diagnosed with T2DM at two community health service centers between November 2019 and July 2021. Logistic regression was applied to analyze the influencing factors of MAFLD. RESULTS: Totally 219 cases were included. Compared with diabetic individuals without MAFLD (n = 105), diabetics with MAFLD (n = 114) had younger ages, higher body mass index values, shorter time from T2DM diagnosis, increased waist-to-hip ratios, elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-C), elevated alanine aminotransferase (ALT), elevated γ-glutaryl transferase, elevated fasting insulin, and elevated HOMA-IR (all P < 0.05). Serum asprosin levels were elevated in diabetics with MAFLD in comparison with the non-MAFLD group (291.71 ± 73.69 vs. 255.24 ± 82.52 pg/ml, P = 0.001). Multivariable analysis revealed, after adjusted for age, time from T2DM diagnosis, HDL-C, and ALT, serum asprosin level (OR = 1.006, 95%CI: 1.001-1.010, P = 0.014) were independently associated with MAFLD in T2DM. CONCLUSIONS: High asprosin level are associated with MAFLD in older patients with T2DM, after adjusted for age, time from T2DM diagnosis, WHR, TG, HDL-C, ALT, GGT, FINS, and HOMA-IR.

The correlation between serum asprosin and left ventricular diastolic dysfunction in elderly patients with type 2 diabetes mellitus in the community.

AIMS/INTRODUCTION: Serum asprosin is expected to become a screening indicator in early-stage diabetic heart disease. The relationship between serum asprosin and left ventricular diastolic dysfunction (LVDD) was studied in elderly patients with type 2 diabetes mellitus in the community. MATERIALS AND METHODS: A total of 252 elderly patients with type 2 diabetes mellitus were recruited from Zhuoma Community Care Station and Chengbei West Street Community Care Service Center in Changzhi City of Shanxi Province from November 2019 to July 2021. Patients were divided into the LVDD group (n = 195) and the non-LVDD group (n = 57). The t-test, Mann-Whitney U test, and χ2 test were used to compare indicators between the LVDD group and the non-LVDD group. Pearson or Spearman correlation analysis was adopted to evaluate the correlation between serum asprosin and other clinical data. Multivariate logistic regression analysis was applied to analyze the influencing factors on LVDD. RESULTS: Compared with patients without LVDD, patients with LVDD had a higher level of low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FPG), and asprosin, but a lower level of early diastolic movement speed (A) to diastolic movement velocity (E) (E/A). Asprosin was positively associated with waist circumference (WC), body mass index (BMI), creatinine, triglycerides (P < 0.05), and negatively associated with E/A and high density lipoprotein cholesterol HDL-C (P < 0.05). The risk of LVDD increased with elevated asprosin levels after adjustment for age, systolic blood pressure (SBP), BMI, FPG, and LDL-C. Compared with patients in the lowest tertile of serum asprosin (<275.25 pg/mL), a serum level of asprosin between 275.25-355.08 pg/mL [OR (95% CI) is 2.368 (1.169-4.796), P < 0.05] and asprosin >355.08 pg/mL [OR (95% CI) is 2.549 (1.275-5.095), P < 0.05] patients have a higher risk of left ventricular diastolic dysfunction. CONCLUSIONS: Serum asprosin was positively associated with left ventricular diastolic dysfunction, and the risk of LVDD increased significantly with increased serum levels of asprosin.

Glucose metabolism profile recorded by flash glucose monitoring system in patients with hypopituitarism during prednisone replacement.

BACKGROUND: Commonly used glucocorticoids replacement regimens in patients with hypopituitarism have difficulty mimicking physiological cortisol rhythms and are usually accompanied by risks of over-treatment, with adverse effects on glucose metabolism. Disorders associated with glucose metabolism are established risk factors of cardiovascular events, one of the life-threatening ramifications. AIM: To investigate the glycometabolism profile in patients with hypopituitarism receiving prednisone (Pred) replacement, and to clarify the impacts of different Pred doses on glycometabolism and consequent adverse cardiovascular outcomes. METHODS: Twenty patients with hypopituitarism receiving Pred replacement [patient group (PG)] and 20 normal controls (NCs) were recruited. A flash glucose monitoring system was used to record continuous glucose levels during the day, which provided information on glucose-target-rate, glucose variability (GV), period glucose level, and hypoglycemia occurrence at certain periods. Islet ß-cell function was also assessed. Based on the administered Pred dose per day, the PG was then regrouped into Pred > 5 mg/d and Pred ≤ 5 mg/d subgroups. Comparative analysis was carried out between the PG and NCs. RESULTS: Significantly altered glucose metabolism profiles were identified in the PG. This includes significant reductions in glucose-target-rate and nocturnal glucose level, along with elevations in GV, hypoglycemia occurrence and postprandial glucose level, when compared with those in NCs. Subgroup analysis indicated more significant glucose metabolism impairment in the Pred > 5 mg/d group, including significantly decreased glucose-target-rate and nocturnal glucose level, along with increased GV, hypoglycemia occurrence, and postprandial glucose level. With regard to islet ß-cell function, PG showed significant difference in homeostasis model assessment (HOMA)-ß compared with that of NCs; a notable difference in HOMA-ß was identified in Pred > 5 mg/d group when compared with those of NCs; as for Pred ≤ 5 mg/d group, significant differences were found in HOMA-ß, and fasting glucose/insulin ratio when compared with NCs. CONCLUSION: Our results demonstrated that Pred replacement disrupted glycometabolic homeostasis in patients with hypopituitarism. A Pred dose of > 5 mg/d seemed to cause more adverse effects on glycometabolism than a dose of ≤ 5 mg/d. Comprehensive and accurate evaluation is necessary to consider a suitable Pred replacement regimen, wherein, flash glucose monitoring system is a kind of promising and reliable assessment device. The present data allows us to thoroughly examine our modern treatment standards, especially in difficult cases such as hormonal replacement mimicking delicate natural cycles, in conditions such as diabetes mellitus that are rapidly growing in worldwide prevalence.

Integrin ß6 mediates epithelial-mesenchymal transition in diabetic kidney disease.

The progression of diabetic kidney disease (DKD) is associated with increased fibronectin (FN) levels in proximal tubular epithelial cells. Bioinformatics analysis showed that integrin ß6 and cell adhesion function were significantly changed in the cortices of db/db mice. Remodelling of cell adhesion is one of the core changes during epithelial-mesenchymal transition (EMT) in DKD. Integrin is a family of transmembrane proteins that regulates cell adhesion and migration, and extracellular FN is the major ligand of integrin ß6. We found that the expression of integrin ß6 was elevated in the proximal tubules of db/db mice and FN-induced renal proximal tubule cells. The levels of EMT were also significantly increased in vivo and in vitro. In addition, FN treatment activated the Fak/Src pathway, increased the expression of p-YAP, and then upregulated the Notch1 pathway in diabetic proximal tubules. Knockdown of integrin ß6 or Notch1 reduced the EMT aggravation induced by FN. Furthermore, urinary integrin ß6 was significantly increased in DKD patients. Our findings reveal a critical role of integrin ß6 in regulating EMT in proximal tubular epithelial cells and identify a novel direction for the detection and treatment of DKD.

Research on the Sustainable Renewal of Architectural Heritage Sites from the Perspective of Extenics-Using the Example of Tulou Renovations in LantianVillage, Longyan City.

Fujian Tulous in China are important international architectural heritage sites that reflect precious human cultural heritage. Currently, only a small number of Tulou buildings have been listed as world cultural heritage sites, resulting in a lack of attention and financial support for most Tulou buildings. Thus, it is difficult to effectively renovate and repair Tulou buildings to adapt to modern life, and therefore they are facing the severe challenge of abandonment and desolation. Due to the special conditions of Tulou buildings, there are significant limitations in renovation and repair work, with a number of problems such as the lack of innovative renovations. Therefore, through a problem model analysis of a design system for Tulou renovations, in this study, we adopt the methods of divergent tree, conjugate pair, correlative net, implied system, and split-merge chain analyses in extenics to carry out extension transformation and solve the problem and we verify its feasibility using the example of the Tulou renovation projects in Lantian Village, Longyan City. We explore an innovative methodology for scientific renovation of Tulou buildings, and we establish a design system for Tulou building renovations that enriches and supplements original renovation methods; thus, we provide a basis for the repair and reuse of Tulou buildings, to extend their service life and to realize the sustainable development of Tulou buildings. The research results show that extenics can be implemented in innovative renovations of Tulou buildings, and it is concluded that the essence of achieving sustainable renewal in Tulou building renovations is to solve contradictory problems, including contradictions in conditions, objectives, and design. This study verifies the possibility of applying extenics in the design of Tulou building renovations, makes corresponding contributions to the application of extension methods in the renovation and renewal of Tulou buildings, and also contributes to the renovation, renewal, and protection of other types of architectural heritage sites.

Rare combination of simple virilizing form of 21-hydroxylase deficiency, Graves' disease and 47, XXX in a woman: A case report.

RATIONALE: Coexistence of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Graves' disease and 47, XXX is rare. We report a case of a 25-year-old woman presented with masculine appearance, hirsutism and enlarged clitoris. Lab tests showed elevated serum 17 hydroxyprogesterone, testosterone, dehydroepiandrosterone. Gene test revealed heterozygous gene mutation in CYP21A2:NM_000500:exon4:c.518 T > A, NM_000500:exon8:c.C1024T. Karyotype analysis showed 47, XXX. After prednisone replacement and antithyroid therapy, she got a normal menstruation and normal level of testosterone. These findings demonstrate that patients with abnormal chromosome are likely to combine 21-hydroxylase deficiency (21-OHD), thus karyotyping test should not be neglected for those who have been already diagnosed as 21-OHD. Additionally, chromosomal abnormality such as 47, XXX and Turner syndrome had susceptibility to develop autoimmune thyroid disease because a gene on X chromosome may be responsible for the occurrence of autoimmune thyroid disease. Moreover, both 21-OHD and Graves' disease (GD) can lead to high level of testosterone, thus we should keep in mind to test chromosome and thyroid function in 21-OHD patients to avoid misdiagnose or missed diagnosis. To the best of our knowledge, this is the first report of simple virilizing (SV) 21-OHD patient combined with 47, XXX and Graves disease. PATIENT CONCERNS: A 24-years-old female of Han ethnicity was admitted to the endocrinology department complaining of absence of menses for half a year. The patient didn't noticed her enlarged clitoris until she was 17 years old. Her menarche was 16 years old and the final height was 163 centimeter. She was diagnosed with GD 2 months before admission to our hospital due to palpitation, heat intolerance, muscle weakness. DIAGNOSES: The patient was diagnosed with SV 21-OHD, Graves disease and 47, XXX. INTERVENTIONS: At first, the patient was given 10 mg methimazole twice a day as well as 5 mg predisone in the morning and 2.5 mg in the evening. After a year of regular medication and reexamination, she got a regular menstruation and thyroid function and now is taking 2.5 mg prednisone twice a day. OUTCOMES: The patient got a regular menstruation and thyroid function. Laboratory results showed: testosterone declined to 0.1nmol/L (0.1-1.67nmol/L) and 17 hydroxyprogesterone get back to normal level: 1.01ng/ml (0.30-2.34ng/mL). However, her enlarged clitoris has not narrowed. LESSONS: Patients with abnormal chromosome are likely to combine 21-OHD, thus karyotyping test should not be neglected for those who have been already diagnosed as 21-OHD. Additionally, chromosomal abnormality such as 47, XXX and Turner syndrome had susceptibility to develop autoimmune thyroid disease because a gene on X chromosome may be responsible for the occurrence of autoimmune thyroid disease. Moreover, both 21-OHD and GD can lead to high level of testosterone, thus we should keep in mind to test chromosome and thyroid function in 21-OHD patients to avoid misdiagnose or missed diagnosis. To the best of our knowledge, this is the first report of SV 21-OHD patient combined with 47, XXX and Graves disease.

Association Between Serum Asprosin and Diabetic Nephropathy in Patients with Type 2 Diabetes Mellitus in the Community: A Cross-Sectional Study.

Objective: To explore the association between serum asprosin and diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM) in the community. Methods: In this cross-sectional study, we retrospectively collected the clinical data of T2DM patients from a community health service center in southeastern Shanxi Province between November 2019 and July 2021. Logistic regression analysis was used to calculate the odds ratio (OR) and the 95% confidence interval (95% CI) of asprosin levels on the risk of DN. Results: Among 498 T2DM patients included in this study, 221 had microalbuminuria, 105 had massive albuminuria, and 172 did not have any signs of nephropathy. Serum asprosin level was positively correlated with diastolic blood pressure, body mass index, triglycerides, aspartate aminotransferase, alanine aminotransferase, creatinine, ACR and albumin-to-creatinine ratio (all P < 0.05) and negatively correlated with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fasting plasma glucose, HbA1c and estimated glomerular filtration rate (all P < 0.05). After adjusting for covariates, increased asprosin was associated with diabetic nephropathy (all OR = 2.560, 95% CI: 1.1592-4.116; P < 0.001). Conclusion: The risk of DN significantly increases with serum asprosin levels, especially among female patients.

Smartphone-Based Platforms for Clinical Detections in Lung-Cancer-Related Exhaled Breath Biomarkers: A Review.

Lung cancer has been studied for decades because of its high morbidity and high mortality. Traditional methods involving bronchoscopy and needle biopsy are invasive and expensive, which makes patients suffer more risks and costs. Various noninvasive lung cancer markers, such as medical imaging indices, volatile organic compounds (VOCs), and exhaled breath condensates (EBCs), have been discovered for application in screening, diagnosis, and prognosis. However, the detection of markers still relies on bulky and professional instruments, which are limited to training personnel or laboratories. This seriously hinders population screening for early diagnosis of lung cancer. Advanced smartphones integrated with powerful applications can provide easy operation and real-time monitoring for healthcare, which demonstrates tremendous application scenarios in the biomedical analysis region from medical institutions or laboratories to personalized medicine. In this review, we propose an overview of lung-cancer-related noninvasive markers from exhaled breath, focusing on the novel development of smartphone-based platforms for the detection of these biomarkers. Lastly, we discuss the current limitations and potential solutions.

Empagliflozin Inhibits Hepatic Gluconeogenesis and Increases Glycogen Synthesis by AMPK/CREB/GSK3ß Signalling Pathway.

Increases in glucose production and decreases in hepatic glycogen storage induce glucose metabolic abnormalities in type 2 diabetes (T2DM). Empagliflozin, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, is an effective hypoglycemic drug; however, the effects of empagliflozin on hepatic gluconeogenesis and glycogenesis are still unclear. In this study, we investigated the effects and mechanisms of empagliflozin on hepatic gluconeogenesis and glycogenesis in vivo and in vitro. Empagliflozin was administered via gavage to db/db mice for 8 weeks, and human hepatocyte HL7702 cells were treated with empagliflozin after palmitic acid (PA) stimulation. Compared with the control db/db mice, empagliflozin-treated mice showed a significant reduction in urine glucose levels, blood glucose levels, body weight and intraperitoneal glucose tolerance test (IPGTT) blood glucose levels. Moreover, the expression levels and activities of key gluconeogenesis enzymes PEPCK and G6Pase were dramatically reduced in the empagliflozin-treated mice, and the protein expression levels of AMPK/CREB/GSK3ß signalling pathway-related molecules were significantly changed. In HL7702 cells, empagliflozin ameliorated glucose production and PEPCK and G6Pase expression and activity. Empagliflozin could also prevent the decreases in glycogen content and regulate the protein expression levels of AMPK/CREB/GSK3ß signalling pathway-related molecules. Then, we selected the AMPK agonist AICAR and inhibitor compound C to further verify the effects of the AMPK signalling pathway on hepatic gluconeogenesis and glycogen synthesis. The results of the 5-Aminoimidazole-4-carboxamide1-ß-D-ribofuranoside (AIACR) intervention in HL7702 cells were consistent with those of empagliflozin treatment, and the effects of empagliflozin were abolished by compound C. In summary, empagliflozin could maintain glucose homoeostasis by reducing gluconeogenesis and increasing glycogenesis through the AMPK/CREB/GSK3ß signalling pathway.

Artificial Intelligent Olfactory System for the Diagnosis of Parkinson's Disease.

Background: Currently, Parkinson's disease (PD) diagnosis is mainly based on medical history and physical examination, and there is no objective and consistent basis. By the time of diagnosis, the disease would have progressed to the middle and late stages. Pilot studies have shown that a unique smell was present in the skin sebum of PD patients. This increases the possibility of a noninvasive diagnosis of PD using an odor profile. Methods: Fast gas chromatography (GC) combined with a surface acoustic wave sensor with embedded machine learning (ML) algorithms was proposed to establish an artificial intelligent olfactory (AIO) system for the diagnosis of Parkinson's through smell. Sebum samples of 43 PD patients and 44 healthy controls (HCs) from Fourth Affiliated Hospital of Zhejiang University School of Medicine, China, were smelled by the AIO system. Univariate and multivariate methods were used to identify the significant volatile organic compound (VOC) features in the chromatograms. ML algorithms, including support vector machine, random forest (RF), k nearest neighbor (KNN), AdaBoost (AB), and Naive Bayes (NB), were used to distinguish PD patients from HC based on the VOC peaks in the chromatograms of sebum samples. Results: VOC peaks with average retention times of 5.7, 6.0, and 10.6 s, respectively, corresponding to octanal, hexyl acetate, and perillic aldehyde, were significantly different in PD and HC. The accuracy of the classification based on the significant features was 70.8%. Based on the odor profile, the classification had the highest accuracy and F1 of the five models with 0.855 from NB and 0.846 from AB, respectively, in the process of model establishing. The highest specificity and sensitivity of the five classifiers were 91.6% from NB and 91.7% from RF and KNN, respectively, in the evaluating set. Conclusions: The proposed AIO system can be used to diagnose PD through the odor profile of sebum. Using the AIO system is helpful for the screening and diagnosis of PD and is conducive to further tracking and frequent monitoring of the PD treatment process.

Empagliflozin Induces White Adipocyte Browning and Modulates Mitochondrial Dynamics in KK Cg-Ay/J Mice and Mouse Adipocytes.

Background: White adipose tissue (WAT) browning is a promising target for obesity prevention and treatment. Empagliflozin has emerged as an agent with weight-loss potential in clinical and in vivo studies, but the mechanisms underlying its effect are not fully understood. Here, we investigated whether empagliflozin could induce WAT browning and mitochondrial alterations in KK Cg-Ay/J (KKAy) mice, and explored the mechanisms of its effects. Methods: Eight-week-old male KKAy mice were administered empagliflozin or saline for 8 weeks and compared with control C57BL/6J mice. Mature 3T3-L1 adipocytes were treated in the presence or absence of empagliflozin. Mitochondrial biosynthesis, dynamics, and function were evaluated by gene expression analyses, fluorescence microscopy, and enzymatic assays. The roles of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1-alpha (PGC-1α) were determined through AICAR (5-Aminoimidazole-4-carboxamide1-ß-D-ribofuranoside)/Compound C and RNA interference, respectively. Results: Empagliflozin substantially reduced the bodyweight of KKAy mice. Mice treated with empagliflozin exhibited elevated cold-induced thermogenesis and higher expression levels of uncoupling protein 1 (UCP1) and other brown adipose tissue signature proteins in epididymal and perirenal WAT, which was an indication of browning in these WAT depots. At the same time, empagliflozin enhanced fusion protein mitofusin 2 (MFN2) expression, while decreasing the levels of the fission marker phosphorylated dynamin-related protein 1 (Ser616) [p-DRP1 (Ser616)] in epididymal and perirenal WAT. Empagliflozin also increased mitochondrial biogenesis and fusion, improved mitochondrial integrity and function, and promoted browning of 3T3-L1 adipocytes. Further, we found that AMPK signaling activity played an indispensable role in empagliflozin-induced browning and mitochondrial biogenesis, and that PGC-1α was required for empagliflozin-induced fusion. Whether empagliflozin activates AMPK by inhibition of SGLT2 or by independent mechanisms remains to be tested. Conclusion: Our results suggest that empagliflozin is a promising anti-obesity treatment, which can immediately induce WAT browning mitochondrial biogenesis, and regulate mitochondrial dynamics.

Calculated indices of volatile organic compounds (VOCs) in exhalation for lung cancer screening and early detection.

BACKGROUND: Breath analysis is a promising noninvasive technique that offers a wide range of opportunities to facilitate early diagnosis of lung cancer (LC). METHOD: Exhaled breath samples of 352 subjects including 160 with lung cancer (LC), 70 with benign pulmonary nodule (BPN) and 122 healthy controls (HC) were analyzed through thermal desorption coupled with gas chromatography-mass spectrometry (TD-GC-MS) to obtain the metabolic information from volatile organic compounds (VOCs). Statistical classification models were used to find diagnostic clusters of VOCs for the discrimination of HC, BPN and LC patients' early and advanced stages, as well as subtypes of LC. Receiver operator characteristics (ROC) curves with 5-fold validations were used to evaluate the accuracy of these models. RESULTS: The analysis revealed that 20, 19, 19, and 20 VOCs discriminated LC from HC, LC from BPN, histology and LC stages respectively. The calculated diagnostic indices showed a large area under the curve (AUC) to distinguish HC from LC (AUC: 0.987, 95 % confidence interval (CI): 0.976-0.997), BPN from LC (AUC: 0.809, 95 % CI: 0.758-0.860), NSCLC from SCLC (AUC: 0.939, 95 % CI: 0.875-0.995) and Stage III from stage III-IV (AUC: 0.827, 95 % CI: 0.768-0.886). The comparison between the high-risk groups (BPN and HC smokers) and early stages LC resulted in the AUC of 0.756 (95 %CI: 0.681-0.817) for BPN vs. early stage LC and AUC of 0.986 (95 % CI: 0.972-0.994) for HC smoker vs. early stage LC. CONCLUSION: Volatome of breath of the LC patients was significantly different from that of both BPN patients and HC and showed an ability of distinguishing early from advance stage LC and NSCLC from SCLC. We conclude that the volatome has a potential to help improve early diagnosis of LC.

Urinary miR-3137 and miR-4270 as potential biomarkers for diabetic kidney disease.

BACKGROUND: As one of the most prevalent diagnostic indicators of diabetic kidney disease (DKD), albumin-to-creatinine ratio (ACR) shows considerably limited predictive power in clinical application. We analyzed microarray expression profiling of urine to seek for differentially expressed miRNAs for potential biomarkers of DKD. METHODS: Urine samples from type 2 diabetes mellitus (T2DM) patients with (30 mg/g < ACR < 300 mg/g, DKD group) or without DKD (ACR < 30 mg/g, DM group) were collected for miRNA microarray analysis. The differentially expressed miRNAs were screened by bioinformatics analysis and validated by quantitative real-time PCR. Target genes of differentially expressed miRNAs were predicted in miRDB, Targetscan, and microRNA.org databases. We also conducted the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways analysis to explore for potential mechanisms in DKD. RESULTS: Nine miRNAs were down-regulated and seventeen miRNAs were up-regulated in DKD group, compared to DM group. The levels of miR-3137 and miR-4270 in DKD group were 0.670 ± 0.505 and 2.116 ± 1.762 times than those in DM group, respectively, showing great significance. A total of 1076 target genes were simultaneously predicted by miRDB, Targetscan, and microRNA.org databases. According to the GO analysis results, disorders of endomembrane system may be one of the major pathological changes in DKD. In addition, Rap 1 signaling pathway is also altered obviously in DKD, discovered by the KEGG analysis. CONCLUSION: MiR-3137 and miR-4270 show the potential for urinary biomarkers of DKD. The pathological changes of DKD may be related to disorders of endomembrane system and alternation of Rap1 signaling pathway.

Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway.

BACKGROUND AND PURPOSE: Excessive mitochondrial fission was observed in diabetic kidney disease (DKD). Phosphoglycerate mutase family member 5 (PGAM5) plays an important role in mitochondrial fission by dephosphorylating the dynamin-related protein 1 at Ser637 (DRP1S637). Whether PGAM5 participates in the mitochondrial fission in diabetic renal tubular injury is unknown. Clinical trials have observed encouraging effect of Sodium-glucose cotransporter 2 (SGLT2) inhibitors on DKD though the underling mechanisms remain unclear. EXPERIMENTAL APPROACH: We used KK-Ay mice as diabetic model and Empagliflozin (Empa) were administrated by oral gavage. The mitochondrial fission and the expressions of phosphorylated AMP-activated protein kinase (p-AMPK), specificityprotein1 (SP1), PGAM5 and DRP1S637 were tested. We also examined these changes in HK2 cells that cultured in normal glucose (NG), high glucose (HG) and high glucose+Empa (HG + Empa) environment. Then we verified our deduction using AMPK activator (5-aminoimidazole-4-carboximide Riboside, AICAR), inhibitor (Compound C), si-SP1 and si-PGAM5. Lastly, we testified the interaction between SP1 and the PGAM5promotor by CHIP assay. KEY RESULTS: The mitochondrial fission and the expression of SP1, PGAM5 increased and the expression of p-AMPK, DRP1S637 decreased in diabetic or HG environment. These changes were all reversed in Empa or AICAR treated groups. These reversal effects of Empa could be diminished by Compound C. Either si-SP1 or si-PGAM5 could alleviate the mitochondrial fission without affection on AMPK phosphorylation. Finally, the CHIP assay confirmed the interaction between SP1 and the PGAM5 promotor. CONCLUSIONS AND IMPLICATIONS: The PGAM5 aggravated the development of diabetic renal tubular injury and the Empa could improve the DKD by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway.

Investigation of nicotinamide as more than an anti-phosphorus drug in chronic hemodialysis patients: a single-center, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Hyperphosphatemia is a common complication of late-stage chronic kidney disease (CKD). Nicotinamide (NAM) has been reported as an adjunctive therapy for hyperphosphatasemia, but the effect of NAM on fibroblast growth factor 23 (FGF23) and Klotho has rarely been reported. METHODS: We randomly assigned 98 patients who underwent regular hemodialysis to received NAM (0.5-1.5 g per day, or 1-3 tablets per day) or placebo (1-3 tablets per day) as an add-on therapy of calcium-based phosphorus binders in a 1:1 ratio. All enrollments were followed-up for 52 weeks. We investigated the serum phosphorus as the primary outcome and serum FGF23 and Klotho as the secondary outcomes. Abdominal aortic calcification (AAC), which had a good correlation with coronary calcification was also compared between the two groups. RESULTS: In total, 37 patients in the placebo group and 35 patients in the NAM group completed the 52-week follow-up. Compared with the placebo group, the NAM group showed a significant decrease of serum phosphorus at the 8th, 12th, 20th, 44th, and 52nd week. There was a declining trend of FGF23 and Klotho in both the placebo and NAM groups. Linear mixed models (LMMs) for overall comparisons by repeated measures of analysis of variance (ANOVA) revealed a significant decrease of FGF23 and slower declining rate of Klotho in the NAM group. No significant difference of AAC was detected between the two groups (P=0.805). CONCLUSIONS: NAM can not only further decrease the phosphorus level but also reduce the FGF23 level and slow down the descending rate of Klotho in chronic hemodialysis patients.

Generation of stable orbital angular momentum beams with an all-polarization-maintaining fiber structure.

In this paper, we propose a stable orbital angular momentum (OAM) mode fiber laser with an all-polarization-maintaining fiber (PMF) structure based on a combination of two linearly polarized modes. The mode intensity ratio between the two linearly polarized modes can be adjusted by adopting a double-pump structure. A pair of polarization-maintaining long-period fiber gratings (PM-LPFGs) are used as a mode converter. The number of topological charges of the OAM mode beam can be tuned between +1 and -1 by stretching the fiber. By adopting an all-PMF structure, we can build an OAM mode fiber laser without a polarization controller and that is resistant to environmental disturbances. The purity of the OAM mode was approximately 93.6%. This stable and compact OAM mode fiber laser can be used as a laser source in practical applications and scientific research.

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro.

Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood. Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels. Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment. Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

Association between serum uric acid and nonalcoholic fatty liver disease in community patients with type 2 diabetes mellitus.

BACKGROUND: To investigate whether SUA is associated with NAFLD in men and women with T2DM. METHODS: This cross-sectional study enrolled patients with T2DM at Shanxi High-Tech Development Zone Central Hospital (June 2011 to September 2017). Patients were stratified according to gender and presence/absence of NAFLD. Parameters associated with NAFLD were identified using multivariate stepwise linear regression and univariate/multivariate logistic regression. RESULTS: Among 597 patients (325 males) enrolled, 352 had NAFLD. SUA was higher in the NAFLD group than in the non-NAFLD group for both men and women (P < 0.001). Multiple linear regression showed that body mass index (positively), triglycerides (positively) and estimated glomerular filtration rate (negatively) were independently related to SUA (P < 0.001). Univariate logistic regression revealed increased odds of NAFLD for SUA tertiles 2 (P = 0.022) and 3 (P = 0.001) in women and tertile 3 (P = 0.039) in men. After adjustment for multiple clinical parameters, SUA tertiles were significantly associated with NAFLD for tertile 3 in women (P = 0.014), although there were trends toward associations for tertile 2 in women (P = 0.074) and tertiles 2 and 3 in men (P = 0.085 and 0.054, respectively). CONCLUSION: SUA is not independently associated with NAFLD in men or women with T2DM after rigorous adjustment for other metabolic parameters.

Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice.

Cardiovascular complications contribute to the major mortality and morbidity in type 2 diabetes. Diabetic cardiomyopathy (DCM) is increasingly recognized as an important cause of heart failure. EMPA-REG OUTCOME trial has reported that empagliflozin, the sodium-glucose cotransporter 2 inhibitor, exerts cardiovascular benefits on diabetic population. However, the mechanism by which empagliflozin alleviates DCM still remains unclear. In the current study, we investigated the cardiac protective effects of empagliflozin on spontaneous type 2 diabetic db/db mice and its potential mechanism. Eight weeks of empagliflozin treatment (10 mg/kg/day) decreased body weight and blood glucose level, and increased urinary glucose excretion (UGE) in diabetic mice. Echocardiography revealed that both systolic and diastolic functions of db/db mice were also obviously improved by empagliflozin. Furthermore, empagliflozin-treated diabetic mice presented with amelioration of cardiac hypertrophy and fibrosis. In addition, diabetic hearts exhibited the deterioration of oxidative stress, apoptosis and pyroptosis, while these effects were significantly counteracted after empagliflozin treatment. Moreover, empagliflozin rescued diabetes-induced suppression of sGC (soluble guanylate cyclase enzyme)-cGMP (cyclic guanosine monophosphate)-PKG (cGMP-dependent protein kinase) pathway. However, when sGC-ß expression of hearts was inhibited by transvascular delivery of small interfering RNA, cardiac dysfunction was aggravated and the advantages of empagliflozin were reversed through inhibiting sGC-cGMP-PKG pathway. Collectively, these findings indicate that empagliflozin improves cardiac function involving the inhibition of oxidative stress-induced injury via sGC-cGMP-PKG pathway and may be a promising therapeutic option for DCM.

Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: An updated meta-analysis.

BACKGROUND: The aim of the study is to update and determine the effects of sodium glucose cotransporter 2 (SGLT2) inhibitor therapy on fracture and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM). METHODS: We identified 27 eligible randomized controlled trials (RCTs) that compared the efficacy and safety of SGLT2 inhibitors to a placebo in 20 895 T2DM participants, with an average duration of 64.22 weeks. The relative risk (RR) of bone fracture and weighted mean difference (WMD) of changes in the BMD from baseline were determined to evaluate the risk of fracture. The degree of heterogeneity was evaluated by the I2 statistic, and publication bias was estimated using a funnel plot and Egger test. RESULTS: The pooled RR was 1.02 (95% CI [0.81, 1.28]) with low heterogeneity, indicating that SGLT2 inhibitor treatment was not correlated with a higher risk of fracture. Additionally, no increased risk was found for patients with different ages, sexes, and levels of HbA1c and some biochemical indicators. Three trials with 1303 patients reported a change in the BMD from baseline. SGLT2 inhibitor treatment did not decrease the BMD at four skeletal sites (lumbar spine, femoral neck, total hip, and distal forearm), and the overall WMD was 0.08 (95% CI [-0.09, 0.26]). No significant publication bias was detected. CONCLUSIONS: No increased risk for bone fracture was detected in patients with T2DM treated with SGLT2 inhibitors in this meta-analysis. SGLT2 inhibitor therapy did not appear to affect bone health, but more long-term detailed data are needed to validate this conclusion.