Combined serum CTRP7 and CTRP15 levels as a novel biomarker for insulin resistance and type 2 diabetes mellitus.

Aims: This study aimed to examine the alterations in the serum CTRP7 and CTRP15 concentrations in patients newly diagnosed with type 2 diabetes mellitus (T2DM) and to assess the diagnostic potential of the log10 (CTRP7+CTRP15) for insulin resistance (IR) and T2DM. Methods: Serum CTRP7, CTRP15, and adiponectin levels were measured using an enzyme-linked immunosorbent assay (ELISA). Bioinformatics analysis was conducted to investigate CTRP7 and CTRP15-related genes and metabolic signaling pathways. Results: Log10 (CTRP7+CTRP15) levels were notably elevated in the impaired glucose tolerance (IGT) and T2DM cohorts compared with those in the normal control (NGT) cohort. Log10(CTRP7+CTRP15) exhibited positive correlations with HOMA-IR, area under the glucose curve (AUCg), HbA1c%, triglyceride (TG), visceral adiposity index (VAI), body mass index (BMI), and free fatty acid (FFA), levels but negative correlations with adiponectin. Multivariate stepwise regression analysis revealed that HOMA-IR, BMI, HbA1c and FFA levels were independent factors affecting the log10 (CTRP7+CTRP15). Logistic regression analysis revealed that log10 (CTRP7+CTRP15) was independently associated with T2DM and significantly associated with increased risk. Receiver operating characteristic (ROC) curve analysis indicated that the predictive value of log10 (CTRP7+CTRP15) for T2DM and IR was superior to that of CTRP7 or CTRP15 alone. Intervention studies demonstrated that insulin, FFAs and acute exercise contribute to the elevation of serum CTRP7 levels, while hyperglycemia inhibited CTRP7 secretion. Short-term changes in blood glucose, insulin, FFA and acute exercise had minimal effects on serum CTRP15 levels. Bioinformatics analysis revealed that CTRP7 and CTRP15 interact with multiple metabolism-related genes and are enriched in glucose and lipid metabolism-related pathways. Conclusion: Log10 (CTRP7+CTRP15) may serve as a valuable diagnostic marker for the management of metabolic-related diseases, particularly T2DM and IR.

Metabolic dysfunction, rather than obesity, is a risk factor for chronic kidney disease in Chinese population.

BACKGROUND: Metabolic dysfunction and obesity are closely related to chronic kidney disease (CKD). However, studies on the relationship between various metabolic syndrome-body mass index (MetS-BMI) phenotypes and the risk of CKD in the Chinese population have not yet been explored. MATERIALS AND METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) 2015 were analyzed in this study. This study enrolled 12,054 participants. Participants were divided into six distinct groups according to their MetS-BMI status. Across the different MetS-BMI groups, the odd ratios (ORs) for CKD were determined using multivariable logistic regression models. RESULTS: The prevalence of CKD was higher in metabolically unhealthy groups than in the corresponding healthy groups. Moreover, the fully adjusted model showed that all metabolically unhealthy individuals had an increased risk of developing CKD compared to the metabolically healthy normal weight group (OR = 1.62, p = 0.002 for the metabolically unhealthy normal weight group; OR = 1.55, p < 0.001 for the metabolically unhealthy overweight group; and OR = 1.77, p < 0.001 for the metabolically unhealthy obesity group. CONCLUSIONS: This study is the first to evaluate the relationship between the MetS-BMI phenotype and renal prognosis in the Chinese population. Individuals with normal weights are at different risk of developing CKD depending on their different metabolic phenotypes.

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Association of lactate dehydrogenase and diabetic retinopathy in US adults with diabetes mellitus.

OBJECTIVES: The purpose of our investigation is to evaluate the level of relationship between lactate dehydrogenase (LDH) and the occurrence of diabetic retinopathy (DR) in adults with diabetes mellitus (DM). METHODS: The investigation involved an analysis of five sectional data cycles acquired from the National Health and Nutrition Examination Survey from 2009 to 2018. The present study involved the selection of DM samples from a complex multistage probability sample. These samples were subsequently classified into two distinct groups, namely the No DR (NDR) and DR groups. The present study comprehensively investigated the biological and social risk factors associated with DR. The biological factors examined in this investigation included blood pressure, blood routine, hemoglobin A1c, blood glucose, and comorbidities. The social dimensions encompass education and sex. RESULTS: After considering all factors, multivariate regression models indicated a significant relationship between DR and increased LDH (adjusted odds ratio = 1.007, 95% confidence interval: 1.003-1.011). The subgroup analysis revealed that the effect size of LDH on the existence of DR in the subgroups remained consistent, as indicated by all p values greater than .05. A statistically significant relationship was identified between elevated LDH levels > 134 U/L and a raised risk of DR in people with DM. CONCLUSION: LDH concentrations were connected with an increased prevalence of DR in participants with DM. Our study highlights that patients with LDH > 134 U/L are distinguishably related to DM complicated by DR. DR is more common in diabetic individuals with coronary heart disease.

Mesenchymal stem cells-based drug delivery systems for diabetic foot ulcer: A review.

The complication of diabetes, which is known as diabetic foot ulcer (DFU), is a significant concern due to its association with high rates of disability and mortality. It not only severely affects patients' quality of life, but also imposes a substantial burden on the healthcare system. In spite of efforts made in clinical practice, treating DFU remains a challenging task. While mesenchymal stem cell (MSC) therapy has been extensively studied in treating DFU, the current efficacy of DFU healing using this method is still inadequate. However, in recent years, several MSCs-based drug delivery systems have emerged, which have shown to increase the efficacy of MSC therapy, especially in treating DFU. This review summarized the application of diverse MSCs-based drug delivery systems in treating DFU and suggested potential prospects for the future research.

Effect of C-reactive protein deficiency on insulin resistance reversal in rats with polycystic ovary syndrome through augmented leptin action.

BACKGROUND: C-reactive protein(CRP), is an inflammatory marker that weaken leptin bioavailability and insulin sensitivity to disturb energy and glucose metabolism. Polycystic ovary syndrome (PCOS) exhibit a metabolic component consisting of higher plasma CRP levels, hyperinsulinemic and hyperleptinemia. The ability of leptin to regulation of hepatic glucose production (HGP) in the absence of CRP in PCOS remain unknown. METHODS: Dehydroepiandrosterone (DHEA) was used to induce PCOS in rats. We assessed the effects of CRP gene knockout in PCOS model rats on body weight, energy expenditure glucose metabolism and insulin sensitivity. We conducted experiments involving the administration of leptin to both the peripheral and central systems in PCOS model rats with CRP knockout, and studied the effects on changes in glucose kinetics during hyperinsulinemic-euglycemic clamps. RESULTS: In female PCOS rats, the lack of CRP resulted in decreased leptin resistance and weight gain, increased energy expenditure, and improved insulin sensitivity. Additionally, the deletion of the CRP gene strengthened the HGP-lowering effects of leptin when administered peripherally or centrally. This effect was accompanied by a decrease in the expression of hepatic gluconeogenic enzymes and an increase in hepatic insulin signaling. Finally, inhibition of glucose production was also enhanced for central leptin administration during lipid infusion in PCOS rats. CONCLUSIONS: Our findings highlight the therapeutic potential of targeting CRP to restore glucose homeostasis and insulin sensitivity for leptin in PCOS.

Adiponectin and metabolic cardiovascular diseases: Therapeutic opportunities and challenges.

Metabolic cardiovascular diseases have become a global health concern, and some of their risk factors are linked to several metabolic disorders. They are the leading causes of death in developing countries. Adipose tissues secrete a variety of adipokines that participate in regulating metabolism and various pathophysiological processes. Adiponectin is the most abundant pleiotropic adipokine and can increase insulin sensitivity, improve atherosclerosis, have anti-inflammatory properties, and exert a cardioprotective effect. Low adiponectin concentrations are correlated with myocardial infarction, coronary atherosclerotic heart disease, hypertrophy, hypertension, and other metabolic cardiovascular dysfunctions. However, the relationship between adiponectin and cardiovascular diseases is complex, and the specific mechanism of action is not fully understood. Our summary and analysis of these issues are expected to contribute to future treatment options.

Hedgehog interacting protein as a circulating biomarker in women with obesity: a cross-sectional study and intervention studies.

BACKGROUND: Although a study found a significant increase in serum hedgehog interacting protein (HHIP) concentrations in impaired fasting blood glucose, impaired glucose tolerance and newly diagnosed T2DM patients, the variation in circulating HHIP levels in obese individuals remains unknown. PATIENTS AND METHODS: Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes and signal pathways. The study is comprised of a total of 452 young women, including 248 obese individuals and 204 controls. Circulating HHIP and Adipoq levels were determined with ELISA kits. Euglycemic-hyperinsulinemic clamps (EHC) and oral glucose tolerance test (OGTT) were conducted in every subject. 32 women were given metformin and 49 were given liraglutide treatment for 6 weeks. The study was registered with www.chictr.org.cn (ChiCTR2000032878 and ChiCTR1800019776). RESULTS: Obesity was significantly associated with the cAMP signal pathway, and HHIP was a secreted protein related to cAMP signalling, as determined by KEGG analysis. In this population-based cohort study, we found that the level of circulating HHIP was significantly elevated in obese women, and positively correlated with body mass index and blood glucose, blood lipid, insulin, homeostasis model assessment of insulin resistance, dehydroepiandrostenedione sulphate, and luteinizing hormone, while negatively correlated with M-value and Adipoq. Insulin resistance (IR) and ove™rweight/obesity were associated with the higher HHIP concentration. OGTT and EHC tests revealed that the levels of circulating HHIP were regulated by blood glucose but to a less extent by insulin. After therapy with metformin and liraglutide, circulating HHIP levels were decreased, whereas Adipoq levels increased significantly. CONCLUSIONS: Our findings support HHIP as a potential biomarker for predicting obesity and IR. In addition, drugs targeting HHIP may be a new strategy to treat obesity.

Mortality prediction in patients with hyperglycaemic crisis using explainable machine learning: a prospective, multicentre study based on tertiary hospitals.

BACKGROUND: Experiencing a hyperglycaemic crisis is associated with a short- and long-term increased risk of mortality. We aimed to develop an explainable machine learning model for predicting 3-year mortality and providing individualized risk factor assessment of patients with hyperglycaemic crisis after admission. METHODS: Based on five representative machine learning algorithms, we trained prediction models on data from patients with hyperglycaemic crisis admitted to two tertiary hospitals between 2016 and 2020. The models were internally validated by tenfold cross-validation and externally validated using previously unseen data from two other tertiary hospitals. A SHapley Additive exPlanations algorithm was used to interpret the predictions of the best performing model, and the relative importance of the features in the model was compared with the traditional statistical test results. RESULTS: A total of 337 patients with hyperglycaemic crisis were enrolled in the study, 3-year mortality was 13.6% (46 patients). 257 patients were used to train the models, and 80 patients were used for model validation. The Light Gradient Boosting Machine model performed best across testing cohorts (area under the ROC curve 0.89 [95% CI 0.77-0.97]). Advanced age, higher blood glucose and blood urea nitrogen were the three most important predictors for increased mortality. CONCLUSION: The developed explainable model can provide estimates of the mortality and visual contribution of the features to the prediction for an individual patient with hyperglycaemic crisis. Advanced age, metabolic disorders, and impaired renal and cardiac function were important factors that predicted non-survival. TRIAL REGISTRATION NUMBER: ChiCTR1800015981, 2018/05/04.

Circulating HHIP Levels in Women with Insulin Resistance and PCOS: Effects of Physical Activity, Cold Stimulation and Anti-Diabetic Drug Therapy.

Serum human hedgehog-interacting protein (HHIP) concentration is associated with diabetes. However, the relationship between HHIP and polycystic ovary syndrome (PCOS) or abnormal sex hormones remains unknown. This study was an observational cross-sectional study, with additional short-term intervention studies and follow-up studies. Bioinformatics analysis was performed to explore the association of PCOS with metabolic-related genes and signaling pathways. OGTT and EHC were performed on all participants. Lipid infusion, cold exposure, and 45-min treadmill test were performed on all healthy women. A total of 137 women with PCOS were treated with metformin, GLP-1RA, or TZDs for 24 weeks. Serum HHIP levels were higher in insulin resistance (IR) and PCOS women. Circulating HHIP levels were significantly correlated with adiponectin (Adipoq) levels, obesity, IR, and metabolic indicators. A correlation presented between HHIP and DHEA-S, FAI, SHBG, and FSH. Serum HHIP levels were significantly elevated by oral glucose challenge in healthy women, but not affected by EHC. Lipid infusion decreased serum HHIP levels, while cold exposure increased HHIP levels in healthy women. GLP-1RA and TZD treatment reduced serum HHIP levels in PCOS women, while metformin treatment did not affect HHIP levels. HHIP may be a useful biomarker and novel drug target for PCOS and IR individuals.

TXNIP Exacerbates the Senescence and Aging-Related Dysfunction of ß Cells by Inducing Cell Cycle Arrest Through p38-p16/p21-CDK-Rb Pathway.

Aims: Thioredoxin-interacting protein (TXNIP) is a crucial molecular promoter of oxidative stress and has been identified to be associated with cellular senescence. It is an important mediator of ß cell insulin secretion and has effects on ß cell mass. However, its role in ß cell senescence is unclear. The present study was designed to investigate the effects and mechanisms of TXNIP on the senescence and aging- and diet-related dysfunction of ß cells. Methods: Human pancreatic paraffin tissues and serum samples from different ages were collected to detect TXNIP expression. TXNIP-/- and C57BL/6J mice were fed either a normal chow diet (NCD) or a high-fat diet (HFD) until 5, 11, 14, or 20 months. The recapitulation experiment was conducted with TXNIP protein injection. MIN6 cells were transfected with LV-TXNIP and LV-siTXNIP. The biochemical indexes, ageing-related markers, cell cycle proteins, and pathways were examined both in vivo and in vitro. Results: TXNIP expression showed an age-related increase in ß cells and serum samples from humans. TXNIP significantly impaired glucose metabolism and insulin secretion in an age-dependent manner. TXNIP aggravated age-related and obesity-induced structural failure, oxidative stress, decreased proliferation, increased apoptosis in ß cells, and induced the cell cycle arrest. TXNIP interacted with p38 mitogen-activated protein kinase (p38MAPK) and modulated the p16/p21-CDK-Rb axis to accelerate ß cell senescence. Innovation and Conclusions: The present study demonstrated that TXNIP may exacerbate pancreatic ß cell senescence and age-related dysfunction by inducing cell cycle arrest through the p38-p16/p21-CDK-Rb pathway, in natural and pathological states. Antioxid. Redox Signal. 38, 480-495.

Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies.

Objective: GPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans. Methods: Bioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans. Results: Bioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased. Conclusions: Our results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women.

The impact of hyperglycaemic crisis episodes on long-term outcomes for inpatients presenting with acute organ injury: A prospective, multicentre follow-up study.

Background: The long-term clinical outcome of poor prognosis in patients with diabetic hyperglycaemic crisis episodes (HCE) remains unknown, which may be related to acute organ injury (AOI) and its continuous damage after hospital discharge. This study aimed to observe the clinical differences and relevant risk factors in HCE with or without AOI. Methods: A total of 339 inpatients were divided into an AOI group (n=69) and a non-AOI group (n=270), and their differences and risk factors were explored. The differences in clinical outcomes and prediction models for evaluating the long-term adverse events after hospital discharge were established. Results: The mortality among cases complicated by AOI was significantly higher than that among patients without AOI [8 (11.59%) vs. 11 (4.07%), Q = 0.034] during hospitalization. After a 2-year follow-up, the mortality was also significantly higher in patients with concomitant AOI than in patients without AOI after hospital discharge during follow-up [13 (21.31%) vs. 15 (5.8%), Q < 0.001]. The long-term adverse events in patients with concomitant AOI were significantly higher than those in patients without AOI during follow-up [15 (24.59%) vs. 31 (11.97%), Q = 0.015]. Furthermore, Blood ß-hydroxybutyric acid (P = 0.003), Cystatin C (P <0.001), serum potassium levels (P = 0.001) were significantly associated with long-term adverse events after hospital discharge. Conclusions: The long-term prognosis of HCE patients complicated with AOI was significantly worse than that of HCE patients without AOI. The laboratory indicators were closely correlated with AOI, and future studies should explore the improvement of clinical outcome in response to timely interventions.

Vitamin D categories and postpartum thyroid function in women with hypothyroidism.

Objective: To analyze the related factors of the postpartum thyroid function in women with overt hypothyroidism (OH)/subclinical hypothyroidism (SCH) and explore the effects of vitamin D categories. Methods: Thyroid hormones, thyroid autoantibody, and serum 25OHD levels were continuously recorded from the first trimester of pregnancy (T1) to the 12th postpartum month. Logistic regression analysis and Cox regression analysis were used to screen the related factors of postpartum thyroid function, and the Latent Class Growth Model was performed to analyze the trajectory characteristics of serum 25OHD levels. Results: Totally, 252 pregnant women with OH/SCH were enrolled in the study. In the 12th month postpartum, 36.5% of the patients improved thyroid function, 37.3% continued hypothyroidism, and 26.2% developed thyroid dysfunction. Vitamin D sufficiency, positive TPOAb, and positive TgAb in T1 were independent prognostic factors of postpartum thyroid function. Vitamin D sufficiency in T1 was illustrated as an independent factor of the improved postpartum thyroid function, but the protective effect for the developed postpartum thyroid dysfunction was only confirmed in TPOAb-positive patients. Cox regression analysis further confirmed the effects of vitamin D categories. Notably, the high-level 25OHD trajectory during pregnancy and postpartum could predict improved postpartum thyroid function and decrease the risk of developed postpartum thyroid dysfunction. Conclusion: Appropriate vitamin D nutrition during pregnancy and postpartum may be beneficial to postpartum thyroid function.

Bone morphogenetic protein-9 maybe an important factor which improves insulin resistance in PCOS.

BACKGROUND: Polycystic ovary syndrome (PCOS) is closely related to insulin resistance (IR). Bone morphogenetic protein-9 (BMP-9) plays an important role in maintaining glucose homeostasis, but an association between BMP-9 and PCOS has not been reported. Here, we report the changes in BMP-9 and the influence of this protein on IR in PCOS. METHODS: 57 PCOS patients were selected (among them 25 received interventional treatment with exenatide (EX) for 3 months, and 32 received no treatment). 22 normal control individuals and 30 IR patients were also recruited. We evaluated IR with the euglycaemic-hyperinsulinaemic clamp (EHC) technique. IR and the glucose metabolism rate were assessed by EHC and [3-3H]glucose tracer experiments. We determined the protein expression levels of BMP-9, p-AKT (protein kinase B) and androgen receptor in the ovaries and liver by Western blotting. RESULTS: We found that circulating BMP-9 levels were significantly decreased in PCOS with IR patients. Circulating BMP-9 levels and p-AKT levels were decreased in HFD and PCOS rats and increased after MF and EX treatment. The glucose infusion rate, glucose disappearance rate and suppression of hepatic glucose production decreased in the HFD and PCOS groups, the opposite results were found for HGP. AR protein expression levels increased in the HFD and PCOS groups and decreased in the MF and EX groups. CONCLUSIONS: Our study results suggest that BMP-9 is an independent factor that influences IR in PCOS patients. The decrease in BMP-9 levels in the liver and ovaries may be involved in IR through the PI3K/AKT signaling pathway in PCOS rats.

GPHB5 Is a Biomarker in Women With Metabolic Syndrome: Results From Cross-Sectional and Intervention Studies.

Background: Animal studies have found that GPHB5 has a similar effect on system metabolism as TSH. However, the relationship between GPHB5 and metabolic diseases remains unknown. This study investigates the relationship between GPHB5 and MetS in young women. Methods: Bioinformatics analysis was undertaken to explore the relationship between GPHB5 and metabolic-related genes and signaling pathways. EHC and OGTT were performed on all individuals. Lipid-infusion, physical activity, and cold-exposure tests were performed on healthy individuals. Serum GPHB5 concentrations were measured by an ELISA kit. Results: PPI network showed that 11 genes interacted with GPHB5, in which POMC and KISS1R were involved in glucose and lipid metabolism. GO analysis showed 56 pathways for BP and 16 pathways for MF, in which OPRM1 and MCR families were related to energy metabolism. KEGG analysis found that GPHB5 is associated with lipolysis and neuroactive ligand-receptor interaction pathways. The levels of circulating GPHB5 were significantly increased, while serum adiponectin levels were lower in MetS women compared with healthy women. Obese/overweight individuals had lower adiponectin levels and higher GPHB5 levels. Circulating GPHB5 levels were positively correlated with BMI, WHR, blood pressure, FBG, 2 h-BG, HbA1c, FIns, 2h-Ins, LDL-C, FFA, HOMA-IR, and AUCg, etc. but negatively correlated with HDL-C, adiponectin, and M-values. Serum GPHB5 levels did not change significantly during the OGTT, EHC, and lipid infusion. Physical activity and cold-exposure tests did not lead to changes in GPHB5 levels. GLP-1RA treatment resulted in a significant decrease in serum GPHB5 levels. Conclusions: GPHB5 may be a biomarker for MetS.

Identification and Verification of Diagnostic Biomarkers for Glomerular Injury in Diabetic Nephropathy Based on Machine Learning Algorithms.

Diabetic nephropathy (DN) is regarded as the leading cause of end-stage renal disease worldwide and lacks novel therapeutic targets. To screen and verify special biomarkers for glomerular injury in patients with DN, fifteen datasets were retrieved from the Gene Expression Omnibus (GEO) database, correspondingly divided into training and testing cohorts and then merged. Using the limma package, 140 differentially expressed genes (DEGs) were screened out between 81 glomerular DN samples and 41 normal ones from the training cohort. With the help of the ConsensusClusterPlus and WGCNA packages, the 81 glomerular DN samples were distinctly divided into two subclusters, and two highly associated modules were identified. By using machine learning algorithms (LASSO, RF, and SVM-RFE) and the Venn diagram, two overlapping genes (PRKAR2B and TGFBI) were finally determined as potential biomarkers, which were further validated in external testing datasets and the HFD/STZ-induced mouse models. Based on the biomarkers, the diagnostic model was developed with reliable predictive ability for diabetic glomerular injury. Enrichment analyses indicated the apparent abnormal immune status in patients with DN, and the two biomarkers played an important role in the immune microenvironment. The identified biomarkers demonstrated a meaningful correlation between the immune cells' infiltration and renal function. In conclusion, two robust genes were identified as diagnostic biomarkers and may serve as potential targets for therapeutics of DN, which were closely associated with multiple immune cells.

TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation.

Transient receptor potential channel 5 (TRPC5) is predominantly distributed in the brain, especially in the central amygdala (CeA), which is closely associated with pain and addiction. Although mounting evidence indicates that the CeA is related to energy homeostasis, the possible regulatory effect of TRPC5 in the CeA on metabolism remains unclear. Here, we reported that the expression of TRPC5 in the CeA of mice was increased under a high-fat diet (HFD). Specifically, the deleted TRPC5 protein in the CeA of mice using adeno-associated virus resisted HFD-induced weight gain, accompanied by increased food intake. Furthermore, the energy expenditure of CeA-specific TRPC5 deletion mice (TRPC5 KO) was elevated due to augmented white adipose tissue (WAT) browning and brown adipose tissue (BAT) activity. Mechanistically, deficiency of TRPC5 in the CeA boosted nonshivering thermogenesis under cold stimulation by stimulating sympathetic nerves, as the ß3-adrenoceptor (Adrb3) antagonist SR59230A blocked the effect of TRPC5 KO on this process. In summary, TRPC5 deletion in the CeA alleviated the metabolic deterioration of mice fed a HFD, and these phenotypic improvements were correlated with the increased sympathetic distribution and activity of adipose tissue.

C-reactive protein perturbs alveolar bone homeostasis: An experimental study of periodontitis and diabetes in the rat.

AIM: To explore the role of C-reactive protein (CRP) in periodontitis and diabetes and its mechanism in alveolar bone homeostasis. MATERIALS AND METHODS: In vivo, normal, and Crp knockout (KO) rats were randomly divided into control, diabetes, periodontitis, and diabetes and periodontitis groups, respectively. The diabetes model was established using a high-fat diet combined with streptozotocin injection. The periodontitis model was established by ligature combined with lipopolysaccharide (LPS) injection. Alveolar bones were analysed using micro-computed tomography, histology, and immunohistochemistry. In vitro, human periodontal ligament cells (hPDLCs) were treated with LPS and high glucose. CRP knockdown lentivirus or CRP overexpression adenovirus combined with a PI3K/AKT signalling inhibitor or agonist were used to explore the regulatory mechanism of CRP in osteogenesis and osteoclastogenesis of hPDLCs, as evidenced by alkaline phosphatase staining, Western blot, and quantitative polymerase chain reaction. RESULTS: In periodontitis and diabetes, CRP KO decreased the alveolar bone loss and the expression levels of osteoclastogenic markers, while increasing the expression levels of osteogenic markers. CRP constrained osteogenesis while promoting the osteoclastogenesis of hPDLCs via PI3K/AKT signalling under high glucose and pro-inflammatory conditions. CONCLUSIONS: CRP inhibits osteogenesis and promotes osteoclastogenesis via PI3K/AKT signalling under diabetic and pro-inflammatory conditions, thus perturbing alveolar bone homeostasis.

CTRP7 Is a Biomarker Related to Insulin Resistance and Oxidative Stress: Cross-Sectional and Intervention Studies In Vivo and In Vitro.

Objective: CTRP7 is a cytokine that is known to be associated with obesity. However, its relationship with insulin resistance (IR) and metabolic diseases remains unknown. The aim of this study is to investigate the relationship between CTRP7 and IR under in vivo and in vitro conditions. Methods: CTRP7 expression in mice and hepatocytes was determined using RT-qPCR and western blotting. Circulating CTRP7 concentrations were measured with an ELISA kit. EHC, OGTT, lipid-infusion, physical activity, and cold-stimulation experiments were performed in humans and mice. SOD, GSH, and MDA were measured by commercial kits. ROS levels were detected using dichlorofluorescein diacetate. Results: The expression levels of CTRP7 protein in the liver and fat of ob/ob and db/db mice were higher than that of WT mice. Individuals with IGT, T2DM, and obesity had higher circulating CTRP7 levels. CTRP7 levels were associated with HOMA-IR, obesity, and other metabolic parameters. During OGTT, serum CTRP7 levels gradually decreased, while CTRP7 levels significantly increased during EHC in response to hyperinsulinemia in healthy individuals without IR. In addition, lipid infusion-induced IR further increased serum CTRP7 levels in healthy adults. Physical activity increased serum CTRP7 levels in healthy individuals and CTRP7 protein expression in iWAT and skeletal muscle in mice. Under in vitro conditions, the expression of the CTRP7 protein was inhibited in a glucose concentration-dependent manner but was promoted by FFAs and insulin stimulation in hepatocytes. Furthermore, CTRP7 overexpression facilitated oxidative stress and suppressed the phosphorylation of insulin signaling molecules in hepatocytes. Conclusions: Our evidence shows that CTRP7 could be a useful biomarker and potential treatment target in IR and metabolic disorders.