Diabetes最新文献

GLP-1-mediated targeting of inflammation corrects obesogenic memory in male mice

IF 7.7 1区医学

Diabetes Pub Date : 2025-04-11 DOI: 10.2337/db24-1071

Stéphane Léon, Julie Benoit, Samantha Clark, Philippe Zizzari, Bin Yang, Isabelle Dugail, Fatiha Merabtene, Karine Clement, Louise Eygret, Nathalie Dupuy, Jean-Christophe Delpech, Moïra Rossitto, Matthias Mack, Thierry Lesté-Lasserre, Brian Finan, Daniela Cota, Carmelo Quarta

{"title":"GLP-1-mediated targeting of inflammation corrects obesogenic memory in male mice","authors":"Stéphane Léon, Julie Benoit, Samantha Clark, Philippe Zizzari, Bin Yang, Isabelle Dugail, Fatiha Merabtene, Karine Clement, Louise Eygret, Nathalie Dupuy, Jean-Christophe Delpech, Moïra Rossitto, Matthias Mack, Thierry Lesté-Lasserre, Brian Finan, Daniela Cota, Carmelo Quarta","doi":"10.2337/db24-1071","DOIUrl":"https://doi.org/10.2337/db24-1071","url":null,"abstract":"Obesity-induced biological changes often persist after weight loss and are difficult to reverse, a phenomenon known as ‘obesogenic memory’. This enduring effect is associated with metabolic inflammation, particularly in adipose tissue. In this study, we characterise a mouse model of obesogenic memory and evaluate the efficacy of the unimolecular conjugate GLP-1/Dexa, which selectively and safely delivers the anti-inflammatory drug dexamethasone to GLP-1 receptor (GLP-1R)-expressing cells. We document that this precision pharmacological approach outperforms treatment with GLP-1 or dexamethasone alone, significantly reducing body weight, food intake, adiposity and markers of adipose tissue inflammation in male mice with obesogenic memory. In addition, we identify the CCR2/CCL2 inflammatory pathway as an important mediator of glucose intolerance and adipose tissue inflammation associated with obesogenic memory. Our findings suggest that targeting inflammation via GLP-1R signalling may be a promising therapeutic strategy to alleviate obesogenic memory and improve the long-term clinical management of metabolic diseases.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"39 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BAP1 suppresses white adipose tissue browning and thermogenesis through deubiquitinating KDM1B

IF 7.7 1区医学

Diabetes Pub Date : 2025-04-10 DOI: 10.2337/db24-1011

Pengchao Wang, Jingbo Zhu, Liuye Yang, Yilong Wang, Minglu Liang, Fengcen Li, Ze Wang, Kaiyuan Liu, Mingfa Ai, Dazhu Li, Kai Huang, Meng Du

{"title":"BAP1 suppresses white adipose tissue browning and thermogenesis through deubiquitinating KDM1B","authors":"Pengchao Wang, Jingbo Zhu, Liuye Yang, Yilong Wang, Minglu Liang, Fengcen Li, Ze Wang, Kaiyuan Liu, Mingfa Ai, Dazhu Li, Kai Huang, Meng Du","doi":"10.2337/db24-1011","DOIUrl":"https://doi.org/10.2337/db24-1011","url":null,"abstract":"Obesity is a growing global health threat, and inducing browning of white adipose tissue (WAT) to increase energy expenditure has become an attractive strategy for treating obesity and related metabolic complications. BRCA1-associated protein 1 (BAP1), a ubiquitin C-terminal hydrolase (UCH) domain-containing deubiquitinase (DUB) expressed broadly across tissues, has previously been shown to play an important role in liver carbohydrate and lipid metabolism. However, its role in the browning of inguinal white adipose tissue (iWAT) has not been studied. Our study initially found that BAP1 expression was downregulated in cold-induced mouse iWAT but upregulated in obese conditions. Furthermore, overexpression of BAP1 in the inguinal fat tissue suppressed iWAT browning and thermogenesis. Mechanistically, we found that BAP1 interacts with KDM1B and stabilizes it through deubiquitination. Subsequently, KDM1B demethylates H3K4me1/2 modifications in proximity to thermogenesis-related genes, thereby inhibiting the expression of genes essential for browning. In summary, our study shows that BAP1 negatively regulates iWAT browning via a mechanism mediated by KDM1B.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"74 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Randomized-Controlled, Double-Masked Cross-Over Study of a GPR119 Agonist on Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes

IF 7.7 1区医学

Diabetes Pub Date : 2025-04-02 DOI: 10.2337/db25-0096

Anika Bilal, Anna Casu, Fanchao Yi, Tumpa Dutta, Justine M. Mucinski, Gina Mercouffer, Martin C. Marak, Marcus Hompesch, David Kelley, Richard E. Pratley

{"title":"A Randomized-Controlled, Double-Masked Cross-Over Study of a GPR119 Agonist on Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes","authors":"Anika Bilal, Anna Casu, Fanchao Yi, Tumpa Dutta, Justine M. Mucinski, Gina Mercouffer, Martin C. Marak, Marcus Hompesch, David Kelley, Richard E. Pratley","doi":"10.2337/db25-0096","DOIUrl":"https://doi.org/10.2337/db25-0096","url":null,"abstract":"Activation of GPR119 receptors, expressed on enteroendocrine and pancreatic islet cells, augments glucagon counterregulatory responses to hypoglycemia in pre-clinical models. We hypothesized that MBX-2982, a GPR119 agonist, would augment counterregulatory responses to experimental hypoglycemia in participants with type 1 diabetes. To assess this, we designed a phase 2a double-masked, cross-over trial in 18 participants (20–60 years) with type 1 diabetes. Participants were randomized to treatment with 600 mg MBX-2982 or placebo daily for 14 days with a two-week washout between treatments. Counterregulatory responses to hypoglycemia during a hyperinsulinemic-hypoglycemic clamp and hormonal responses during a mixed meal test (MMT) were measured. The maximum glucagon response, glucagon area under the curve (AUC) and incremental AUC were not significantly different during MBX-2982 vs placebo treatment. MBX-2982 did not alter epinephrine, norepinephrine, pancreatic polypeptide, free fatty acid, or endogenous glucose production responses to hypoglycemia compared to placebo. However, glucagon-like peptide-1 (GLP-1) response during the MMT was 17% higher with MBX-2982 compared to placebo treatment. In conclusion, GPR119 activation with MBX-2982 did not improve counterregulatory responses to hypoglycemia in people with type 1 diabetes. Increases in GLP-1 during the MMT are consistent with GPR119 target engagement and the expected pharmacodynamic response from L-cells.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"27 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Disposition Index in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes

IF 7.7 1区医学

Diabetes Pub Date : 2025-04-02 DOI: 10.2337/db24-1000

Heba M Ismail, David Cuthbertson, Alfonso Galderisi, Ingrid Libman, Laura Jacobsen, Antoinette Moran, Alessandra Petrelli, Mark Atkinson, Maria J. Redondo, Tamara Hannon, Kieren J Mather, Jay M. Sosenko

{"title":"The Disposition Index in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes","authors":"Heba M Ismail, David Cuthbertson, Alfonso Galderisi, Ingrid Libman, Laura Jacobsen, Antoinette Moran, Alessandra Petrelli, Mark Atkinson, Maria J. Redondo, Tamara Hannon, Kieren J Mather, Jay M. Sosenko","doi":"10.2337/db24-1000","DOIUrl":"https://doi.org/10.2337/db24-1000","url":null,"abstract":"Since little is known about the disposition index (DI) in autoantibody-positive individuals, we have assessed whether DI has a similar association between insulin secretion and resistance to the association observed in other populations. In TrialNet Pathway to Prevention (TNPTP; n=6620) and Diabetes Prevention Trial-Type 1 (DPT-1; n=704) study participants, two secretion-sensitivity pairs each representing a DI were analyzed cross-sectionally at baseline: AUC C-peptide/AUC glucose (AUC Ratio) and Matsuda Index (MI) from TNPTP OGTTs (oral DI), first-phase insulin response (FPIR) and 1/fasting insulin (1/FI) from DPT-1 from IVGTTs (DI). Participants were followed for progression to type 1 diabetes. Within the normal and diabetes glucose ranges, associations of AUC ratio with MI in TNPTP, and FPIR with 1/FI in DPT-1, had inverse curvilinear patterns with convexities to the origin. After logarithmic transformations to linearize the secretion and sensitivity measures, the inverse slope was steeper for the diabetes range (p&lt;0.0001). In a Cox regression model including the AUC Ratio and MI as variables and another model including FPIR and 1/FI, the interaction terms of secretion x sensitivity (i.e., the DI/ODI), predicted stage 3 type 1 diabetes in both (p&lt;0.0001). The DI remained significantly predictive (p&lt;0.0001) when the DPT-1 risk score was added as a covariate in regression models. In autoantibody-positive populations, insulin secretion is inversely related to sensitivity in a quasi-hyperbolic relationship in normal and diabetes ranges of glucose. The DI can be represented by a statistical and physiologic interaction between secretion and sensitivity that is predictive of stage 3 type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"107 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DA-1241, a GPR119 agonist, ameliorates fatty liver through the upregulation of TFEB-mediated autophagy

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-28 DOI: 10.2337/db24-0370

Jin Yoo, Ji Eun Jun, In-Kyung Jeong, Kyu Jeung Ahn, Ho Yeon Chung, Myung-Shik Lee, You-Cheol Hwang

{"title":"DA-1241, a GPR119 agonist, ameliorates fatty liver through the upregulation of TFEB-mediated autophagy","authors":"Jin Yoo, Ji Eun Jun, In-Kyung Jeong, Kyu Jeung Ahn, Ho Yeon Chung, Myung-Shik Lee, You-Cheol Hwang","doi":"10.2337/db24-0370","DOIUrl":"https://doi.org/10.2337/db24-0370","url":null,"abstract":"G protein-coupled receptor 119 (GPR119) is predominantly expressed in pancreatic β-cells, enteroendocrine cells, and the liver. It is a novel therapeutic for dyslipidemia and type 2 diabetes. DA-1241, a GPR119 agonist, improves glucose tolerance by inhibiting gluconeogenesis and enhancing insulin secretion. It mitigates hepatic inflammation by inhibiting NFĸB signaling. However, the mechanism by which DA-1241 ameliorates nonalcoholic fatty liver disease (NAFLD) remains unknown. We hypothesized that DA-1241 improves liver steatosis by inducing autophagy in a TFEB-dependent manner. It induced autophagy and TFEB nuclear translocation, and decreased lipid content in liver cell lines. Lysotracker staining and DQ-Red BSA assay revealed it increased lysosomal activity. Furthermore, DA-1241 increased the colocalization of mRFP-LC3 and lipid droplets, which were completely abolished by GPR119 knockdown. DA-1241 treatment improved glucose tolerance and insulin sensitivity, and decreased liver enzymes activity and hepatic triglyceride levels, and the NAFLD activity score with increased number of autophagosomes and lysosomes in high-fat diet-fed mice. Despite DA-1241 treatment, lysosomal activity and subsequent lipid content reduction were not induced in tfeb knockout HeLa cells. DA-1241 treatment failed to produce favorable metabolic effects, including reduced hepatic triglyceride levels, in liver-specific Tfeb knockout mice. Thus, DA-1241 attenuates hepatic steatosis through TFEB-mediated autophagy induction.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Special Thanks to the Reviewers of Diabetes

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-20 DOI: 10.2337/db25-en04

引用次数: 0

Hepatic PKA Mediates the Liver and Pancreatic Alpha-Cell Crosstalk

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-17 DOI: 10.2337/db24-0958

Kehan Bao, Jason Berger, Erqian Na, Qi Su, Gabor Halasz, Mark Sleeman, Haruka Okamoto

引用次数: 0

Cardioprotection during myocardial infarction in diabetic cardiomyopathy

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-13 DOI: 10.2337/db24-0510

Sebastià Alcover, Sergi López, Lisaidy Ramos, Natàlia Muñoz-García, Alex Gallinat, Rosa Suades, Lina Badimon, Gemma Vilahur

{"title":"Cardioprotection during myocardial infarction in diabetic cardiomyopathy","authors":"Sebastià Alcover, Sergi López, Lisaidy Ramos, Natàlia Muñoz-García, Alex Gallinat, Rosa Suades, Lina Badimon, Gemma Vilahur","doi":"10.2337/db24-0510","DOIUrl":"https://doi.org/10.2337/db24-0510","url":null,"abstract":"Diabetic patients are at an increased risk of diabetic cardiomyopathy (DCM) and acute myocardial infarction (AMI). Protecting the heart against AMI is more challenging in DCM than non-diabetic hearts. We investigated whether intravenous atorvastatin administration during AMI exerts cardioprotection in DCM as seen in non-diabetic hearts. Sprague-Dawley rats were divided into streptozotocin-induced DCM and normoglycemic-control groups. Our model of DCM rats exhibited interstitial fibrosis and cardiac dysfunction at 5 weeks. At this time point, all animals underwent AMI-induction (coronary ligation for 45min), receiving intravenous atorvastatin or vehicle during ischemia. Animals were reperfused and sacrificed 24h later for myocardial infarct size analysis and cardiac tissue sampling. Echocardiography was performed. DCM vehicle rats had larger infarcts than normoglycemic vehicle-treated animals at comparable area-at-risk. Intravenous atorvastatin reduced infarct size and preserved systolic function in both groups. In comparison to vehicle animals, intravenous atorvastatin inhibited RhoA membrane translocation, induced AMPK phosphorylation, prevented apoptosis execution and improved cardiac remodelling in the infarcted heart of both groups whereas innate immune cell infiltration was further reduced in intravenous atorvastatin-treated DCM animals. The proven cardioprotective effectiveness of this intravenous statin formulation in the presence of DCM warrants its further development into a clinically therapeutic option.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"9 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel cell-to-cell communications between macrophages and fibroblasts regulate obesity-induced adipose tissue fibrosis

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-10 DOI: 10.2337/db24-0762

Hiro Kohda, Miyako Tanaka, Shigeyuki Shichino, Satoko Arakawa, Tadasuke Komori, Ayaka Ito, Eri Wada, Kozue Ochi, Xunmei Yuan, Takehiko Takeda, Atsuhito Saiki, Ichiro Tatsuno, Kenji Ikeda, Yuki Miyai, Atsushi Enomoto, Yoshihiro Morikawa, Shigeomi Shimizu, Satoshi Ueha, Kouji Matsushima, Yoshihiro Ogawa, Takayoshi Suganami

{"title":"Novel cell-to-cell communications between macrophages and fibroblasts regulate obesity-induced adipose tissue fibrosis","authors":"Hiro Kohda, Miyako Tanaka, Shigeyuki Shichino, Satoko Arakawa, Tadasuke Komori, Ayaka Ito, Eri Wada, Kozue Ochi, Xunmei Yuan, Takehiko Takeda, Atsuhito Saiki, Ichiro Tatsuno, Kenji Ikeda, Yuki Miyai, Atsushi Enomoto, Yoshihiro Morikawa, Shigeomi Shimizu, Satoshi Ueha, Kouji Matsushima, Yoshihiro Ogawa, Takayoshi Suganami","doi":"10.2337/db24-0762","DOIUrl":"https://doi.org/10.2337/db24-0762","url":null,"abstract":"Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular crosstalk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we employed single-cell analytical approaches to investigate cell-tocell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLSs), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported Lipid-associated macrophages (LAMs), we found a small subcluster expressing Macrophage-inducible C-type lectin (Mincle), specifically localizing to CLSs. Mincle signaling increased the expression of Oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm-deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, Osm expression was positively correlated with Mincle expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLSs.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"14 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143590212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Soluble HLA class I is released from human β-cells following exposure to interferons

IF 7.7 1区医学

Diabetes Pub Date : 2025-03-10 DOI: 10.2337/db24-0827

Pouria Akhbari, Javier Perez-Hernandez, Mark A. Russell, Shalinee Dhayal, K. Afi Leslie, Stephanie L. Hunter, Kathryn Murrall, Alexia Carré, Noel G. Morgan, Roberto Mallone, Sarah J. Richardson

{"title":"Soluble HLA class I is released from human β-cells following exposure to interferons","authors":"Pouria Akhbari, Javier Perez-Hernandez, Mark A. Russell, Shalinee Dhayal, K. Afi Leslie, Stephanie L. Hunter, Kathryn Murrall, Alexia Carré, Noel G. Morgan, Roberto Mallone, Sarah J. Richardson","doi":"10.2337/db24-0827","DOIUrl":"https://doi.org/10.2337/db24-0827","url":null,"abstract":"HLA class I (HLA-I) molecules present intracellular antigenic peptides to CD8+ T lymphocytes during immune surveillance. In donors with type 1 diabetes, hyperexpression of HLA-I occurs in islets with residual insulin-producing β-cells as a hallmark of the disease. HLA-I hyperexpression is frequently detected beyond the islet boundary, forming a ‘halo’. We hypothesized that this halo may reflect the diffusion of soluble forms of HLA-I (sHLA-I) from the islets to the surrounding pancreatic parenchyma. To verify this, we assessed the expression of total, cell surface and sHLA-I in β-cell lines and isolated human islets, following treatment with interferons (IFN)-α and IFN-γ. Consistent with the expression patterns of HLA-I in situ, both β-cell lines and cultured human islets dramatically upregulated total and surface HLA-I when exposed to IFNs. Concomitantly, sHLA-I release was significantly increased. HLA-I released within extracellular vesicles and cleaved forms of HLA-I did not significantly contribute to the sHLA-I pool. Rather, IFNs upregulated mRNA splice variants lacking the transmembrane domain. Our findings suggest that β-cells respond to IFNs by upregulating cellassociated and soluble forms of HLA-I. Soluble HLA-I may play a role in modulating islet inflammation during the autoimmune attack.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"36 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143590276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0