{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T08:10:51Z","timestamp":1774512651517,"version":"3.50.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diabetes mellitus (DM) disrupts the metabolic environment of extensively drug-resistant tuberculosis (XDR) patients, promoting mycobacterial persistence. Key factors influencing bacterial clearance remain unclear. This study aimed to identify critical host factors and assess the therapeutic value of intensive glucose control.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      A 48-month single-center retrospective cohort study compared sputum smear conversion (bacterial clearance) between 57 XDR-only (XDR) and 84 XDR with DM (XDR\u202f+\u202fDM) patients (similar treatment, consistent\n                      <jats:italic>in vitro<\/jats:italic>\n                      MIC resistance profiles). Kaplan\u2013Meier analysis, Cox regression, generalized linear models, and mediation analysis were used to explore associations between diabetic status, blood glucose (GLU) levels, and bacterial clearance, as well as the impact of glucose control on treatment progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with XDR patients, the XDR\u202f+\u202fDM group exhibited a significantly lower bacterial clearance rate (80.7% vs. 45.2%) and longer median clearance time (6 vs. 12\u202fmonths), despite comparable baseline smear grades. Crucially, XDR\u202f+\u202fDM patients displayed distinct immunometabolic dysregulation, characterized by elevated inflammatory markers (CRP) and a disrupted CD4+ \/CD8+ T-cell balance (increased CD4+, decreased CD8+ counts). Multivariable analysis identified hyperglycemia as the primary driver of delayed clearance (aHR\u202f=\u202f1.48, 95% CI: 1.23\u20131.77,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001), serving as a significant mediator between DM and impaired outcomes (mediation effect: -0.82,\n                      <jats:italic>p<\/jats:italic>\n                      =\u202f0.006). A glucose \u201cdose\u2013response\u201d relationship was observed: severe hyperglycemia (GLU\u202f\u2265\u202f11.1\u202fmmol\/L) markedly increased clearance delay risk (aHR\u202f=\u202f5.29,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001), whereas optimal control (GLU\u202f&amp;lt;\u202f7\u202fmmol\/L) mitigated these disadvantages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Dysregulated glucose metabolism and subsequent immune imbalance in diabetes are key drivers of delayed bacterial clearance in XDR patients, independent of the anti-tuberculosis regimen. Precise glucose control should be regarded as a core strategy, on a par with anti-XDR treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpubh.2026.1746879","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T06:36:58Z","timestamp":1774507018000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Glucose driven bacterial persistence in extensively drug-resistant tuberculosis with diabetes"],"prefix":"10.3389","volume":"14","author":[{"given":"Xin","family":"Yao","sequence":"first","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University","place":["Guiyang, China"]},{"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yarong","family":"Shi","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University","place":["Guiyang, China"]},{"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minghao","family":"Kong","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University","place":["Guiyang, China"]},{"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujie","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University","place":["Guiyang, China"]},{"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxia","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjuan","family":"Wang","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhonghua","family":"Liu","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University","place":["Guiyang, China"]},{"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/S2213-8587(14)70011-7","article-title":"Tandem: understanding diabetes and tuberculosis","volume":"2","author":"Crevel","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41572-024-00504-2","article-title":"Multidrug-resistant tuberculosis","volume":"10","author":"Dheda","year":"2024","journal-title":"Nat Rev Dis Primers"},{"key":"ref3","year":"2023"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/S2213-2600(25)00194-8","article-title":"Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): an open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial","volume":"13","author":"Guglielmetti","year":"2025","journal-title":"Lancet Respir Med"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/S2213-2600(17)30079-6","article-title":"The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable 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proliferation","volume":"235","author":"K\u00fcbler","year":"2015","journal-title":"J Pathol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"2539","DOI":"10.3390\/diagnostics14222539","article-title":"The complex relationship between tuberculosis and hyperglycemia","volume":"14","author":"Byers","year":"2024","journal-title":"Diagnostics (Basel)"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/S2213-2600(15)00036-3","article-title":"Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies","volume":"3","author":"Kurbatova","year":"2015","journal-title":"Lancet Respir Med"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e0108622","DOI":"10.1128\/mbio.01086-22","article-title":"High glucose and carbonyl stress impair HIF-1-regulated responses and the control of Mycobacterium tuberculosis in 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Mycobacterium tuberculosis","volume":"8","author":"Ferlita","year":"2019","journal-title":"J Clin Med"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"492","DOI":"10.3390\/antiox14040492","article-title":"Advanced glycation end products in disease development and potential interventions","volume":"14","author":"Zhang","year":"2025","journal-title":"Antioxidants"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"865","DOI":"10.2147\/DMSO.S300460","article-title":"Platelet indices and its association with microvascular complications among type 2 diabetes mellitus patients in Northeast Ethiopia: a cross-sectional study","volume":"14","author":"Taderegew","year":"2021","journal-title":"Diabetes Metab Syndr Obes"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1053\/j.ajkd.2011.02.389","article-title":"Cystatin C in prediction of acute kidney injury: a systemic review and 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Immunol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2949","DOI":"10.1038\/s41564-025-02140-2","article-title":"Mycobacterium tuberculosis-derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages","volume":"10","author":"Cheng","year":"2025","journal-title":"Nat Microbiol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"6275","DOI":"10.4049\/jimmunol.1000304","article-title":"Diabetic mice display a delayed adaptive immune response to Mycobacterium tuberculosis","volume":"184","author":"allerskog","year":"2010","journal-title":"J Immunol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1228045","DOI":"10.3389\/fendo.2023.1228045","article-title":"The role of autophagy in the treatment of type II diabetes and its complications: a review","volume":"14","author":"Zhao","year":"2023","journal-title":"Front Endocrinol 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