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In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 \u00b1 2.8 years; males\/females, 54:46; HbA1c 66.1 [12.3] mmol\/mol; diabetes duration 10.7 \u00b1 5.2 years; and BMI 24.5 [5.3] kg\/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E\u2212\/\u2212 mice. Kidney biopsies were used to examine infiltration of KIM-1\u2013expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACRAUC0\u201310yrs, 29.7 \u00b1 8.8 vs. 4.5 \u00b1 0.5; P &amp;lt; 0.01 vs. low risk) and early kidney dysfunction, including \u223c8.3 mL\/min\/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; Padj &amp;lt; 0.031 vs. low risk) and plasma KIM-1 concentrations (\u223c15% higher vs. low risk; P &amp;lt; 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium\u2013glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T-cell production of KIM-1.<\/jats:p>","DOI":"10.2337\/db20-1081","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T18:35:11Z","timestamp":1616092511000},"page":"1754-1766","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":17,"title":["T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes"],"prefix":"10.2337","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5595-8174","authenticated-orcid":false,"given":"Josephine M.","family":"Forbes","sequence":"first","affiliation":[{"name":"Mater Research Institute\u2013The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia"},{"name":"Mater Young Adult Health Centre, Mater Misericordiae Ltd, South Brisbane, Queensland, Australia"},{"name":"Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia"},{"name":"Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica A.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Mater Research Institute\u2013The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Kassianos","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia"},{"name":"Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston, Queensland, Australia"},{"name":"Kidney Health Service, Royal Brisbane and Women\u2019s Hospital, Brisbane, Queensland, 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Australia"},{"name":"Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston, Queensland, Australia"},{"name":"Kidney Health Service, Royal Brisbane and Women\u2019s Hospital, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca","family":"Grivei","sequence":"additional","affiliation":[{"name":"Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston, Queensland, Australia"},{"name":"Kidney Health Service, Royal Brisbane and Women\u2019s Hospital, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle C.","family":"Flynn","sequence":"additional","affiliation":[{"name":"Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell A.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Mater Research Institute\u2013The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia"},{"name":"Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preeti","family":"Chandrashekar","sequence":"additional","affiliation":[{"name":"Mater Research Institute\u2013The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia"},{"name":"Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, 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