{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T19:27:47Z","timestamp":1787254067087,"version":"build-2736575974"},"reference-count":50,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272272"],"award-info":[{"award-number":["82272272"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>The progressive decline of functional \u03b2-cell mass is a hallmark of type 2 diabetes (T2D), yet no current therapies effectively halt this process. While chronic inflammation and metabolic stress contribute to \u03b2-cell dysfunction, the key signals integrating these pathways remain elusive. Circulating adenosine deaminase (ADA) elevation in people with diabetes is often viewed as a bystander effect, not a pathogenic component. Here, we show that this elevation reflects a failed compensatory response in a previously unknown purinergic pathway linking dyslipidemia to \u03b2-cell failure. Circulating lipids trigger rapid ATP release from erythrocytes, converted to adenosine (ADO). Accumulated ADO drives tissue-specific ADA upregulation in organs affected by diabetes complications, including spleen, kidney, and islets. When this defense fails, toxic ADO selectively causes apoptosis in macrophages, podocytes, and \u03b2-cells via defined mechanisms. We show that exogenous ADA performs systemic clearance and local decompression, boosting circulatory adenosine clearance, normalizing tissue ADA hyperactivity, and rescuing islet immunopathology and function. These findings redefine a fundamental pathogenic circuit in T2D and establish the restoration of ADO homeostasis as a therapeutic strategy capable of producing functional \u03b2-cell recovery, thereby positioning disease remission as a mechanistically grounded and attainable goal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Challenging the view that elevated circulating adenosine deaminase (ADA) is merely a secondary phenomenon, this study defines its pathogenic role in linking dyslipidemia to \u03b2-cell failure and establishes adenosine (ADO) homeostasis restoration as a disease-remitting therapy. We identify tissue-specific compensatory ADA upregulation that paradoxically fails to prevent systemic ADO accumulation, with elevated adenosine selectively inducing apoptosis in immune and pancreatic \u03b2-cells. We establish a novel systemic clearance-local decompression therapeutic mechanism in which exogenous ADA reduces circulating ADO, normalizes compensatory tissue ADA hyperactivity, and rescues islet function. This work redefines plasma ADA from a diagnostic marker to a therapeutic target, providing the rationale for an ADA-based therapy that uniquely combines immune modulation with metabolic correction to halt \u03b2-cell failure progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db26-0052","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:34:21Z","timestamp":1782844461000},"page":"1525-1538","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the ADA\/ADO Axis Rescues \u03b2-Cell Failure in Type 2 Diabetes"],"prefix":"10.2337","volume":"75","author":[{"given":"Yingxin","family":"Zhang","sequence":"first","affiliation":[{"name":"Center for Molecular Metabolism, Nanjing University of Science and Technology , Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Molecular Metabolism, Nanjing University of Science and Technology , Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Fang","sequence":"additional","affiliation":[{"name":"Center for Molecular Metabolism, Nanjing University of Science and Technology , Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Molecular Metabolism, Nanjing University of Science and Technology , Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Molecular Metabolism, Nanjing University of Science and Technology , Nanjing, 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