{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:52:57Z","timestamp":1790016777336,"version":"4.0.1"},"reference-count":131,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathophysiology"],"abstract":"<jats:p>Type 1 diabetes mellitus (T1DM) is regarded as an autoimmune disorder characterized by a progressive loss of \u03b2-cells, culminating in insulin deficiency and hyperglycemia. Currently, T1DM is managed through exogenous insulin administration. Continued efforts to decipher T1DM pathogenesis have yielded significant progress, which can be harnessed to develop disease-modifying therapeutic modalities. Immunological and genetic studies have demonstrated pathogenetic mechanisms that underpin the sensitivity and risk of developing autoimmunity, ultimately leading to the destruction of \u03b2-cells. Genetic and immunological studies, therefore, suggest that certain individuals are at risk of developing T1DM; and that autoantibodies against \u03b2-cells develop and circulate years before the onset of symptomatic T1DM. Furthermore, the onset of autoimmunity has been associated with specific triggers in genetically susceptible individuals. Recent developments have revealed how viral infections, gut dysbiosis, dietary factors, and obesity trigger autoimmunity and \u03b2-cell damage. In this review, we present the current, consolidated understanding of T1DM pathogenesis, informed by recent research. We further identify opportunities for early-detection strategies and drug development targeting the asymptomatic phase of T1DM to slow disease progression. Currently, immunomodulatory strategies have yielded promising outcomes in clinical trials. These strategies seek to target immune cells and inflammatory mediators implicated in the pathogenesis of T1DM. Other strategies include tolerogenic strategies against autoimmune cells, whilst others employ \u03b2-cell protection. The emergence of regenerative therapies also offers promising avenues toward T1DM.<\/jats:p>","DOI":"10.3390\/pathophysiology33030048","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:16:22Z","timestamp":1783592182000},"page":"48","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Type 1 Diabetes Mellitus Pathogenesis: Mechanisms, Early Diagnostic Strategies, and Emerging Therapeutic Approaches"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0513-991X","authenticated-orcid":false,"given":"Nokwanda N.","family":"Ngcobo","sequence":"first","affiliation":[{"name":"Discipline of Pharmaceutical Sciences, School of Health Sciences, Durban 4001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5894-8935","authenticated-orcid":false,"given":"Ntethelelo H.","family":"Sibiya","sequence":"additional","affiliation":[{"name":"Pharmacology Division, Faculty of Pharmacy, Rhodes University, Makhanda 6139, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s42269-024-01197-z","article-title":"Type 1 diabetes mellitus: Retrospect and prospect","volume":"48","author":"Addissouky","year":"2024","journal-title":"Bull. 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