{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:02:33Z","timestamp":1783566153291,"version":"3.55.0"},"reference-count":186,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic \u03b2-cells to produce adequate insulin, usually as a consequence of extensive pancreatic \u03b2-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic \u03b2-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic \u03b2-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic \u03b2-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic \u03b2-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin\u2019s induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, N-acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic \u03b2-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic \u03b2-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway\u2014including by bacteriophages\u2014contributes to not only pancreatic \u03b2-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic \u03b2-cell loss as well as \u2018autoimmune\u2019 effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications.<\/jats:p>","DOI":"10.3390\/ijms24043300","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:01:45Z","timestamp":1675825305000},"page":"3300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the \u2018Bystander\u2019 Activation of Memory CD8+ T Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7243-0817","authenticated-orcid":false,"given":"George","family":"Anderson","sequence":"first","affiliation":[{"name":"CRC Scotland & London, Eccleston Square, London SW1V 1PG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/s00125-022-05836-w","article-title":"The effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes","volume":"66","author":"Ferrannini","year":"2023","journal-title":"Diabetologia."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13195-022-01072-x","article-title":"Immune-mediated diseases are associated with a higher incidence of dementia: A prospective cohort study of 375,894 individuals","volume":"14","author":"Zhang","year":"2022","journal-title":"Alzheimers Res Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1007\/s00125-015-3515-x","article-title":"Risk of dementia in patients hospitalised with type 1 and type 2 diabetes in England, 1998-2011: A retrospective national record linkage cohort study","volume":"58","author":"Smolina","year":"2015","journal-title":"Diabetologia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1080\/21678421.2020.1861022","article-title":"Associations between autoimmune diseases and amyotrophic lateral sclerosis: A register-based study","volume":"22","author":"Cui","year":"2021","journal-title":"Amyotroph Lateral Scler Front. 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