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In the renal vasculature, amylin aggregation disrupts microvascular integrity, activating hypoxia signaling pathways and contributing to maladaptive erythropoietic responses, including excess erythrocytosis. We hypothesized that amyloid\u2010forming amylin would activate hypoxia\u2010inducible factor (HIF) signaling, leading to metabolic alterations in liver and heart during T2D pathogenesis. To investigate this, we used the HIP rat, which expresses human amylin specifically in pancreatic \u03b2\u2010cells, comparing tissues from 14 to 16\u2010month\u2010old rats with those from age\u2010matched wild\u2010type, hyperglycemic UCD and amylin\u2010knockout (AKO) rats. We found greater accumulation of HIF\u20101\u03b1 and HIF\u20102\u03b1 in HIP rat livers compared with those in other groups, alongside increased expression of HIF\u20101 target genes. Mitochondrial ETS capacity was elevated in HIP rat livers, in conjunction with the formation of mitochondrial supercomplexes. Amylin aggregates formed in the hearts of HIP rats, alongside HIF\u20101\u03b1 and HIF\u20102\u03b1 accumulation. This was associated with suppression of ETS capacity, and increased p\u2010AMPK\/AMPK, indicating possible cardiac energetic impairment. Pancreatic secretion of amyloidogenic amylin is thus associated with HIF activation in key metabolic organs beyond the renal vasculature, and occurs alongside mitochondrial alterations in liver and heart that are consistent with sustained hypoxic stress. Our results, alongside previous work, suggest that amylin dysregulation is an overlooked, human\u2010relevant aspect of diabetes pathogenesis, and as such, a potential therapeutic target.<\/jats:p>","DOI":"10.1002\/cph4.70252","type":"journal-article","created":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:04:27Z","timestamp":1788584667000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Amyloid\u2010Forming Amylin Secreted by the Pancreas Promotes Hypoxia\u2010Inducible Factor Activation and Mitochondrial Alterations in Liver and Heart During Type 2 Diabetes Pathogenesis"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3512-157X","authenticated-orcid":false,"given":"Alice E.","family":"Knapton","sequence":"first","affiliation":[{"name":"Department of Physiology Development and Neuroscience  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmal","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5794-8626","authenticated-orcid":false,"given":"Deepak","family":"Kotiya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3718-7783","authenticated-orcid":false,"given":"Alice P.","family":"Sowton","sequence":"additional","affiliation":[{"name":"Department of Physiology Development and Neuroscience  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin D.","family":"Thackray","sequence":"additional","affiliation":[{"name":"Department of Physiology Development and Neuroscience  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8350-2142","authenticated-orcid":false,"given":"Lorenz M. 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