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In laboratory models of type-2 diabetes, accumulation of aggregated amylin in blood and the cerebral microvasculature induces brain microhemorrhages and reduces cerebral blood flow leading to white matter ischemia and neurological deficits. At the cellular level, aggregated amylin causes cell membrane lipid peroxidation injury, downregulation of tight junction proteins, and activation of proinflammatory signaling pathways which, in turn, induces macrophage activation and macrophage infiltration in vascular areas positive for amylin deposition. We review each step of this cascade based on experimental and clinical evidence and propose the hypothesis that systemic amylin dyshomeostasis may underlie the disparity between glycemic control and stroke risk and may be a therapeutic target to reduce the risk of small vessel ischemic stroke in patients with type-2 diabetes.<\/jats:p>","DOI":"10.1161\/strokeaha.121.034363","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T05:01:30Z","timestamp":1620190890000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Amylin Dyshomeostasis Hypothesis: Small Vessel\u2013Type Ischemic Stroke in the Setting of Type-2 Diabetes"],"prefix":"10.1161","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5879-6449","authenticated-orcid":true,"given":"Florin","family":"Despa","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences (F.D.), University of Kentucky, Lexington."},{"name":"Department of Neurology (F.D., L.B.G.), University of Kentucky, Lexington."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7747-128X","authenticated-orcid":true,"given":"Larry B.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Department of Neurology (F.D., L.B.G.), University of Kentucky, Lexington."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.9346"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21983"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.39.5.634"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8227(92)90074-2"},{"key":"e_1_3_3_6_2","first-page":"245","article-title":"Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAPP) immunoreactivity in pancreatic beta cells.","volume":"135","author":"Johnson KH","year":"1989","unstructured":"Johnson, KH, O\u2019Brien, TD, Jordan, K, Westermark, P. 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