{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:01:01Z","timestamp":1791914461026,"version":"4.3.4"},"reference-count":142,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T00:00:00Z","timestamp":1616371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer\u2019s disease and other dementias, Parkinson\u2019s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.<\/jats:p>","DOI":"10.3390\/life11030262","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T12:55:07Z","timestamp":1616417707000},"page":"262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions"],"prefix":"10.3390","volume":"11","author":[{"given":"Igor","family":"Pomytkin","sequence":"first","affiliation":[{"name":"Department of Advanced Cell Technologies, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod","family":"Pinelis","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Children\u2019s Health, 119296 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1093\/ije\/dyt203","article-title":"Diabetes mellitus: Its differentiation into insulin-sensitive and insulin-insensitive types","volume":"42","author":"Himsworth","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (1998). Consensus Development Conference on Insulin Resistance. 5\u20136 November 1997. 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