{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:34:56Z","timestamp":1791923696610,"version":"4.3.4"},"reference-count":156,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Insulin is a key anabolic hormone traditionally considered to be exclusively produced by pancreatic \u03b2-cells. Insulin exerts several systemic effects involved in glucose uptake and metabolism. In the retina, insulin signaling acts as a regulator of photoreceptor- retinal pigment epithelium (RPE) metabolic coupling as well as of neuronal survival via the PI3K\/Akt and MAPK\/ERK pathways. Impaired insulin signaling contributes to diabetic retinopathy, retinitis pigmentosa, and age-related degeneration by disrupting energy homeostasis and trophic support. However, growing evidence suggests that the retina, particularly RPE, locally synthesizes and secretes insulin. Although the role of local insulin production in the retina remains to be clarified, this discovery introduces a paradigm shift in retinal physiology, suggesting a self-sustaining insulin signaling system that supports glucose uptake, lipid metabolism, and neurovascular integrity. Emerging data indicate that RPE-derived insulin is stimulated by photoreceptor outer segment (POS) phagocytosis and may act through autocrine and paracrine mechanisms to maintain retinal function, even under conditions of systemic insulin deficiency. Understanding this extra-pancreatic insulin source opens new therapeutic perspectives aimed at enhancing local insulin signaling to preserve vision and prevent retinal degeneration. Thus, the objective of this review is to summarize current evidence on RPE-derived insulin and to discuss its potential implications for retinal homeostasis and disease.<\/jats:p>","DOI":"10.3390\/biom15111570","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:35:31Z","timestamp":1762770931000},"page":"1570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Local Insulin for Local Needs? Insights into Retinal Insulin Signaling and RPE Metabolism"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-6786","authenticated-orcid":false,"given":"Matilde","family":"Balbi","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9084-2636","authenticated-orcid":false,"given":"Alessandra","family":"Puddu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genova, Viale Benedetto XV 6, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0494-7942","authenticated-orcid":false,"given":"Andrea","family":"Amaroli","sequence":"additional","affiliation":[{"name":"BIO-Photonics Overarching Research Laboratory (BIOPHOR), Department of Earth, Environmental and Life Sciences (DISTAV), University of Genoa, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3928-1295","authenticated-orcid":false,"given":"Davide","family":"Maggi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genova, Viale Benedetto XV 6, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-1128","authenticated-orcid":false,"given":"Isabella","family":"Panfoli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy\u2014(DIFAR), University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0803-1042","authenticated-orcid":false,"given":"Silvia","family":"Ravera","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genova, Italy"},{"name":"IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s42255-022-00728-0","article-title":"Phagocytosis in the Retina Promotes Local Insulin Production in the Eye","volume":"5","author":"Etchegaray","year":"2023","journal-title":"Nat. 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