{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:17:09Z","timestamp":1788585429533,"version":"build-2803163510"},"reference-count":74,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK143292"],"award-info":[{"award-number":["R01 DK143292"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK48280"],"award-info":[{"award-number":["R01 DK48280"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["T32 DK101357"],"award-info":[{"award-number":["T32 DK101357"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01 DK143292"],"award-info":[{"award-number":["R01 DK143292"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 DK48280"],"award-info":[{"award-number":["R01 DK48280"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32 DK101357"],"award-info":[{"award-number":["T32 DK101357"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Through fasting and feeding (both in vivo and in vitro), nutrient availability fluctuates over time. Pancreatic \u03b2-cells must respond to nutrients not only by regulated insulin secretion but also by insulin synthesis, which depends upon proinsulin. \u03b2-cells respond biosynthetically to glucose, but little is known about amino acids as regulators of proinsulin levels. We find that in INS1E (rat) \u03b2-cells, isolated murine islets, and isolated human islets\u2014even in the presence of abundant glucose, proinsulin levels remain sensitive to reduced availability of other nutrients contained in \u03b2-cell\/islet bathing medium. A low proinsulin level upon in vitro fasting is accompanied by diminished ribosomal phospho-S6 and phospho-eIF4E-BP1 plus increased phospho-eIF2\u03b1, reversed upon re-feeding. Even as extracellular glucose levels remained steady, INS1E cells consumed the majority of extracellular glutamine and serine (measured by mass spectrometry); concurrently, six nonessential amino acids (most notably proline and alanine, plus glutamic and aspartic acid) were actually exported from cells to media. Proinsulin suppression in response to amino acid limitation appears to be \u03b2-cell-autonomous, is linked to proinsulin biosynthesis, and is ameliorated upon GCN2 inhibition in INS1E cells. Upon re-feeding amino acid-containing medium, the mTORC1 inhibitor rapamycin fully suppressed phospho-S6 but did not block the recovery of proinsulin levels, whereas Torin1 inhibition of mTOR inhibited the amino acid-dependent increase in proinsulin biosynthesis. Altogether, these data indicate that inadequate amino acid-triggered \u03b2-cell signaling can blunt the proinsulin biosynthetic response, contributing to insulin deficiency\u2014a finding that has potential relevance to the pathogenesis of malnutrition-related diabetes.<\/jats:p>","DOI":"10.3390\/cells15171584","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:05:26Z","timestamp":1788224726000},"page":"1584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beta Cell Proinsulin Response to Amino Acid Availability"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7837-0883","authenticated-orcid":false,"given":"Yuting","family":"Ruan","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9696-4781","authenticated-orcid":false,"given":"Noah F.","family":"Gleason","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":false,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41574-020-0355-7","article-title":"Pancreatic beta-cells in type 1 and type 2 diabetes mellitus: Different pathways to failure","volume":"16","author":"Eizirik","year":"2020","journal-title":"Nat. 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