{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:05:20Z","timestamp":1789517120591,"version":"build-2803163510"},"reference-count":31,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000025","name":"NIMH","doi-asserted-by":"publisher","award":["R21-MH093948"],"award-info":[{"award-number":["R21-MH093948"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["7-12NEURO-15"],"award-info":[{"award-number":["7-12NEURO-15"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed biological samples from two cohorts of clinical trial participants: (1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPAR\u03b3 agonist, N = 12) or placebo and (2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Participants who received pioglitazone experienced broader changes, with significant increases in GSK3\u03b2 (Ser9), mTOR (Ser2448), and RPS6 (Ser235\/Ser236; all P \u2264 .02) compared with placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; P = .04 and P = .025, respectively) compared with placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings demonstrate CNS-specific biomarker responses to both PPAR\u03b3 agonists and GLP1 receptor agonists.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag176","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:40:30Z","timestamp":1776339630000},"page":"2871-2882","source":"Crossref","is-referenced-by-count":0,"title":["Insights from changes in NDEV biomarkers of metabolism: effects of PPAR\u03b3 and GLP1 receptor agonists on brain metabolism"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6765-7686","authenticated-orcid":false,"given":"Audrey","family":"Evers","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine , Stanford, CA ,","place":["USA"]},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine , Stanford, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahim","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Stanford University School of Medicine , Stanford, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashfia","family":"Haque","sequence":"additional","affiliation":[{"name":"NeuroDex Inc. , Natick, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Verma","sequence":"additional","affiliation":[{"name":"NeuroDex Inc. , Natick, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erez","family":"Eitan","sequence":"additional","affiliation":[{"name":"NeuroDex Inc. , Natick, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2894-2353","authenticated-orcid":false,"given":"Natalie","family":"Rasgon","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine , Stanford, CA ,","place":["USA"]},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY 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