{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:46:08Z","timestamp":1785818768764,"version":"3.56.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with an increased risk of cardiovascular and metabolic complications. Emerging evidence suggests a close relationship between PA and type 2 diabetes mellitus (T2DM), with a higher prevalence of impaired glucose metabolism observed in PA patients. However, the underlying molecular mechanisms linking PA and T2DM remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>This study aimed to investigate the causal relationship between PA and T2DM and to explore the underlying molecular mechanisms and potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>Mendelian randomization (MR) was performed to evaluate the causal association between PA and T2DM. Shared disease-associated genes were identified from public databases, followed by protein-protein interaction (PPI) construction and pathway enrichment analysis. Experimental validation was conducted in NCI-H295R and HepG2 cells. Virtual screening and molecular docking were applied to identify candidate small-molecule compounds targeting key genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MR suggested a potential positive causal association between PA and T2DM. Integrated bioinformatics and experimental analyses identified SRC as a central regulatory hub gene in PA-associated metabolic dysfunction. Functional experiments showed that aldosterone-induced SRC activation impaired insulin signaling through the AKT-IRS1-GLUT4 axis, while SRC inhibition partially restored insulin response. Pathway analysis highlighted the AGE-RAGE signaling pathway as a key inflammatory mediator linking PA to T2DM. Furthermore, SRC-mediated metabolic signaling and AGE-RAGE-driven inflammatory responses appeared to synergistically contribute to disease progression. Virtual screening identified Grossularine-1 as a promising SRC-targeting compound.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrate a genetic association between PA and T2DM, with SRC identified as a potential key mediator in their pathogenesis. We further highlight the pivotal role of the AGE-RAGE pathway in PA-induced T2DM and propose Grossularine 1 as a promising candidate.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1863900","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:26:43Z","timestamp":1785817603000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association between primary aldosteronism and type 2 diabetes and identification of potential molecular mechanisms"],"prefix":"10.3389","volume":"17","author":[{"given":"Chaoyan","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]},{"name":"Department of Endocrinology, The Six Affiliated Hospital of Guangxi Medical University","place":["Yulin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liheng","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyun","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Six Affiliated Hospital of Guangxi Medical University","place":["Yulin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xian","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuihong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingfen","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2012.230","article-title":"Role of KCNJ5 in familial and sporadic primary aldosteronism","volume":"9","author":"Mulatero","year":"2013","journal-title":"Nat Rev 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