{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T18:33:21Z","timestamp":1776364401549,"version":"3.51.2"},"reference-count":71,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"self-funded scientific research project of Guangxi Health and Wellness Committee","award":["Z-R20231923"],"award-info":[{"award-number":["Z-R20231923"]}]},{"name":"Guangxi Natural Science Foundation","award":["2025GXNSFAA069286"],"award-info":[{"award-number":["2025GXNSFAA069286"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81660724"],"award-info":[{"award-number":["81660724"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81960705"],"award-info":[{"award-number":["81960705"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) has emerged as a major global public health concern, characterized by increasing prevalence and serious complications that contribute substantially to societal healthcare costs. Concurrently, endoplasmic reticulum stress (ERS) has been increasingly appreciated as a central pathogenic mechanism underpinning the development and progression of T2DM. Calcitriol has been shown to have a beneficial effect in the treatment of T2DM. However, the therapeutic targets and potential mechanisms of calcitriol against T2DM through modulated ERS-related pathways remain poorly understood. To systematically investigate these mechanisms, we adopted an integrated approach combining network pharmacology, molecular docking and experimental validation. Initial network pharmacology analysis identified STAT3, HSP90AA1, MAPK1, and PIK3R1 as potential key targets mediating calcitriol\u2019s anti-T2DM effects. These computational predictions were then experimentally validated using a high glucose (HG)-induced MIN6 cell model. Functional assessments using CCK-8 assays and flow cytometry demonstrated that calcitriol improved the survival of pancreatic \u03b2-cells and reduced glucose-induced cell death. Moreover, the results from real-time fluorescent quantitative PCR and western blot analysis revealed that calcitriol reversed the HG induced upregulation of STAT3, HSP90AA1, MAPK1 and PIK3R1 mRNA and protein levels in MIN6 cells. The findings from our study may offer insights into the underlying mechanisms through which calcitriol exerts its therapeutic effects on T2DM by targeting potential ERS-related pathways.<\/jats:p>","DOI":"10.1371\/journal.pone.0347246","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T17:31:48Z","timestamp":1776360708000},"page":"e0347246","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling the mechanism of calcitriol in treating type 2 diabetes mellitus: A combined network pharmacology and in vitro approach targeting ERS-related pathways"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9764-730X","authenticated-orcid":true,"given":"Fanqiang","family":"Zeng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimei","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianping","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengjian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuihua","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shudan","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liya","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Huo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhigang","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5214-440X","authenticated-orcid":true,"given":"Yongli","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"issue":"4","key":"pone.0347246.ref001","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/XCE.0000000000000210","article-title":"Estimating life years lost to diabetes: outcomes from analysis of National Diabetes Audit and Office of National Statistics data","volume":"9","author":"AH Heald","year":"2020","journal-title":"Cardiovasc Endocrinol Metab"},{"key":"pone.0347246.ref002","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"H Sun","year":"2022","journal-title":"Diabetes Res Clin Pract"},{"issue":"5","key":"pone.0347246.ref003","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1039\/D1FO04164A","article-title":"Fucoidan protects the pancreas and improves glucose metabolism through inhibiting inflammation and endoplasmic reticulum stress in T2DM rats","volume":"13","author":"Y Liu","year":"2022","journal-title":"Food Funct"},{"issue":"18","key":"pone.0347246.ref004","doi-asserted-by":"crossref","first-page":"6842","DOI":"10.3390\/ijms21186842","article-title":"Pharmacogenetics of Type 2 Diabetes-Progress and Prospects","volume":"21","author":"YA Nasykhova","year":"2020","journal-title":"Int J Mol Sci"},{"key":"pone.0347246.ref005","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.nutres.2019.09.005","article-title":"Phenolic-enriched blueberry-leaf extract attenuates glucose homeostasis, pancreatic \u03b2-cell function, and insulin sensitivity in high-fat diet-induced diabetic mice","volume":"73","author":"H Li","year":"2020","journal-title":"Nutr Res"},{"issue":"9","key":"pone.0347246.ref006","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3390\/md18090485","article-title":"Fucoidan from Ascophyllumnodosum Suppresses Postprandial Hyperglycemia by Inhibiting Na+\/Glucose Cotransporter 1 Activity","volume":"18","author":"X Shan","year":"2020","journal-title":"Mar Drugs"},{"issue":"7","key":"pone.0347246.ref007","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1172\/JCI29103","article-title":"Islet beta cell failure in type 2 diabetes","volume":"116","author":"M Prentki","year":"2006","journal-title":"J Clin Invest"},{"issue":"8","key":"pone.0347246.ref008","doi-asserted-by":"crossref","first-page":"8597","DOI":"10.1021\/acsnano.9b02050","article-title":"Gadofullerene Nanoparticles Reverse Dysfunctions of Pancreas and Improve Hepatic Insulin Resistance for Type 2 Diabetes Mellitus Treatment","volume":"13","author":"X Li","year":"2019","journal-title":"ACS Nano"},{"issue":"2","key":"pone.0347246.ref009","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqz028","article-title":"The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells","volume":"161","author":"IX Zhang","year":"2020","journal-title":"Endocrinology"},{"issue":"6","key":"pone.0347246.ref010","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.cell.2010.02.034","article-title":"Endoplasmic reticulum stress and the inflammatory basis of metabolic disease","volume":"140","author":"GS Hotamisligil","year":"2010","journal-title":"Cell"},{"key":"pone.0347246.ref011","doi-asserted-by":"crossref","first-page":"1060095","DOI":"10.3389\/fnut.2022.1060095","article-title":"Integrated bioinformatics and in silico approaches reveal the biological targets and molecular mechanisms of 1,25-dihydroxyvitamin D against COVID-19 and diabetes mellitus","volume":"9","author":"F Zeng","year":"2022","journal-title":"Front Nutr"},{"issue":"11","key":"pone.0347246.ref012","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.2337\/dc20-1109","article-title":"Baseline Vitamin D Status, Sleep Patterns, and the Risk of Incident Type 2 Diabetes in Data From the UK Biobank Study","volume":"43","author":"M Wang","year":"2020","journal-title":"Diabetes Care"},{"issue":"1","key":"pone.0347246.ref013","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s12902-020-00641-1","article-title":"Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications","volume":"20","author":"LHM Ahmed","year":"2020","journal-title":"BMC Endocr Disord"},{"key":"pone.0347246.ref014","doi-asserted-by":"crossref","DOI":"10.1016\/j.mce.2025.112472","article-title":"Vitamin D augments insulin secretion via calcium influx and upregulation of voltage calcium channels: Findings from INS-1 cells and human islets","volume":"599","author":"J Taneera","year":"2025","journal-title":"Mol Cell Endocrinol"},{"issue":"2","key":"pone.0347246.ref015","doi-asserted-by":"crossref","first-page":"84","DOI":"10.3177\/jnsv.67.84","article-title":"Early 1,25-Dihydroxyvitamin D(3) Supplementation Effectively Lowers the Incidence of Type 2 Diabetes Mellitus via Ameliorating Inflammation In KK-A(y) Mice","volume":"67","author":"LQ Tian","year":"2021","journal-title":"J Nutr Sci Vitaminol (Tokyo)"},{"key":"pone.0347246.ref016","doi-asserted-by":"crossref","first-page":"108864","DOI":"10.1016\/j.jnutbio.2021.108864","article-title":"1\u03b1,25-(OH)(2) vitamin D(3) prevents insulin resistance and regulates coordinated exocytosis and insulin secretion","volume":"99","author":"AKB Mendes","year":"2022","journal-title":"J Nutr Biochem"},{"key":"pone.0347246.ref017","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.cccn.2005.02.020","article-title":"Effect of cholecalciferol supplementation on blood glucose in an experimental model of type 2 diabetes mellitus in spontaneously hypertensive rats and Wistar rats","volume":"358","author":"R de Souza Santos","year":"2005","journal-title":"Clin Chim Acta"},{"issue":"43","key":"pone.0347246.ref018","first-page":"3407","article-title":"Effects of vitamin D supplementation on insulin resistance in patients with type 2 diabetes mellitus","volume":"94","author":"J Zhou","year":"2014","journal-title":"Zhonghua Yi Xue Za Zhi"},{"issue":"3","key":"pone.0347246.ref019","article-title":"Vitamin D supplementation improves foot ulcers among diabetic patients: Pooled analysis of randomized controlled trials","volume":"1","author":"MIA Putra","year":"2023","journal-title":"Narra X"},{"key":"pone.0347246.ref020","doi-asserted-by":"crossref","first-page":"2040622320924159","DOI":"10.1177\/2040622320924159","article-title":"Association of vitamin D3 and its metabolites in patients with and without type 2 diabetes and their relationship to diabetes complications","volume":"11","author":"AE Butler","year":"2020","journal-title":"Ther Adv Chronic Dis"},{"issue":"1","key":"pone.0347246.ref021","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3892\/br.2020.1394","article-title":"Relationship between total vitamin D metabolites and complications in patients with type 2 diabetes","volume":"14","author":"LHM Ahmed","year":"2021","journal-title":"Biomed Rep"},{"issue":"4458","key":"pone.0347246.ref022","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1126\/science.6250216","article-title":"Vitamin D deficiency inhibits pancreatic secretion of insulin","volume":"209","author":"AW Norman","year":"1980","journal-title":"Science"},{"issue":"1","key":"pone.0347246.ref023","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1210\/endo-119-1-84","article-title":"Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo","volume":"119","author":"C Cade","year":"1986","journal-title":"Endocrinology"},{"issue":"1","key":"pone.0347246.ref024","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1677\/joe.0.1600087","article-title":"Influence of vitamin D3 deficiency and 1,25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat endocrine pancreas","volume":"160","author":"PM Bourlon","year":"1999","journal-title":"J Endocrinol"},{"issue":"1","key":"pone.0347246.ref025","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1093\/abbs\/gmaa138","article-title":"1,25-(OH)2D3 protects pancreatic beta cells against H2O2-induced apoptosis through inhibiting the PERK-ATF4-CHOP pathway","volume":"53","author":"X Hu","year":"2021","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"issue":"8","key":"pone.0347246.ref026","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1161\/CIRCULATIONAHA.109.856070","article-title":"1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus","volume":"120","author":"J Oh","year":"2009","journal-title":"Circulation"},{"issue":"3","key":"pone.0347246.ref027","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1139\/bcb-2014-0155","article-title":"The effect of calcitriol on endoplasmic reticulum stress response","volume":"93","author":"E Haddur","year":"2015","journal-title":"Biochem Cell Biol"},{"issue":"1","key":"pone.0347246.ref028","doi-asserted-by":"crossref","first-page":"20849","DOI":"10.1038\/s41598-021-00293-8","article-title":"Mechanisms of Rhizoma Coptidis against type 2 diabetes mellitus explored by network pharmacology combined with molecular docking and experimental validation","volume":"11","author":"W An","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0347246.ref029","doi-asserted-by":"crossref","first-page":"106346","DOI":"10.1016\/j.intimp.2020.106346","article-title":"Calcitriol inhibits lipopolysaccharide-induced proliferation, migration and invasion of prostate cancer cells through suppressing STAT3 signal activation","volume":"82","author":"W-Y Xing","year":"2020","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pone.0347246.ref030","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41418-019-0344-3","article-title":"STAT3 dictates \u03b2-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia","volume":"27","author":"Q Weng","year":"2020","journal-title":"Cell Death Differ"},{"key":"pone.0347246.ref031","doi-asserted-by":"crossref","first-page":"118391","DOI":"10.1016\/j.biopha.2025.118391","article-title":"Vitamin D and SIRT1 activator SRT2104 cooperate in antiproliferative activity in lung cancer through ferroptosis induction","volume":"190","author":"E Maj","year":"2025","journal-title":"Biomed Pharmacother"},{"issue":"2","key":"pone.0347246.ref032","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/imm.12723","article-title":"Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90\u03b1","volume":"151","author":"GJ Oca\u00f1a","year":"2017","journal-title":"Immunology"},{"key":"pone.0347246.ref033","doi-asserted-by":"crossref","first-page":"146239","DOI":"10.1016\/j.gene.2022.146239","article-title":"Calcitriol ameliorates renal injury with high-salt diet-induced hypertension by upregulating GLIS2 expression and AMPK\/mTOR-regulated autophagy","volume":"820","author":"R Ding","year":"2022","journal-title":"Gene"},{"issue":"12","key":"pone.0347246.ref034","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.tem.2017.10.007","article-title":"Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism","volume":"28","author":"A Lawan","year":"2017","journal-title":"Trends Endocrinol Metab"},{"key":"pone.0347246.ref035","doi-asserted-by":"crossref","first-page":"26375","DOI":"10.1038\/srep26375","article-title":"Prevention of antipsychotic-induced hyperglycaemia by vitamin D: a data mining prediction followed by experimental exploration of the molecular mechanism","volume":"6","author":"T Nagashima","year":"2016","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0347246.ref036","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s13287-022-02832-0","article-title":"Melatonin treatment improves human umbilical cord mesenchymal stem cell therapy in a mouse model of type II diabetes mellitus via the PI3K\/AKT signaling pathway","volume":"13","author":"A Aierken","year":"2022","journal-title":"Stem Cell Res Ther"},{"issue":"1","key":"pone.0347246.ref037","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00125-018-4711-2","article-title":"Global trends in diabetes complications: a review of current evidence","volume":"62","author":"JL Harding","year":"2019","journal-title":"Diabetologia"},{"issue":"1","key":"pone.0347246.ref038","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1038\/s41467-022-29486-z","article-title":"Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice","volume":"13","author":"E Vacurova","year":"2022","journal-title":"Nat Commun"},{"key":"pone.0347246.ref039","doi-asserted-by":"crossref","first-page":"4741","DOI":"10.2147\/DMSO.S551390","article-title":"Vitamin D and its regulatory role in pancreatic \u03b2-cell function: implications for diabetes","volume":"18","author":"X Meng","year":"2025","journal-title":"Diabetes, metabolic syndrome and obesity: targets and therapy"},{"issue":"3","key":"pone.0347246.ref040","doi-asserted-by":"crossref","DOI":"10.52225\/narra.v4i3.1342","article-title":"Effects of cholecalciferol supplementation on depressive symptoms, C-peptide, serotonin, and neurotrophin-3 in type 2 diabetes mellitus: A double-blind, randomized, placebo-controlled trial","volume":"4","author":"R Putranto","year":"2024","journal-title":"Narra J"},{"issue":"8","key":"pone.0347246.ref041","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.3390\/nu15081997","article-title":"Vitamin D in Diabetes: Uncovering the Sunshine Hormone\u2019s Role in Glucose Metabolism and Beyond","volume":"15","author":"J Wu","year":"2023","journal-title":"Nutrients"},{"issue":"21","key":"pone.0347246.ref042","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1038\/sj.onc.1203551","article-title":"Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors","volume":"19","author":"T Hirano","year":"2000","journal-title":"Oncogene"},{"issue":"13","key":"pone.0347246.ref043","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.1101\/gad.12.13.2048","article-title":"Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3","volume":"12","author":"H Niwa","year":"1998","journal-title":"Genes Dev"},{"issue":"3","key":"pone.0347246.ref044","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.bbrc.2005.06.162","article-title":"The transcription factor Stat3 is dispensable for pancreatic beta-cell development and function","volume":"334","author":"J-Y Lee","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0347246.ref045","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ebiom.2018.09.035","article-title":"Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factors","volume":"36","author":"M Miura","year":"2018","journal-title":"EBioMedicine"},{"issue":"8","key":"pone.0347246.ref046","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1210\/en.2004-1468","article-title":"Interleukin-6 depletion selectively improves hepatic insulin action in obesity","volume":"146","author":"PJ Klover","year":"2005","journal-title":"Endocrinology"},{"issue":"3","key":"pone.0347246.ref047","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1096\/fj.201700710R","article-title":"Exercise training protects human and rodent \u03b2 cells against endoplasmic reticulum stress and apoptosis","volume":"32","author":"FMM Paula","year":"2018","journal-title":"FASEB J"},{"issue":"7","key":"pone.0347246.ref048","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1142\/S0192415X21500816","article-title":"Puerarin Inhibits the PERK-eIF2[Formula: see text]-ATF4-CHOP Pathway through Inactivating JAK2\/STAT3 Signal in Pancreatic beta-Cells","volume":"49","author":"X Hu","year":"2021","journal-title":"Am J Chin Med"},{"issue":"4","key":"pone.0347246.ref049","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s00592-016-0852-2","article-title":"Potential role of Hsp90 in rat islet function under the condition of high glucose","volume":"53","author":"X Yang","year":"2016","journal-title":"Acta Diabetol"},{"issue":"1","key":"pone.0347246.ref050","doi-asserted-by":"crossref","DOI":"10.1136\/bmjdrc-2021-002579","article-title":"Extracellular Hsp90\u03b1, which participates in vascular inflammation, is a novel serum predictor of atherosclerosis in type 2 diabetes","volume":"10","author":"X Ding","year":"2022","journal-title":"BMJ Open Diabetes Res Care"},{"issue":"24","key":"pone.0347246.ref051","doi-asserted-by":"crossref","first-page":"8506","DOI":"10.1128\/MCB.22.24.8506-8513.2002","article-title":"Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha","volume":"22","author":"MG Marcu","year":"2002","journal-title":"Mol Cell Biol"},{"issue":"3","key":"pone.0347246.ref052","first-page":"1997","article-title":"ERK\/MAPK signalling pathway and tumorigenesis","volume":"19","author":"Y-J Guo","year":"2020","journal-title":"Exp Ther Med"},{"issue":"6","key":"pone.0347246.ref053","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.2337\/diabetes.52.6.1319","article-title":"Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes","volume":"52","author":"K Bouzakri","year":"2003","journal-title":"Diabetes"},{"issue":"9","key":"pone.0347246.ref054","doi-asserted-by":"crossref","first-page":"8112","DOI":"10.1039\/D0FO01753A","article-title":"Peptides from walnut (Juglans mandshurica Maxim.) protect hepatic HepG2 cells from high glucose-induced insulin resistance and oxidative stress","volume":"11","author":"J Wang","year":"2020","journal-title":"Food Funct"},{"issue":"12","key":"pone.0347246.ref055","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/nrneph.2016.145","article-title":"The impact of insulin resistance on the kidney and vasculature","volume":"12","author":"F Artunc","year":"2016","journal-title":"Nat Rev Nephrol"},{"issue":"5453","key":"pone.0347246.ref056","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1126\/science.287.5453.664","article-title":"Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1","volume":"287","author":"F Urano","year":"2000","journal-title":"Science"},{"issue":"5695","key":"pone.0347246.ref057","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1126\/science.1103160","article-title":"Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes","volume":"306","author":"U Ozcan","year":"2004","journal-title":"Science"},{"issue":"9","key":"pone.0347246.ref058","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1097\/WNR.0000000000001461","article-title":"Inhibition of PI3K\/AKT\/mTOR signaling pathway promotes autophagy and relieves hyperalgesia in diabetic rats","volume":"31","author":"K Liu","year":"2020","journal-title":"Neuroreport"},{"issue":"8","key":"pone.0347246.ref059","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41580-023-00585-z","article-title":"Autophagy and autophagy-related pathways in cancer","volume":"24","author":"J Debnath","year":"2023","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"9","key":"pone.0347246.ref060","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.2337\/diabetes.53.9.2261","article-title":"Increased serum leptin protects from adiposity despite the increased glucose uptake in white adipose tissue in mice lacking p85alpha phosphoinositide 3-kinase","volume":"53","author":"Y Terauchi","year":"2004","journal-title":"Diabetes"},{"issue":"4","key":"pone.0347246.ref061","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/nm.2121","article-title":"A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response","volume":"16","author":"JN Winnay","year":"2010","journal-title":"Nat Med"},{"issue":"2","key":"pone.0347246.ref062","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1007\/s12033-025-01388-7","article-title":"Genome Mining for Hub Genes Related to Endoplasmic Reticulum Stress in Pancreatitis: A Perspective from In Silico Characterization","volume":"68","author":"H Ye","year":"2026","journal-title":"Mol Biotechnol"},{"issue":"1","key":"pone.0347246.ref063","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41574-018-0096-z","article-title":"The role of hypoxia-inducible factors in metabolic diseases","volume":"15","author":"FJ Gonzalez","year":"2018","journal-title":"Nat Rev Endocrinol"},{"issue":"1","key":"pone.0347246.ref064","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/jcb.26174","article-title":"Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus","volume":"119","author":"MSH Akash","year":"2018","journal-title":"J Cell Biochem"},{"issue":"6","key":"pone.0347246.ref065","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.1016\/j.apsb.2021.12.023","article-title":"Gentiopicroside targets PAQR3 to activate the PI3K\/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism","volume":"12","author":"H Xiao","year":"2022","journal-title":"Acta Pharm Sin B"},{"issue":"1","key":"pone.0347246.ref066","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1530\/JME-13-0302","article-title":"Puerarin protects pancreatic \u03b2-cell survival via PI3K\/Akt signaling pathway","volume":"53","author":"Z Li","year":"2014","journal-title":"J Mol Endocrinol"},{"key":"pone.0347246.ref067","doi-asserted-by":"crossref","first-page":"113289","DOI":"10.1016\/j.jep.2020.113289","article-title":"Identification of potential bioactive compounds and mechanisms of GegenQinlian decoction on improving insulin resistance in adipose, liver, and muscle tissue by integrating system pharmacology and bioinformatics analysis","volume":"264","author":"Z Cao","year":"2021","journal-title":"J Ethnopharmacol"},{"issue":"3","key":"pone.0347246.ref068","first-page":"85","article-title":"The prolactin receptor: Diverse and emerging roles in pathophysiology","volume":"2","author":"CM Gorvin","year":"2015","journal-title":"J Clin Transl Endocrinol"},{"key":"pone.0347246.ref069","doi-asserted-by":"crossref","first-page":"579768","DOI":"10.3389\/fphar.2020.579768","article-title":"Discovery of Novel IDH1 Inhibitor Through Comparative Structure-Based Virtual Screening","volume":"11","author":"Y Wang","year":"2020","journal-title":"Front Pharmacol"},{"issue":"10","key":"pone.0347246.ref070","doi-asserted-by":"crossref","first-page":"4018","DOI":"10.1210\/en.2002-220200","article-title":"Antitumorigenic and antiinsulinogenic effects of calcitriol on insulinoma cells and solid beta-cell tumors","volume":"143","author":"F Galbiati","year":"2002","journal-title":"Endocrinology"},{"issue":"2","key":"pone.0347246.ref071","doi-asserted-by":"crossref","DOI":"10.3390\/ijms23020956","article-title":"The action of vitamin D in adipose tissue: is there the link between vitamin D deficiency and adipose tissue-related metabolic disorders?","volume":"23","author":"I Szymczak-Pajor","year":"2022","journal-title":"International Journal of Molecular Sciences"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0347246","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T17:32:03Z","timestamp":1776360723000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0347246"}},"subtitle":[],"editor":[{"given":"Muhammad","family":"Iqhrammullah","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":71,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0347246","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}