{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:29:04Z","timestamp":1788496144245,"version":"build-2803163510"},"reference-count":78,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,9,18]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Prior studies have shown that nutrient excess induces endoplasmic reticulum (\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      ) stress in nonvascular tissues from patients with diabetes mellitus (\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      ).\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      stress contributes to endothelial dysfunction in patients with DM remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      To characterize vascular\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      stress, we isolated endothelial cells from 42 patients with\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      and 37 subjects without DM. Endothelial cells from patients with\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      displayed higher levels of\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase\u2013like ER eukaryotic initiation factor\u20102a kinase and inositol\u2010requiring ER\u2010to\u2010nucleus signaling protein 1 (\n                      <jats:italic>P<\/jats:italic>\n                      =0.02,\n                      <jats:italic>P<\/jats:italic>\n                      =0.007, respectively), and the chronic\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      stress response evidenced by higher C\/\n                      <jats:styled-content style=\"fixed-case\">EBP<\/jats:styled-content>\n                      \u03b1\u2010homologous protein (\n                      <jats:italic>P<\/jats:italic>\n                      =0.02), were activated in patients with\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      . Higher inositol\u2010requiring ER\u2010to\u2010nucleus signaling protein 1 activation was associated with lower flow\u2013mediated dilation, consistent with endothelial dysfunction (\n                      <jats:italic>r<\/jats:italic>\n                      =0.53,\n                      <jats:italic>P<\/jats:italic>\n                      =0.02). Acute treatment with liraglutide, a glucagon\u2010like peptide 1 receptor agonist, reduced p\u2010inositol\u2010requiring ER\u2010to\u2010nucleus signaling protein 1 (\n                      <jats:italic>P<\/jats:italic>\n                      =0.01), and the activation of its downstream target c\u2010jun N\u2010terminal kinase (\n                      <jats:italic>P<\/jats:italic>\n                      =0.025) in endothelial cells from patients with\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      . Furthermore, liraglutide restored insulin\u2010stimulated endothelial nitric oxide synthase activation in patients with\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      =0.019).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      In summary, our data suggest that\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      stress contributes to vascular insulin resistance and endothelial dysfunction in patients with\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      . Further, we have demonstrated that liraglutide ameliorates\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      stress, decreases c\u2010jun N\u2010terminal kinase activation and restores insulin\u2010mediated endothelial nitric oxide synthase activation in endothelial cells from patients with\n                      <jats:styled-content style=\"fixed-case\">DM<\/jats:styled-content>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.118.009379","type":"journal-article","created":{"date-parts":[[2018,9,16]],"date-time":"2018-09-16T21:27:02Z","timestamp":1537133222000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes 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