{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:54:08Z","timestamp":1787316848024,"version":"build-2736575974"},"reference-count":24,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Metabolism Res"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      Hormone sensitive lipase (HSL), encoded by the\n                      <jats:italic>LIPE<\/jats:italic>\n                      gene, is involved in lipolysis. Based on prior animal and human studies,\n                      <jats:italic>LIPE<\/jats:italic>\n                      was analysed as a candidate gene for the development of type 2 diabetes (T2D) in a community\u2010based sample of American Indians.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      Whole\u2010exome sequence data from 6782 participants with longitudinal clinical measures were used to identify variation in\n                      <jats:italic>LIPE<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Amongst the 16 missense variants identified, an Arg611Cys variant (rs34052647; Cys\u2010allele frequency\u00a0=\u00a00.087) significantly associated with T2D (OR [95% CI]\u00a0=\u00a01.38 [1.17\u20131.64],\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0002, adjusted for age, sex, birth year, and the first five genetic principal components) and an earlier onset age of T2D (HR\u00a0=\u00a01.22 [1.09\u20131.36],\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0005). This variant was further analysed for quantitative traits related to T2D. Amongst non\u2010diabetic American Indians, those with the T2D risk Cys\u2010allele had increased insulin levels during an oral glucose tolerance test (0.07 SD per Cys\u2010allele,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.04) and a mixed meal test (0.08 log\n                      <jats:sub>10<\/jats:sub>\n                      \u00b5U\/ml per Cys\u2010allele,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.003), and had increased lipid oxidation rates post\u2010absorptively and during insulin infusion (0.07\u00a0mg [kg estimated metabolic body size {EMBS}]\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u00a0min\n                      <jats:sup>\u22121<\/jats:sup>\n                      per Cys\u2010allele for both,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.01 and 0.009, respectively), compared to individuals with\u00a0the non\u2010risk Arg\u2010allele.\n                      <jats:italic>In vitro<\/jats:italic>\n                      functional studies showed that cells expressing the Cys\u2010allele had a 17.2% decrease in lipolysis under isoproterenol stimulation\u00a0(\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.03) and a 21.3% decrease in lipase enzyme activity measured by using\n                      <jats:italic>p<\/jats:italic>\n                      \u2010nitrophenyl butyrate as a substrate (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.04) compared to the Arg\u2010allele.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The Arg611Cys variant causes a modest impairment in lipolysis, thereby affecting glucose homoeostasis and risk of T2D.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/dmrr.3504","type":"journal-article","created":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T19:44:30Z","timestamp":1634586270000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A missense variant Arg611Cys in\n                    <i>LIPE<\/i>\n                    which encodes hormone sensitive lipase decreases lipolysis and increases risk of type 2 diabetes in American Indians"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5007-2107","authenticated-orcid":false,"given":"Yunhua L.","family":"Muller","sequence":"first","affiliation":[{"name":"Phoenix Epidemiology and Clinical Research Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health  Phoenix Arizona 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