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CD26\/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the\n                      <jats:italic>DPP4<\/jats:italic>\n                      gene control of dysglycaemia is not proven.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We dissected the genetic control of post-OGTT and insulin release responses by the\n                      <jats:italic>DPP4<\/jats:italic>\n                      gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of\n                      <jats:italic>Dpp4<\/jats:italic>\n                      deficiency and hyperenergetic diet.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In individuals with normoglycaemia,\n                      <jats:italic>DPP4<\/jats:italic>\n                      single-nucleotide variants governed glycaemic excursions (rs4664446,\n                      <jats:italic>p<\/jats:italic>\n                      =1.63x10\n                      <jats:sup>\u22127<\/jats:sup>\n                      ) and C-peptide release responses (rs2300757,\n                      <jats:italic>p<\/jats:italic>\n                      =6.86x10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ) upon OGTT. Association with blood glucose levels was stronger at 30\u00a0min OGTT, but a higher association with the genetic control of insulin secretion was detected in later phases of the post-OGTT response, suggesting that the\n                      <jats:italic>DPP4<\/jats:italic>\n                      gene directly senses glucose challenges. Accordingly, in mice fed a normal chow diet but not a high-fat diet, we found that, under OGTT, expression of\n                      <jats:italic>Dpp4<\/jats:italic>\n                      is strongly downregulated at 30\u00a0min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by\n                      <jats:italic>DPP4<\/jats:italic>\n                      is abrogated in prediabetes. Furthermore,\n                      <jats:italic>Dpp4<\/jats:italic>\n                      KO mice provided concordant evidence that\n                      <jats:italic>Dpp4<\/jats:italic>\n                      modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      These results showed the\n                      <jats:italic>DPP4<\/jats:italic>\n                      gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in\n                      <jats:italic>DPP4<\/jats:italic>\n                      control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-021-05638-6","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:02:41Z","timestamp":1645480961000},"page":"861-871","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion"],"prefix":"10.1007","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-2917","authenticated-orcid":false,"given":"Rita S.","family":"Patarr\u00e3o","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4477-4492","authenticated-orcid":false,"given":"N\u00e1dia","family":"Duarte","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2357-2477","authenticated-orcid":false,"given":"In\u00eas","family":"Coelho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0951-8511","authenticated-orcid":false,"given":"Joey","family":"Ward","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8840-7208","authenticated-orcid":false,"given":"Rog\u00e9rio T.","family":"Ribeiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8236-5411","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Meneses","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2433-9319","authenticated-orcid":false,"given":"Rita","family":"Andrade","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3590-5849","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Costa","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8396-5761","authenticated-orcid":false,"given":"Isabel","family":"Correia","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9977-9995","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Boavida","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3334-0066","authenticated-orcid":false,"given":"Rui","family":"Duarte","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3093-7307","authenticated-orcid":false,"given":"Lu\u00eds","family":"Gardete-Correia","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7229-9679","authenticated-orcid":false,"given":"Jos\u00e9 Lu\u00eds","family":"Medina","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8898-7035","authenticated-orcid":false,"given":"Jill","family":"Pell","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4894-9819","authenticated-orcid":false,"given":"John","family":"Petrie","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2589-7208","authenticated-orcid":false,"given":"Jo\u00e3o F.","family":"Raposo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2549-0275","authenticated-orcid":false,"given":"Maria Paula","family":"Macedo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7225-1907","authenticated-orcid":false,"given":"Carlos","family":"Penha-Gon\u00e7alves","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"issue":"2","key":"5638_CR1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/nrendo.2017.151","volume":"14","author":"Y Zheng","year":"2018","unstructured":"Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. 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