Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2022 |
| Outros Autores: | , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10362/134691 |
Resumo: | Funding Information: The PREVADIAB-2 study was supported by a grant from the Portuguese Directorate General of Health. This work was financed by Fundação para a Ciência e Tecnologia (reference number PTDC/BIM/MET/4265/2014), by iNOVA4Health UIDB/Multi/04462/2020 and by ONEIDA (project E-411021.01, Lisboa-01-0145-FEDER-016417, co-funded by FEEI [Fundos Europeus Estruturais e de Investimento] from Programa Operacional Regional Lisboa 2020. We also acknowledge the research infrastructure CONGENTO (project LISBOA-01-0145-FEDER-022170), co-financed by Lisboa Regional Operational Programme (Lisboa 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund and the Foundation for Science and Technology (Portugal). |
| id |
RCAP_8d896ffb76b8ea66472a396f5e67797b |
|---|---|
| oai_identifier_str |
oai:run.unl.pt:10362/134691 |
| network_acronym_str |
RCAP |
| network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| repository_id_str |
7160 |
| spelling |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretionCD26/DPP4DysglycaemiaGenetic associationHyperenergetic dietHyperinsulinaemiaInsulin secretionPostprandial glucosePrediabetesInternal MedicineEndocrinology, Diabetes and MetabolismSDG 3 - Good Health and Well-beingFunding Information: The PREVADIAB-2 study was supported by a grant from the Portuguese Directorate General of Health. This work was financed by Fundação para a Ciência e Tecnologia (reference number PTDC/BIM/MET/4265/2014), by iNOVA4Health UIDB/Multi/04462/2020 and by ONEIDA (project E-411021.01, Lisboa-01-0145-FEDER-016417, co-funded by FEEI [Fundos Europeus Estruturais e de Investimento] from Programa Operacional Regional Lisboa 2020. We also acknowledge the research infrastructure CONGENTO (project LISBOA-01-0145-FEDER-022170), co-financed by Lisboa Regional Operational Programme (Lisboa 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund and the Foundation for Science and Technology (Portugal).Aims/hypothesis: Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven. Methods: We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet. Results: In individuals with normoglycaemia, DPP4 single-nucleotide variants governed glycaemic excursions (rs4664446, p=1.63x10−7) and C-peptide release responses (rs2300757, p=6.86x10−5) upon OGTT. Association with blood glucose levels was stronger at 30 min 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 DPP4 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 Dpp4 is strongly downregulated at 30 min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals, indicating that post-OGTT control by DPP4 is abrogated in prediabetes. Furthermore, Dpp4 KO mice provided concordant evidence that Dpp4 modulates post-OGTT C-peptide release in normoglycaemic but not dysmetabolic states. Conclusions/interpretation: These results showed the DPP4 gene as a strong determinant of post-OGTT levels via glucose-sensing mechanisms that are abrogated in prediabetes. We propose that impairments in DPP4 control of post-OGTT insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with type 2 diabetes. Graphical abstract: [Figure not available: see fulltext.]NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)RUNPatarrão, Rita S.Duarte, NádiaCoelho, InêsWard, JoeyRibeiro, Rogério T.Meneses, Maria JoãoAndrade, RitaCosta, JoãoCorreia, IsabelBoavida, José ManuelDuarte, RuiGardete-Correia, LuísMedina, José LuísPell, JillPetrie, JohnRaposo, João F.Macedo, Maria PaulaPenha-Gonçalves, Carlos2022-03-16T23:23:32Z2022-052022-05-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/134691eng0012-186XPURE: 42135567https://doi.org/10.1007/s00125-021-05638-6info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:13:09Zoai:run.unl.pt:10362/134691Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:48:12.255240Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| title |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| spellingShingle |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion Patarrão, Rita S. CD26/DPP4 Dysglycaemia Genetic association Hyperenergetic diet Hyperinsulinaemia Insulin secretion Postprandial glucose Prediabetes Internal Medicine Endocrinology, Diabetes and Metabolism SDG 3 - Good Health and Well-being |
| title_short |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| title_full |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| title_fullStr |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| title_full_unstemmed |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| title_sort |
Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| author |
Patarrão, Rita S. |
| author_facet |
Patarrão, Rita S. Duarte, Nádia Coelho, Inês Ward, Joey Ribeiro, Rogério T. Meneses, Maria João Andrade, Rita Costa, João Correia, Isabel Boavida, José Manuel Duarte, Rui Gardete-Correia, Luís Medina, José Luís Pell, Jill Petrie, John Raposo, João F. Macedo, Maria Paula Penha-Gonçalves, Carlos |
| author_role |
author |
| author2 |
Duarte, Nádia Coelho, Inês Ward, Joey Ribeiro, Rogério T. Meneses, Maria João Andrade, Rita Costa, João Correia, Isabel Boavida, José Manuel Duarte, Rui Gardete-Correia, Luís Medina, José Luís Pell, Jill Petrie, John Raposo, João F. Macedo, Maria Paula Penha-Gonçalves, Carlos |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) Centro de Estudos de Doenças Crónicas (CEDOC) RUN |
| dc.contributor.author.fl_str_mv |
Patarrão, Rita S. Duarte, Nádia Coelho, Inês Ward, Joey Ribeiro, Rogério T. Meneses, Maria João Andrade, Rita Costa, João Correia, Isabel Boavida, José Manuel Duarte, Rui Gardete-Correia, Luís Medina, José Luís Pell, Jill Petrie, John Raposo, João F. Macedo, Maria Paula Penha-Gonçalves, Carlos |
| dc.subject.por.fl_str_mv |
CD26/DPP4 Dysglycaemia Genetic association Hyperenergetic diet Hyperinsulinaemia Insulin secretion Postprandial glucose Prediabetes Internal Medicine Endocrinology, Diabetes and Metabolism SDG 3 - Good Health and Well-being |
| topic |
CD26/DPP4 Dysglycaemia Genetic association Hyperenergetic diet Hyperinsulinaemia Insulin secretion Postprandial glucose Prediabetes Internal Medicine Endocrinology, Diabetes and Metabolism SDG 3 - Good Health and Well-being |
| description |
Funding Information: The PREVADIAB-2 study was supported by a grant from the Portuguese Directorate General of Health. This work was financed by Fundação para a Ciência e Tecnologia (reference number PTDC/BIM/MET/4265/2014), by iNOVA4Health UIDB/Multi/04462/2020 and by ONEIDA (project E-411021.01, Lisboa-01-0145-FEDER-016417, co-funded by FEEI [Fundos Europeus Estruturais e de Investimento] from Programa Operacional Regional Lisboa 2020. We also acknowledge the research infrastructure CONGENTO (project LISBOA-01-0145-FEDER-022170), co-financed by Lisboa Regional Operational Programme (Lisboa 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund and the Foundation for Science and Technology (Portugal). |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022-03-16T23:23:32Z 2022-05 2022-05-01T00:00:00Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/134691 |
| url |
http://hdl.handle.net/10362/134691 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
0012-186X PURE: 42135567 https://doi.org/10.1007/s00125-021-05638-6 |
| dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
| instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
| instacron_str |
RCAAP |
| institution |
RCAAP |
| reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
| repository.mail.fl_str_mv |
|
| _version_ |
1799138083329802240 |