Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion
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 molecu...
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| Veröffentlicht in: | Diabetologia 2022-05, Vol.65 (5), p.861-871 |
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| creator | 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 |
| description | 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 |
| doi_str_mv | 10.1007/s00125-021-05638-6 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8960640</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2631864886</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-f1e1e9090e3924485dd06e35d9e2c74030340e88a48cec17bdba29e780332d643</originalsourceid><addsrcrecordid>eNp9kUtvEzEUhS0EoiHwB7pAlth0M3D9GI9ng4Ta8pAqNQtQu7M8npvgyrGDPYPUf49DSgssurLk891zH4eQYwZvGUD3rgAw3jbAWQOtErpRT8iCScEbkFw_JYu93jCtro_Ii1JuAEC0Uj0nR6JlPWjZLcjVKuPo7YATFjqEOU6Fnq1Wkm4w4uQddSlOOQWa1nSXyrTLNlY-0E24dRa33tL6QX0sc_CRFnS5lqX4kjxb21Dw1d27JN8-nn89_dxcXH76cvrhonGyk1OzZsiwhx5Q9FxK3Y4jKBTt2CN3nQQBQgJqbaV26Fg3jIPlPXYahOCjkmJJ3h98d_OwxdFhndYGs8t-a_OtSdabf5Xov5tN-ml0r0DVBktycmeQ048Zy2S2vjgMwUZMczFciXpBqbWq6Jv_0Js051jXq5SUnGmmdKX4gXI5lZJxfT8MA7PPzRxyMzU38zs3s7d-_fca9yV_gqqAOAClSnGD-aH3I7a_AEoDo9c</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2644218168</pqid></control><display><type>article</type><title>Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>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</creator><creatorcontrib>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</creatorcontrib><description>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</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-021-05638-6</identifier><identifier>PMID: 35190847</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animal models ; Animals ; Blood glucose ; Blood Glucose - metabolism ; C-Peptide - metabolism ; Chemoreception ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - metabolism ; Dipeptidyl Peptidase 4 - metabolism ; Dipeptidyl-peptidase IV ; Genetic control ; Glucose ; Glucose metabolism ; Glucose tolerance ; Glucose Tolerance Test ; High fat diet ; Human Physiology ; Humans ; Insulin ; Insulin - metabolism ; Insulin secretion ; Insulin Secretion - genetics ; Internal Medicine ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Mice ; Molecular modelling ; Nutrient deficiency ; Peptidase ; Peptides ; Prediabetic State - metabolism ; Secretion</subject><ispartof>Diabetologia, 2022-05, Vol.65 (5), p.861-871</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-f1e1e9090e3924485dd06e35d9e2c74030340e88a48cec17bdba29e780332d643</citedby><cites>FETCH-LOGICAL-c474t-f1e1e9090e3924485dd06e35d9e2c74030340e88a48cec17bdba29e780332d643</cites><orcidid>0000-0003-2589-7208 ; 0000-0002-2549-0275 ; 0000-0002-9977-9995 ; 0000-0002-3334-0066 ; 0000-0001-8396-5761 ; 0000-0002-4477-4492 ; 0000-0003-2433-9319 ; 0000-0002-8236-5411 ; 0000-0002-4894-9819 ; 0000-0003-2357-2477 ; 0000-0001-8701-2917 ; 0000-0003-3093-7307 ; 0000-0001-7229-9679 ; 0000-0002-8898-7035 ; 0000-0001-7225-1907 ; 0000-0001-8840-7208 ; 0000-0003-0951-8511 ; 0000-0003-3590-5849</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00125-021-05638-6$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00125-021-05638-6$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35190847$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Patarrão, Rita S.</creatorcontrib><creatorcontrib>Duarte, Nádia</creatorcontrib><creatorcontrib>Coelho, Inês</creatorcontrib><creatorcontrib>Ward, Joey</creatorcontrib><creatorcontrib>Ribeiro, Rogério T.</creatorcontrib><creatorcontrib>Meneses, Maria João</creatorcontrib><creatorcontrib>Andrade, Rita</creatorcontrib><creatorcontrib>Costa, João</creatorcontrib><creatorcontrib>Correia, Isabel</creatorcontrib><creatorcontrib>Boavida, José Manuel</creatorcontrib><creatorcontrib>Duarte, Rui</creatorcontrib><creatorcontrib>Gardete-Correia, Luís</creatorcontrib><creatorcontrib>Medina, José Luís</creatorcontrib><creatorcontrib>Pell, Jill</creatorcontrib><creatorcontrib>Petrie, John</creatorcontrib><creatorcontrib>Raposo, João F.</creatorcontrib><creatorcontrib>Macedo, Maria Paula</creatorcontrib><creatorcontrib>Penha-Gonçalves, Carlos</creatorcontrib><title>Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><addtitle>Diabetologia</addtitle><description>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</description><subject>Animal models</subject><subject>Animals</subject><subject>Blood glucose</subject><subject>Blood Glucose - metabolism</subject><subject>C-Peptide - metabolism</subject><subject>Chemoreception</subject><subject>Diabetes</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Dipeptidyl Peptidase 4 - metabolism</subject><subject>Dipeptidyl-peptidase IV</subject><subject>Genetic control</subject><subject>Glucose</subject><subject>Glucose metabolism</subject><subject>Glucose tolerance</subject><subject>Glucose Tolerance Test</subject><subject>High fat diet</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin secretion</subject><subject>Insulin Secretion - genetics</subject><subject>Internal Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>Nutrient deficiency</subject><subject>Peptidase</subject><subject>Peptides</subject><subject>Prediabetic State - 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metabolism</topic><topic>C-Peptide - metabolism</topic><topic>Chemoreception</topic><topic>Diabetes</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Dipeptidyl Peptidase 4 - metabolism</topic><topic>Dipeptidyl-peptidase IV</topic><topic>Genetic control</topic><topic>Glucose</topic><topic>Glucose metabolism</topic><topic>Glucose tolerance</topic><topic>Glucose Tolerance Test</topic><topic>High fat diet</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin secretion</topic><topic>Insulin Secretion - genetics</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Diseases</topic><topic>Mice</topic><topic>Molecular modelling</topic><topic>Nutrient deficiency</topic><topic>Peptidase</topic><topic>Peptides</topic><topic>Prediabetic State - metabolism</topic><topic>Secretion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Patarrão, Rita S.</creatorcontrib><creatorcontrib>Duarte, Nádia</creatorcontrib><creatorcontrib>Coelho, Inês</creatorcontrib><creatorcontrib>Ward, Joey</creatorcontrib><creatorcontrib>Ribeiro, Rogério T.</creatorcontrib><creatorcontrib>Meneses, Maria João</creatorcontrib><creatorcontrib>Andrade, Rita</creatorcontrib><creatorcontrib>Costa, João</creatorcontrib><creatorcontrib>Correia, Isabel</creatorcontrib><creatorcontrib>Boavida, José Manuel</creatorcontrib><creatorcontrib>Duarte, Rui</creatorcontrib><creatorcontrib>Gardete-Correia, Luís</creatorcontrib><creatorcontrib>Medina, José Luís</creatorcontrib><creatorcontrib>Pell, Jill</creatorcontrib><creatorcontrib>Petrie, John</creatorcontrib><creatorcontrib>Raposo, João F.</creatorcontrib><creatorcontrib>Macedo, Maria Paula</creatorcontrib><creatorcontrib>Penha-Gonçalves, Carlos</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Patarrão, Rita S.</au><au>Duarte, Nádia</au><au>Coelho, Inês</au><au>Ward, Joey</au><au>Ribeiro, Rogério T.</au><au>Meneses, Maria João</au><au>Andrade, Rita</au><au>Costa, João</au><au>Correia, Isabel</au><au>Boavida, José Manuel</au><au>Duarte, Rui</au><au>Gardete-Correia, Luís</au><au>Medina, José Luís</au><au>Pell, Jill</au><au>Petrie, John</au><au>Raposo, João F.</au><au>Macedo, Maria Paula</au><au>Penha-Gonçalves, Carlos</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion</atitle><jtitle>Diabetologia</jtitle><stitle>Diabetologia</stitle><addtitle>Diabetologia</addtitle><date>2022-05-01</date><risdate>2022</risdate><volume>65</volume><issue>5</issue><spage>861</spage><epage>871</epage><pages>861-871</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>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.
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| fulltext | fulltext |
| identifier | ISSN: 0012-186X |
| ispartof | Diabetologia, 2022-05, Vol.65 (5), p.861-871 |
| issn | 0012-186X 1432-0428 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8960640 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Animal models Animals Blood glucose Blood Glucose - metabolism C-Peptide - metabolism Chemoreception Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - metabolism Dipeptidyl Peptidase 4 - metabolism Dipeptidyl-peptidase IV Genetic control Glucose Glucose metabolism Glucose tolerance Glucose Tolerance Test High fat diet Human Physiology Humans Insulin Insulin - metabolism Insulin secretion Insulin Secretion - genetics Internal Medicine Medicine Medicine & Public Health Metabolic Diseases Mice Molecular modelling Nutrient deficiency Peptidase Peptides Prediabetic State - metabolism Secretion |
| title | Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T16%3A19%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Prediabetes%20blunts%20DPP4%20genetic%20control%20of%20postprandial%20glycaemia%20and%20insulin%20secretion&rft.jtitle=Diabetologia&rft.au=Patarr%C3%A3o,%20Rita%20S.&rft.date=2022-05-01&rft.volume=65&rft.issue=5&rft.spage=861&rft.epage=871&rft.pages=861-871&rft.issn=0012-186X&rft.eissn=1432-0428&rft_id=info:doi/10.1007/s00125-021-05638-6&rft_dat=%3Cproquest_pubme%3E2631864886%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2644218168&rft_id=info:pmid/35190847&rfr_iscdi=true |