Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion

Patarrão, R. S. et al. (2022) Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion. Diabetologia, 65(5), pp. 861-871. (doi: 10.1007/s00125-021-05638-6) (PMID:35190847)

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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.

Item Type:Articles
Additional 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).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pell, Professor Jill and Ward, Dr Joey and Petrie, Professor John
Authors: Patarrão, R. S., Duarte, N., Coelho, I., Ward, J., Ribeiro, R. T., Meneses, M. J., Andrade, R., Costa, J., Correia, I., Boavida, J. M., Duarte, R., Gardete-Correia, L., Medina, J. L., Pell, J., Petrie, J., Raposo, J. F., Macedo, M. P., and Penha-Gonçalves, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Diabetologia
Publisher:Springer
ISSN:0012-186X
ISSN (Online):1432-0428
Published Online:22 February 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Diabetologia 65(5): 861-871
Publisher Policy:Reproduced under a Creative Commons License

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