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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

Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion