Abstract
Aims/hypothesisImbalances 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.MethodsWe 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.ResultsIn 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/interpretationThese 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
Highlights
Responses to blood glucose variations are effected by the concurrent action of distinct mechanisms that maintain blood glucose levels homeostasis in healthy individuals [1,2,3]
Analysis of blood glucose levels during OGTT evaluated both by point-wise analysis or AUC (Table 1, Fig. 1a) confirmed the expected increase of glycaemic excursions in prediabetic individuals compared with NGT individuals [34]
The C-peptide response at 120 min post-OGTT was clearly higher in prediabetic individuals than in NGT individuals (Table 1, Fig. 1b), showing that post-OGTT pancreatic insulin release is augmented in prediabetes
Summary
Ethics statement All participants were volunteers and provided written informed consent for participation in this study. (c) Correlation of plasma glucose AUC and C-peptide AUC (0–120 min) during OGTT, in NGT participants (blue circles; Pearson’s correlation, r2=0.193, p
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