Prediabetes Blunts CD26/DPP4 Genetic Control of Postprandial Glycemia and Insulin Secretion
Authors: Patarrão Rita S. , Duarte Nádia , Ribeiro Rogério T. , Andrade Rita , Costa João , Correia Isabel , Boavida José Manuel , Duarte Rui , Gardete-Correia Luís , Medina José Luís , Raposo João F. , Macedo M. Paula , Penha-Gonçalves Carlos 
Published: July 2021

Aims/hypothesis

Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes representing dysmetabolism trajectories leading to type 2 diabetes (T2D). CD26/DPP4 is a clinically proven molecular target of diabetes-controlling drugs but the CD26 gene control of disglycemia is unsettled.

Methods

We dissected the genetic control of postprandial glycemic and insulin release responses by the CD26/DPP4 gene in an European/Portuguese population-based cohort that comprised individuals with normoglycemia and prediabetes, and in mouse experimental models of CD26 deficiency and hypercaloric diet.

Results

In individuals with normoglycemia, CD26/DPP4 single-nucleotide variants governed glycemic excursions (rs4664446, P=1.63×10−7) and C-peptide release responses (rs2300757, P=6.86×10−5) upon OGTT. Association with glycemia was stronger at 30min OGTT but the higher association of the genetic control of insulin secretion was detected in later phases of the postprandial response suggesting that CD26/DDP4 gene directly senses glucose challenges. Accordingly, in mice fed normal chow diet but not high fat diet, we found that under OGTT expression of CD26/DPP4 gene is strongly down-regulated at 30min in the mouse liver. Strikingly, no genetic association was found in prediabetic individuals indicating that postprandial glycemic control by CD26/DPP4 is abrogated in prediabetes. Furthermore, CD26 null mice provided concordant evidence that CD26/DPP4 modulates postprandial C-peptide release in normoglycemic but not in dysmetabolic states.

Conclusions/interpretation

These results unveiled CD26/DPP4 gene as a strong determinant of postprandial glycemia via glucose sensing mechanisms that are abrogated in prediabetes. We propose that impairments in CD26/DDP4 control of postprandial glucose-insulin responses are part of molecular mechanisms underlying early metabolic disturbances associated with T2D.

RESEARCH IN CONTEXT

What is already known about this subject?

CD26/DPP4 is a clinically proven molecular target of diabetes-controlling drugs

DPP4 enzymatic activity impacts in glycemia by degrading incretins

DPP4 represents a potential link between dysmetabolism and insulin resistance.

What is the key question?

Is CD26/DPP4 controlling postprandial glycemic and pancreatic responses?

What are the new findings?

Functional link between postprandial glycemia excursions and subsequent insulin release is operational in NGT individuals but is altered in prediabetes.

CD26/DPP4 gene is a robust component of mechanisms that control postprandial glycemia excursions and insulin secretion in NGT individuals.

CD26/DPP4 gene controls postprandial glucose-insulin responses via glucose sensing mechanisms that are abrogated in prediabetes.

Postprandial reduction of hepatic CD26/DPP4 gene expression is abrogated in experimental diet-induced dysglycemia.

CD26/DPP4 gene action in reducing post-prandial insulin release is not operating in experimental diet-induced dysglycemia.

How might this impact on clinical practice in the foreseeable future?

Impairments in the control of postprandial glucose-insulin responses by CD26/DDP4 are indicators of early metabolic disturbances and possible predictors of dysmetabolic trajectories leading to T2D.