Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced β-cell mass.

Diabetes is generally diagnosed too late. Therefore, biomarkers indicating early stages of β-cell dysfunction and mass reduction would facilitate timely counteraction. Transgenic pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) reveal progressive deterioration of glucose control and reduction of β-cell mass, providing a unique opportunity to study metabolic changes during the prediabetic period. Plasma samples from intravenous glucose tolerance tests of 2.5- and 5-month-old GIPR(dn) transgenic and control animals were analyzed for 163 metabolites by targeted mass spectrometry. Analysis of variance revealed that 26 of 163 parameters were influenced by the interaction Genotype × Age (P ≤ 0.0001) and thus are potential markers for progression within the prediabetic state. Among them, the concentrations of seven amino acids (Phe, Orn, Val, xLeu, His, Arg, and Tyr) were increased in 2.5-month-old but decreased in 5-month-old GIPR(dn) transgenic pigs versus controls. Furthermore, specific sphingomyelins, diacylglycerols, and ether phospholipids were decreased in plasma of 5-month-old GIPR(dn) transgenic pigs. Alterations in plasma metabolite concentrations were associated with liver transcriptome changes in relevant pathways. The concentrations of a number of plasma amino acids and lipids correlated significantly with β-cell mass of 5-month-old pigs. These metabolites represent candidate biomarkers of early phases of β-cell dysfunction and mass reduction.