| Type 2 diabetes(T2DM)is associated with a markedly increased incidence of cardiovascular disease(CVD).The rapid development of metabonomics analysis provides the tools to reveal biomarkers for T2DM and CVD,and drives advances in prognostics,diagnostics,and treatment.Several studies have demonstrated the different cardiovascular outcomes in type 2 diabetic patients with glipizide and metformin.Determining the predictive value of baseline metabolites for the long-term cardiovascular effects of metformin or glipizide in high-risk diabetic patients might help make individual metabolites profiles-based decisions about drug selection to better prevent subsequent cardiovascular events.In the present study,we focused on the application of metabonomics analysis in identifing informative lipid and amino acid metabolites that could be used as predictors for the cardiovascular effect of metformin and glipizide.The first part is about baseline lipid profiles predict the effects of anti-diabetic medications on cardiovascular outcomes in high-risk type 2 diabetic patients.Baseline serum samples were obtained from 116 patients(56 in the glipizide group and 60 in the metformin group)and profiled using liquid chromatography-quadrupole time of flight-mass spectrometry(LC-QTOF/MS).119 lipid species were analyzed for their predictive values for cardiovascular events during a median follow-up period of 5.1 years.In the metformin group,SM(d18:1-22:0)was associated with a significant 1.65-fold elevated cardiovascular events risk,whereas in the glipizide group,ChE(20:4)significantly reduced its risk by 13.4%(P=0.039 and 0.039).Of these two species,only SM(d18:1-22:0)was linked with a 1.44-fold increased risk of cardiovascular events in all participants(P=0.048).Our results indicate that the baseline levels of specific serum lipid species are strongly associated with the cardiovascular effects of glipizide and metformin.The second part is about amino acid profiles to predict the effects of anti-diabetic medications on cardiovascular outcomes in high-risk type 2 diabetic patients.In this part,LC-QTOF/MS was performed to identify and quantify amino acid metabolites in serum samples from 44 patients(21 in the glipizide group and 23 in the metformin group)after 0,1,2,and 3 years of intervention.In this study,both glipizide and metformin had a substantial effect on serum amino acid metabolism in type 2 diabetic patients with CAD,but the effects of metformin on serum amino acids were limited compared with the baseline amino acids.We focused on diabetes associated amino acids(histidine,threonine,tyrosine,glycine,alanine,phenylalanine,leucine,and isoleucine),and found that these amino acids significantly increased after 1 and 2 years of intervention,but decreased after 3 years of intervention,except for leucine and isoleucine.Baseline serum levels of ornithine,ornithine/citrulline,and glycine were protective factors for cardiovascular events.The significant difference in the baseline serum level of ornithine/citrulline might account for the different cardiovascular effect of glipizide and metformin in high-risk patients.Dipeptidyl peptidase 4 inhibitors(DPP4i),one promising anti-diabetic agent,block the degradation of incretins leading to the regulation of glucose homeostasis.However,of note,the hypoglycemic DPP4i in treating diabetes was reported to increase the risk of hospitalization for acute pancreatitis,pancreatic tumors and CVD by clinical studies.These findings jointly remain us to carefully re-evaluate the first-line hypoglycemic use of DPP4i in treating T2DM.DPP4 mutations carriers are considered as appropriate and valuable indicators for long-term cardiovascular and metabolic outcomes of DPP4i and incretin mimetic drugs in treating T2DM.The third part is about the long-term incretin effects of AGLP-1(named as hyperglipemia)in DPP4 mutation carriers.In this study,we performed clinical tests,genetic analysis and validation,and molecular biology experiments to explore the novel p.V486M(c.1456 G>A)mutation in DPP4 gene potentially accounting for the unusually high AGLP-1 level of proband,and further assessed subsequent glucose metabolism in terms of glucose,insulin,C-peptide levels as well as DPP4 activities.We first reported that an adult female with extreme hyperglipemia had inherited one loss-of-function mutation from her father in DPP4 gene,effectively blunted its enzymatic activity in the blood and showed a fundamental role in dominating the level of AGLP-1.Several other functionally damaged DPP4 mutants/variants were identified in a relative small-scale Chinese population,which implicated the essential genetic evaluation targeted DPP4 gene before clinical application of these drugs. |
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