Metabonomics Study Of Dedifferentiation Of Islet β Cells Induced By Glucolipotoxicity And Foxo1 Knockout

Diabetes mellitus is a kind of metabolic syndrome whose clinical manifestation is high blood glucose.Type 2 diabetes mellitus has the highest incidence worldwide.Type 2 diabetes mellitus is characterized by insulin resistance and progressive insufficiency of insulin secretion,which show the dysfunction of islet β cell gradually.The molecular mechanisms of Type 2 diabetes mellitus have been widely studied for many years,and there are many theories,most of which focus on β cell dysfunction,such as apoptosis,endoplasmic reticulum stress,autography,mitochondrial damage,glucolipotoxicity and so on.However,there is no exactly comprehensive theory that can explain the process.The hypothesis of "dedifferentiation of β-cells",which has emerged as a theory of β cell dysfunction in recent years,is defined as that β-cells lose the ability to secrete insulin and the characteristic identity,degenerating back to preprogenitor-like islet cells or transdifferentiate into other endocrine cells,such as αcell and so on.But the specific mechanism which explains"dedifferentiation of islet β-cells" is not illustrsted so far.Even if it has been found that high concentrations of glucose and lipid can induce dedifferentiation of β-cells,the particular mechanism remains to be further explored.Foxo1 is a member of Foxo(Forkhead box-containing,o subfamily)family of transcription factors.Foxo1 is abundant in β cells and plays great quantities of significant roles in regulating normal βcell function.Under the conditions of metabolic stress,Foxo1-specific knockout β cells undergo dedifferentiation,but the exact processes remain to be deeply explored.Metabonomics is a burgeoning and relatively mature subject that reveals the nature of life changes through the systematic study of all metabolites in the organism.It has the advantages of convenient detection,reliable data and universal applicability.The aim of this study was to investigate the altered metabolites and metabolic pathways,as well as elucidate possible mechanisms ofβ-cell dedifferentiation which are induced by glucolipidtoxicity and Foxo1 knockout using metabonomics approaches.We found that glucolipotoxicity induced the dedifferentiation of β cells by inhibiting the production of ATP and taurine.The dedifferentiation of Foxo1 knockout cells was mainly caused by the imbalance of iron homeostasis.Glucolipotoxicity aggravating dedifferentiation of Foxo1 knockout β cells were mainly caused by increased uric acid production,impaired fatty acid metabolic pathways and inhibition of mitochondrial oxidative phosphorylation.In conclusion,the metabolic pathways of β-cell dedifferentiation induced by glucolipotoxicity are quite different from those induced by Foxo1 knockout,which may provide novelly trains of thoughts for elucidating the mechanisms of dedifferentiation under different conditions.