Research On The Association Between Lipotoxicity And Type 2 Diabetes Mellitus

Background and Aims:Lipotoxicity plays an important role in the pathogenesis of type2 diabetes mellitus（T2DM）.Insulin resistance often occurred in the early stage of T2DM,and metabolic indexes related to lipid accumulation are also closely related to T2DM.Screening of insulin resistance and pre-diabetes through simple and effective indicators is essential for the early prevention and treatment of T2DM.Our previous research found that lipoprotein lipase（LPL）gene mutations in hypertriglyceridemia（HTG）families directly caused T2DM through HTG.We further studied the pathological mechanism of T2DM induced by lipotoxicity using LPL heterozygous knockout(LPL^+/-)mice as a research model.We found that lipid deposition in pancreatic islets caused abnormalβ-cell function and induced abnormal glucose metabolism.Therefore,this study will seeking for the optimal indicators of pre-diabetes and insulin resistance,and further study the molecular mechanism of isletβ-cell dysfunction caused by lipotoxicity in LPL^+/-mice and hyperlipidemic isletβ-cell models.Methods and Materials:The subjects with different glucose metabolism status were recruited,and the correlations between several indicators with diabetes/pre-diabetes risk and insulin resistance were compared by using logistic regression analysis and receiver operating characteristic curves（ROC）to select the optimal index.The gene chip analysis was used to screen the differentially expressed genes of islet between LPL^+/-mice and normal mice.The gene of the most significant difference in expression and closely related to pancreaticβ-cell function were selected for further research.A hyperlipidemic cell model was constructed in vitro to explore the possible mechanism of lipotoxicity-mediated isletβ-cell dysfunction.Results:The correlation between BMI,WHR,LAP,VAI,and BAI with the risk of diabetes and prediabetes was compared.Logistic regression analysis and ROC curve analysis showed that LAP had the best predictive ability for prediabetes.Furthermore,Spearman’s correlation analysis and ROC curve showed that LAP had the strongest correlation with insulin resistance in non-diabetics.Gene chip analysis showed that expression of Gremlin 1 was significantly reduced in the islet of LPL^+/-mice,which was related to isletβcell function.The results of RT-PCR were consistent with it.The expression of Gremlin-1 was decreased and key molecules in BMP/Smads signaling pathway was increased by high-fat exposure in vitro,which may be related to decrease of glucose stimulated insulin secretion of isletβcell.Conclusions:LAP has a good screening effect on insulin resistance in non-diabetics,and has a strong correlation with the risk of pre-diabetes.β-cell dysfunction induced by lipiotoxicity may be related to inhibition of Gremlin-1 expression and activation of the BMP/Smads signaling pathway.