Correlation Studies Of Insulin Resistance And Cystatin C

Objective The study was designed to discuss the relationship between Cystatin C(Cys C)and insulin resistance(IR).1.The first part is clinical study and test the relation between Cys C level and the development of IR in elderly patients with type 2 diabetes mellitus(T2DM).2.The second part is experimental studies and test the effects of recombinant Cys C on insulin actions in hepatocytes and C2C12 myotubes and explore the involved molecular mechanisms for the attenuation effect of Cys C on insulin signal transduction.Methods 1.A cross-sectional survey research involving 757 elderly patients with T2 DM was performed and patiehts were divided into groups according to Cys C and IR levels.Serum 1evels of fasting insulin(FBI),fasting blood glucose(FPG),fasting C-peptide(FCP),glycosylated hemoglobin A1c(HbA1c),homeostasis model assessment of insulin resistance(IR)(HOMA2-IR-C),homeostasis model assessment of insulin secretion,homeostasis model assessment of insulin sensitivity(HOMA2-%S-C),micro-albuminuria(mALB)and serum lipid were measured and compared among the groups.Possible influence factors were adjusted,and the correlation between Cys C levels and IR was analyzed.The influencing factors on IR were also analyzed.2.First,evaluated Cys C gene expression profiles in the major organs of type 2 diabetic mice(ob/ob)and the lean control mice(B6).Then,treated Hepa 1-6 hepatocytes,primary mouse hepatocytes and C2C12 myotubes with recombinant Cys C and insulin,investigated whether Cys C affects insulin signaling pathway.Measured these gene expressions of endoplasmic reticulum stress(ERS)in Hepa 1-6 cells and C2C12 myotubes treated with Cys C.Furthermore,detected the expression of proteins belonging to UPR pathway and evaluated X box binding protein 1(XBP1)splicing.Hepa 1-6 cells were pretreated with 4-Phenyl butyric acid(4-PBA),then measured these gene and protein expressions.Results 1.There were statistically significant differences in ages,course of T2 DM,FBI,FCP,HbA1 c,urinary mALB,IR,insulin secretion,insulin sensitivity,morbidity rate of coronary heart disease,hypertension and diabetic nephropathy among the three groups(allP<0.05).Insulin sensitivity was decreased with the increase of Cys C level,while others wers increased.Among 757 patients,the level of serum Cys C was positively correlated with FCP,HOMA2-IR-C 1evels,and negatively correlated with HOMA2-%S-C levels(P < 0.05).Multiple logistic regression analysis showed that higher level of Cys C were independent risk factors for IR in elderly T2 DM patients(OR=3.406,95%CI:2.223~5.217,P<0.05).2.These results clearly show that,as compared with lean control mice,the higher mRNA levels of Cys C were observed in type 2 diabetic mouse spleen,small intestine and large intestine.Cys C impairs insulin signal transduction in hepatocytes,while it has no such effects in skeletal myocytes.ERS plays an essential role for the down-regulated insulin signal transduction in Hepa 1-6 cells treated with Cys C.Conclusions 1.Serum Cys C level is closely related with IR in elderly T2 DM,and the elevated level of serum Cys C is one of independent risk factors for elderly T2 DM.2.By inducing ERS,Cys C impairs insulin signal transduction in hepatocytes.