The Correlation Of Apolipoprotein M With Type 2 Diabetes Mellitus-induced Lower Limb Angiopathy

Background and Aim:Type 2 diabetes mellitus(T2DM)has a very high prevalence in China,while T2DM-related lower limb angiopathy(LLA)is a kind of chronic progressive macrovascular disease.It does not represent obvious symptoms in the early stage,but shows progressive claudication,diabetic foot ulcer and infections,with a high risk of amputation.Current research suggests that increased formation of glycosylation terminal products,enhanced oxidative stress and inflammatory factors and lipid metabolism disorder are the mechanisms of LLA,whereas lipid metabolism disorder is the initial cause of the disease.Among the lipids disorders,increased low-density lipoprotein(LDL)promotes the oxidative stress and the release of inflammatory factors,aggravating the development of atherosclerosis,while increased LDL concentrations is the most important risk factor.Atherosclerosis is the basic pathological changes for T2DM-related LLA,while lipids disorder is more frequent in T2 DM patients.LDL cholesterol(LDL-C)is an important target for the III-class intervention of lipid metabolism and prevention of cardiovascular diseases.Previous studies show that treatment with statins plus other lipid-lowering drugs were effective in improving the lesions,prognosis and amputations of these patients,but residual risk is still very high.Meanwhile,recent studies show that serum LDL-C may not truly reflect the true concentrations of LDL.Therefore,identifying new intervention target for improving lipid metabolism is important to address the relationship between LLA and lipids disorders.Apolipoprotein(apo)is a kind of protein that binds to lipids in the blood.Currently,totally 20 kinds of apos were identified,including apoA,apoB,apoC,apoD and apoE and distributing in different lipoproteins.Recent studies indicate that apolipoproteins functions not only by binding to and transporting lipids and stabilizing the structure of lipoproteins,but also by regulating the activities of key enzymes in the lipoproteins,thus playing important roles in the metabolism of lipoproteins.Among them,ApoM is a kind of new apolipoprotein identified by Xu Ning in 1999.Current studies hold that ApoM functions by promoting the formation of pre-β-high-density lipoprotein(pre-β-HDL)and regulating the expression levels of HDL.In animal studies,ApoM is shown to partially relieve the high fat-induced development of atherosclerotic plaque in the aorta.Therefore,ApoM is considered as an anti-atherosclerotic factor.Recent study also suggests that the changed frequency of single nucleotide polymorphism in the promoter region of ApoM is correlated with the onset of diabetes.Meanwhile,some studies indicated that the levels of plasma ApoM were reduced in some diabetes patients,but whether ApoM participates in the development of atherosclerosis,while further plays important role in the onset of T2DM-related LLA is not clear.Materials and Methods:In this study,T2 DM patients with LLA,T2 DM patients without LLA and normal control participants were included.Plasma ApoM expression levels were identified and correlation analysis were conducted to investigate the correlation among the expression levels of ApoM,diabetes-related LLA and atherosclerosis-related parameters,thus explicating the role of ApoM in diabetes and diabetes-induced LLA.The main studying methods are as follows.(1)Blood glucose,blood pressure,medical history,past history,physical examination and medical history were measured in T2 DM patients with LLA and T2 DM patients without LLA.(2)Serologic examination was performed in three groups of participants to detect the biological parameters,lipids metabolism parameters,renal functions and hepatic functions.(3)Ultrasound doppler flow mapping was conducted to measure the vascular functions,including carotid intima-media thickness(IMT),ankle-brachial index and toe-brachial index,etc.(4)Enzyme-linked immunosorbent assay was performed to measure the plasma ApoM expression levels in three groups of participants.(5)SPSS 18.0 software was used in the statistical analysis.The measurement data were presented as mean±standard deviation or median(interquartile range)according to whether the data obey normal distribution.One way ANOVA and nonparametric Kruskal-Wallis comparisons were adopted in the multiple comparisons of measurement data,while enumeration data were analyzed using chi-square test.The correlation analysis between different parameters was analyzed using Spearman correlation method.Two-tailed P<0.05 was regarded as statistical significant.Results:(1)The values of blood glucose and blood pressure in LLA patients were higher compared with T2 DM patients without LLA during baseline characteristics analysis.The lipids parameters between these two groups were without significant differences.(2)The values of ABI in T2 DM patients with LLA were decreased compared with normal controls and T2 DM patients without LLA,whereas the values of TBI present a stepped reduction in normal controls,T2 DM patients without LLA and T2 DM patients without LLA.(3)Two side IMT values presented a stepped increase in normal controls,T2 DM patients without LLA and T2 DM patients without LLA.(4)The plasma ApoM values of T2 DM patients with LLA were 9.4(6.91,11.74)mg/L,which was quite lower compared with normal controls [18.45(15.10,23.93)mg/L,P<0.001] and T2 DM patients without LLA [15.76(11.79,18.63)mg/L,P<0.001].In diabetic patients with LLA,the plasma ApoM levels were increased upon the increased TASC grades.(5)Besides lipids parameters,the plasma ApoM expression levels were correlated with vascular pathological parameters [ABI(r2=0.229)、 TBI(r2=0.252)、 IMT(r2=-0.247,r2=-0.259)],C-reactive protein(r2=-0.229)and cigarette amount(r2=-0.173).Conclusions:The plasma Apo M expression levels in T2 DM patients with LLA were significantly reduced,which was correlated with vascular pathological parameters and IMT levels.These results indicated that ApoM may participate in the development of atherosclerosis in T2 DM patients by regulating lipids metabolism.ApoM may become a new risk factor of LLA.