摘要
目的：探讨代谢综合征患者血清游离脂肪酸(FFAs)谱的变化及与其它糖脂代谢参数之间的关系。
方法：用气相色谱／质谱(GC/MS)联合分析法测定53例代谢综合征、43例2型糖尿病患者及31例正常对照者血清游离脂肪酸谱。
结果：(1)糖尿病组与正常组相比：不饱和脂肪酸UFA(C18:2、C18:1、C20:4、C22:6、C20:3)升高,其中C18：2、C18：1、C20：3差异有统计学意义(P值均<0.05)。饱和脂肪酸(C16：0、C18：0)和SFA/TFA(饱和脂肪酸／总脂肪酸)下降,差异有统计学意义(P<0.01);UFA/TFA(不饱和脂肪酸／总脂肪酸)、PUFA/TFA(多不饱和脂肪酸／总脂肪酸)、PUFA/SFA(多不饱和脂肪酸／饱和脂肪酸)、n6／n3(n-6系列不饱和脂肪酸／n-3系列不饱和脂肪酸)升高,差异有统计学意义(P<0.01)。(2)代谢综合征患者C18：2、C18：1、C20：4、C22：6、C20：3升高,其中C18：2、C18：1、C22：6、C20：3差异有统计学意义(P<0.01), UFA/TFA、PUFA/TFA、PUFA/SFA、n6/n3升高,差异有统计学意义(P<0.01)。C16：0、C18：O和SFA/TFA下降,差异有统计学意义(P值均<0.05)。(3)代谢综合征组与糖尿病组相比：C18:2、UFA/TFA、PUFA/TFA、n6／n3下降(P值均<0.05)。C22:6、C18:3、SFA/TFA升高,差异有统计学意义(P值均<0.05)。(4)血糖与FFAs等参数相关性分析：3组对象的总体相关分析,血糖与UFA/TFA、PUFA/TFA、PUFA/SFA、n6/n3呈正相关(r=0.193,0.174,0.193,0.182,P值均<0.05),校正BMI后,相关性依然存在(r=0.185,0.168,0.194,0.183,P值均<0.05)。血糖与SFA/TFA呈负相关(r=-0.193，P＜0.01),校正BMI后,相关性依然存在(r=-0.189,P＜0.01)。
结论：代谢综合征组、糖尿病组的不饱和脂肪酸、UFA/TFA和PUFA/SFA等升高,说明FFAs组成成分发生了变化,存在游离脂肪酸代谢紊乱。糖尿病可能比不伴有糖尿病的代谢综合征更易受到脂质化损伤。血糖与UFA/TFA、PUFA/TFA、PUFA/SFA、n6/n3呈正相关,血糖与SFA/TFA呈负相关,提示UFA、特别是n6系可能在MS及糖尿病发生发展中起重要作用。
目的：探讨游离脂肪酸(油酸,OA)诱导小鼠胰岛β细胞系MIN6胰岛素分泌功能的变化、基因表达谱的情况及评估潜在的保护因素N-乙酰半胱氨酸(NAC)对游离脂肪酸作用的影响。
方法：以MIN6细胞为对象,分别用OA+BSA、NAC+BSA、OA+BSA+NAC及BSA四组刺激72小时：(1)放射免疫法检测培养液中胰岛素及葡萄糖刺激下的胰岛素分泌量及细胞总胰岛素量。(2)提取RNA,并逆转录为cDNA,用寡核苷酸微阵列扫描基因表达谱,用分析软件分析基因表达谱的改变。(3)采用实时定量RT-PCR比较从基因表达谱挑选出的变化显著的基因的表达情况。
结果：(1)OA增加MIN6细胞基础胰岛素的分泌,但抑制了葡萄糖刺激下的胰岛素分泌。NAC不能改善OA对基础及葡萄糖刺激下的胰岛素分泌的影响。(2)与对照BSA相比较,OA减少MIN6细胞总胰岛素含量约50%,加上NAC后,细胞总胰岛素含量可明显恢复。(3)微阵列结果：对总共12000个基因或已表达序列标志(Expressed sequence tag, ESTs)进行分析,OA可降低约667个基因的表达；上调约265个基因的表达,NAC可显著减少OA下调基因或ESTs的数量[从667±66至192±29 (OA vs. OA+NAC, P＜0.05)]。但OA上调基因或ESTs的数量没有显著性改变[从265±88至212±14(OA vs.OA+NAC,P=0.77)]。(4)从微阵列结果中分析中挑选出45个变化显著的基因作进一步的实时定量PCR检测,证实其中16个基因表达变化＞1.8倍,28个基因变化＞1.2-1.3倍。将受OA调节的基因根据功能分类,涵盖与脂肪代谢功能相关的基因占32%、与细胞生长／分化及信号转导相关基因分别占13%和16%、与复制、蛋白聚集分泌、核小体装配及细胞防御反应相关基因占2-9%。NAC可逆转大部分与细胞生长／分化功能相关基因的表达,但对与代谢相关的基因无明显逆转作用。
结论：(1)OA长期培养胰岛细胞可增加基础胰岛素分泌,抑制葡萄糖刺激下胰岛素分泌,可能的机制是导致了胰岛p细胞功能受损。抗氧化剂NAC并不能恢复OA对GSIS的影响,说明OA的氧化应激作用对葡萄糖刺激下胰岛素分泌的脂毒性不是直接作用。(2)长期暴露于游离脂肪酸可抑制胰岛素的生物合成,导致胰岛素含量减少和胰岛素成熟受阻,且这种影响可被NAC完全逆转。(3)OA可使与脂质代谢相关基因表达显著变化,没有发现与葡萄糖氧化、酵解相关基因的改变。(4)通过基因表达谱的检测,提供了许多与p细胞脂毒性的机制可能相关的候选基因,为今后的进一步研究打下了基础。
目的：探讨代谢综合征患者的与脂代谢密切相关的血清脂联素、视黄醇结合蛋白-4(RBP4),血管生成素样蛋白-3(Angpt13)水平的变化及其意义。
方法：对111例代谢综合征(MS)患者和152例健康对照,采用单克隆抗体双夹心酶联免疫法测定的血清脂联素、视黄醇结合蛋白-4及血管生成素样蛋白-3水平,分析血清脂联素、视黄醇结合蛋白-4及血管生成素样蛋白-3与脂代谢紊乱等MS相关组分的关系。
结果：(1)男性脂联素水平明显低于女性(P<0.001),而RBP4水平明显高于女性(P<0.001),校正BMI后,这种关系仍存在,如加上体脂含量校正后差异消失。Angpt13男女间无差异(P=0.384)。(2)校正年龄和性别后,血清脂联素水平与HDL-C、Angpt13水平显著正相关(P<0.05),与BMI、WC、WHR、体脂含量、FPG、TG、FINS、HOMA-IR、hsCRP水平显著负相关(P＜0.05)；校正年龄、性别和BMI后,血清脂联素与HDL-C、Angpt13水平显著正相关(P<0.05),与FPG、TG、FINS、HOMA-IR负相关(P<0.05),但与WC、WHR、体脂含量、hsCRP水平负相关关系不再显著。校正年龄和性别后,血清Angpt13水平与脂联素水平显著正相关(P<0.001),与FINS、HOMA-IR水平显著负相关(P分别为0.026和0.015)；校正年龄、性别和BMI后,血清Angpt13水平仍与脂联素水平显著正相关(P<0.001),但与FINS、HOMA-IR水平负相关关系不再显著(P分别为0.118和0.086)。校正年龄和性别后,血清RBP4水平与BMI、WC、WHR、体脂含量、PBG、TG、TC、LDL-C、SBP、DBP、FINS、HOMA-IR显著正相关(P<0.05),与HDL-C水平显著负相关(P=0.012)；在校正年龄、性别和BMI后,血清RBP4水平与PBG、TG、TC、LDL-C、SBP、DBP显著正相关(P<0.05),与HDL-C水平显著负相关(P=0.055),而与FINS、HOMA-IR.体脂含量的相关关系消失。(3)用多元逐步回归法,TG、Angpt13、性别、HOMA-IR是血清脂联素的独立决定因素。脂联素是血清Angpt13的独立决定因素。TG、性别、DBP是血清RBP4的独立决定因素。(4)校正年龄、性别和BMI后,高TG组脂联素水平明显低于对照组[4.40(0.97-23.29)vs.6.67(1.12-22.27)ug/ml,P=0.001],低HDL-C组脂联素水平明显低于对照组[4.96(0.97-14.88)vs.5.18(1.12-23.29)ug/ml, P=0.005]。高TG组RBP4水平明显高于对照组(55.22±17.72 vs.45.21±17.72ug/ml, P<0.001)。校正年龄、性别和BMI后,高TG组RBP4水平仍高于对照组(F=9.549,P=0.002)。ANGPTL3水平在高TG组、低HDL-C组与对照组相比较无明显差别[分别为：(424.69±154.06 vs.421.92±138.16 ng/ml, P=0.878)、(428.46±134.06 vs.416.94±158.81 ng/ml, P=0.531)]。(5)非酒精性脂肪肝(NAFLD)组脂联素水平明显低于对照组(P<0.001)。RBP4水平明显高于对照组(P<0.001)。Angpt13与对照组比较无明显差别(P=0.256)。
结论：(1)人血清脂联素水平与血脂紊乱等MS各相关组分呈负相关,NAFLD患者脂联素水平明显降低,提示血清脂联素含量降低可能为MS进展的原因之一。(2) Angpt13与血脂紊乱等MS组分无明显关联,与脂联素呈独立正相关,人体Angpt13对血脂的调节与动物研究的结果不一致,Angpt13在人体和动物体内的差别表现及原因,仍有待进一步研究。(3)RBP4与血脂、中心性肥胖、HOMA-IR、NAFLD等胰岛素抵抗关联的多个代谢参数关系密切,可能是引起脂代谢紊乱和胰岛素抵抗的主要脂肪因子之一,提示RBP4可能是一项新的代谢综合征的血清标志物。
Objective To investigate the changes of serum free fatty acids (FFAs) composition in the patients with metabolic syndrome (MS) and the relationship between FFAs with serum glucose disorder.
Methods The serum free fatty acids profile was measured by the gas chromatograph and mass spectrometer(GC/MS) in 53 patients with metabolic syndrome,43 patients with type 2 diabetes(T2DM) and 31 control subjects.
Results①The patients with T2DM had higher parameters of unsaturated fatty acids UFA (C18:2、C18:1、C20:4、C22:6、C20:3), among them,C18:2、C18:1、C20:3 were significantly increased in the patients with T2DM than those in the normal control (all P<0.05),saturated fatty acids SFA(C16:0、C18:0)and ratio of SFA/TFA(total fatty acids)were remarkably decreased in patients with T2DM(P＜0.01, compared with normal control), the ratio of UFA/TFA,PUFA(polyunsaturated fatty acids)/TFA, PUFA/SFA and n6 PUFA/n3 PUFA were significantly increased in the patient with T2DM compared with normal subjects (P<0.01).②The patients with MS had higher parameters of unsaturated fatty acids UFA (C18:2、C18:1、C20:4、C22:6、C20:3), among them, C18:2、C18:1、C22:6、C20:3 were significantly increased in the patients with MS than those in the normal control (P＜0.01), the ratio of UFA/TFA, PUFA/TFA, PUFA/SFA, n6 PUFA/n3 PUFA were significantly increased in the patient with MS compared with normal subjects (P<0.01), C16:0、C18:0 and SFA/TFA were remarkably decreased in patients with MS (all P<0.05, compared with normal control).③The patients with MS had lower C18:2、UFA/TFA、PUFA/TFA、n6/n3 than those with T2DM (all P＜0.05), but C22:6、C18:3 SFA/TFA were remarkably increased in patients with MS (all P<0.05, compared with T2DM).④Fasting blood glucose had remarkably positive correlation with UFA/TFA、PUFA/TFA、PUFA/SFA、n6/n3 (r=0.193,0.174,0.193,0.182, all P<0.05), and a negative correlation with SFA/TFA (r=-0.193,P<0.01). After BMI calibration, Fasting blood glucose was still positively correlated with UFA/TFA、PUFA/TFA、PUFA/SFA、n6/n3(r=0.185,0.168,0.194,0.183,allP<0.05), and negatively correlated with SFA/TFA (r=-0.189, P＜0.01).
Conclusion The UFA, UFA/TFA and PUFA/SFA are higher in the patients with MS and T2DM than normal subjects, it demonstrated there is the FFAs metabolic abnormality in those patients. The patients with T2DM is easier to get injured by lipid peroxidation than the patient with MS. Fasting blood glucose positively correlated with UFA/TFA、PUFA/TFA、PUFA/SFA、n6/n3 and a negatively correlated with SFA/TFA, increased levels of n6 PUFA may play a role in the pathogenesis of MS and T2DM.
Objective To investigate the effects of free fatty acids(FFAs) on secretory function and the gene expression profiling of pancreaticβ-cell line MIN6, and to evaluate the potential protective effects of N-acetyl--L-cysteine(NAC).
Methods The MIN6 cells are treated for 72 h with either①BSA,②OA (Oleic acid) in BSA,③OA in BSA plus NAC,or④NAC in BSA respectively, then The concentration of insulin in the supernatant and total cellular insulin content are determined by radioimmunoassay. Total RNA was isolated from MIN6 cells and converted to cDNA, oligonucleotide microarrays are used to define gene expression, using software analysis Expression profiling of genes and further classified according to biological function. Genes that were deemed significantly altered by OA treatment are further detected and characterized by Real-time PCR.
Results①OA increased basal insulin, but decreased insulin secretion induced by glucose. Coincubation with NAC did not improve the insulin secretion in response to glucose or normalize increased basal insulin secretion in OA-exposed MIN6 cells.②OA decreased insulin content in MIN6 cells by about 50% compared with BSA control, coincubation with NAC restored insulin content in OA-treated MIN6 cells.③Of the 12,000 genes or ESTs, OA decreased expression of 667 and upregulated genes of 265. Coincubation with NAC markedly reduced the number of OA-down regulated genes or ESTs from 667±66 to 192±29 (P< 0.05 for OA vs. OA+NAC). The number of upregulated genes and ESTs was not significantly reduced (265±88 to 212±14, P= 0.77 for OA vs.OA +NAC).④A total of 45 genes deemed significantly changed by the microarray analysis were further confirmed by real-time PCR, PCR confirmed all 16 genes changed by> 1.8-fold,28 genes shown to be changed by> 1.2-1.3 fold. according to known function, OA signifi-cantly upregulated genes involved inβ-oxidation of lipids comprised the largest functional cluster with 32%,Genes clustered into cell growth/ differentiation and signal transduction groups represent 13% and 16% of the clustered genes, respectively. OA also regulated several genes involved in transcription, protein trafficking and secretion, nucleosome assembly, and cellular defense response, comprising 2-9% of the clustered genes. Genes involved in cell growth and differentiation were normalized by coincubation with NAC, but all genes in the metabolism cluster differentially regulated by OA were not normalized by NAC treatment.
Conclusion①Long-term exposure of MIN6 cells to OA leads to increase in basal insulin secretion with an inhibition of GSIS, it is thought to contribute to the deterioration of islet function in theβ-cell. and antiox- idants NAC failed to restore GSIS following OA suggests that the increase in ROS production associated with chronic OA treatment of P-cells may not be directly implicated in the effects of OA on GSIS.②Prolonged exposure to FFAs inhibits insulin biosynthesis results in decreased insulin content and insulin maturation, and that this could be restored by NAC.③OA significantly changed genes involved in P-oxida-tion of lipid metabolism, but the expression of genes involved in glyco-lysis and glucose oxidation was generally unchanged.④By analyzing the gene expression profiling, many candidate genes associated with lipotoxicity to (3-cells are offered and it put a foundation for future research.
Objective To evaluate new cytokines associated with dyslipidemia including adiponectin, angiopoietin-like protein 3(Angptl3) and retinol-binding protein 4(RBP4) in metabolic syndrome(MS).
Methods Serum adiponectin,Angptl3 and RBP4 levels were measured by sandwich ELISA in a group of 111 patients with metabolic syndrome(MS) and 152 normal controls to analysis the relationships between those new cytokines and dyslipidemia in MS.
Results①Serum adiponectin levels in men were significantly lower than those in women (P＜0.001), Serum RBP4 levels in men were significantly higher than those in women (P＜0.001), After BMI calib-ration, those difference still exist, but After BMI and fat content percen-tage calibration, those difference disappeared. No gender- associated difference in serum Angpt13 levels was observed (P=0.384).②Serum adiponectin levels were positively correlated with high density lipopro-teinemia-C (HDL-C) and Angpt13 after adjusted for age and sex(P<0.05), negatively correlated with BMI, WC, WHR, fat percentage, FPG, TG, FINS, HOMA-IR and hsCRP (P<0.05), after adjusted for age, sex and BMI, adiponectin levels were positively correlated with HDL-C and Angpt13 and negatively correlated with FPG, TG, FINS and HOMA-IR and (P＜0.05), but the correlation with WC, WHR, fat percentage and hsCRP disappeared. Serum Angpt13 concentrations were positively correlated with adiponectin (P＜0.001) after calibration of age and sex, negatively correlated with FINS and HOMA-IR (P=0.026, P=0.015), after calibration of age, sex and BMI, Angpt13 till positively correlated with adiponectin(P＜0.001),but negative correlation with FINS and HOMA-IR disappeared (P=0.118, P=0.086). Serum RBP4 concentrations were positively correlated with BMI, WC, WHR, fat percentage, PBG、TG、TC、LDL-C、SBP、DBP、FINS、HOMA-IR after adjusted for sex and age(P<0.05),negatively correlated with HDL-C (P=0.012). after cali-bration of age, sex and BMI, Serum RBP4 concentrations were positively correlated with PBG、TG、TC、LDL-C、SBP、DBP (P<0.05),negatively correlated with HDL-C(P=0.055), but correlation with FINS、HOMA-IR and fat percentage disappeared.③By multiple regression, TG, Angpt13, sex, and HOMA-IR were found to be independent determinants for serum adiponectin concentrations. The adiponectin was the independent deter-miner influencing angpt13 level. TG, sex, DBP were independent deter-minants for serum RBP4.④Serum adiponectin levels were significantly lower in the hypertriglyceridemia than in the control group [4.40(0.97-23.29)vs.6.67 (1.12-22.27) ug/ml, P=0.001] and significantly lower in the hypo-high density lipoproteinemia group than in the control group [4.96(0.97-14.88) vs.5.18(1.12-23.29) ug/ml, P=0.005)] after calibration of age, sex and BMI. Serum RBP4 concentrations were significantly higher in the hypertriglyceridemia group than in the control group) after calibration of age and sex (55.22±17.72 vs.45.21±17.72ug/ml, PO.001). After calibration of age, sex and BMI, RBP4 concentrations was still higher in hypertriglyceridemia group than in the control group (F=9.549, P=0.002). No difference in serum Angpt13 levels was observed between hypertriglyceridemia group and control group, between hypo-high density lipoproteinemia group and the control group[(424.69±154.06 vs.421.92±138.16 ng/ml,P=0.878),(428.46±134.06 vs.416.94±158.81 ng/ml, P= 0.531) respectively].⑤Serum adiponectin concentrations were signifi-cantly lower in the Non-alcoholic fatty liver disease (NAFLD) group than in the control group(P<0.001). Serum RBP4 were significantly higher in the NAFLD group than in the control group(P<0.001). No difference in serum Angpt13 levels was observed between the NAFLD group and the control group (P=0.256).
Conclusion①Serum adiponectin is negatively correlated with all components of MS, NAFLD sufferers show significantly lower adiponectin, prompting that the decrease of adiponectin content may be a reason of MS progress.②Angpt13 is independent positively correlated with adiponectin, and has no obvious relationship with dyslipidemia and other components of MS. Because the mechanism of lipid metabolism is different, the effects of Angpt13 in human being should be further studied.③Serum RBP4 has closely relationship with blood fat, central obesity, HOAM-IR, NAFLD and etc of MS components, it may be one of main adipocyte factors associated with lipid metabolism, prompting that Serum RBP4 may be a new serum marker of metabolic syndrome.
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