李霞+程亮+张勇+柏凤
【摘要】 目的:探讨内脏脂肪源性丝氨酸蛋白酶抑制剂(visceral adipose tissue derived serine protease inhibitor,Vaspin)检测在初诊2型糖尿病患者中的临床意义。方法:选取初诊2型糖尿病患者116例为T2DM组和健康体检者46例为对照组,检测血清Vaspin水平,并分析Vaspin水平与体重指数(BMI)、腰臀比(WHR)、体脂百分比(BFP)、空腹胰岛素(Fins)及胰岛素抵抗指数(HOMA-IR)之间的关系。结果:T2DM组血清Vaspin水平为(1.05±0.27)ng/mL,低于对照组的(1.14±0.29)ng/mL,但差异无统计学意义(P>0.05);T2DM组的超重/肥胖(OB)患者血清Vaspin水平为(0.73±0.19)ng/mL,
低于正常体重(NW)的(1.37±0.26)ng/mL(P<0.001);T2DM组的男性患者血清Vaspin水平为(0.87±0.25)ng/mL,低于女性患者的(1.23±0.29)ng/mL(P<0.001);Pearson相关分析显示,血清Vaspin水平与BMI(r=-0.312,P=0.027)、WHR(r=-0.253,P=0.007)、BFP(r=-0.419,P=0.011)、Fins(r=-0.295,P=0.017)和HOMA-IR(r=-0.175,P=0.046)呈负相关。结论:Vaspin水平与胰岛素抵抗和肥胖密切相关,或参与了胰岛素抵抗及2型糖尿病发生发展。
【关键词】 初诊2型糖尿病; 内脏脂肪源性丝氨酸蛋白酶抑制剂; 胰岛素抵抗; 肥胖
【Abstract】 Objective:To investigate the clinical significance of visceral adipose tissue derived serine protease inhibitor(Vaspin) in patients with newly diagnosed type 2 diabetes mellitus.Method:116 cases of newly diagnosed type 2 diabetes mellitus were selected as T2DM group and 46 healthy subjects were selected as control group,the serum Vaspin levels were detected,and the relationship between Vaspin levels and body mass index(BMI),waist to hip ratio(WHR),body fat percentage(BFP),blood glucose,blood lipids,fasting insulin(Fins) and insulin resistance index(HOMA-IR) were analyzed.Result:The serum Vaspin level in T2DM group was(1.05±0.27) ng/mL,and control group was(1.14±0.29) ng/mL,the difference was not statistically significant(P>0.05).The serum Vaspin level of overweight/obesity(OB) patients in T2DM group was(0.73±0.19) ng/mL,which was lower than (1.37±0.26) ng/mL of normal weight(NW)(P<0.001).The serum Vaspin level of male patients in T2DM group was(0.87±0.25) ng/mL,which was lower than (1.23±0.29) ng/mL of female patients(P<0.001).Pearson correlation analysis showed that serum Vaspin levels were negatively correlated with BMI
(r=-0.312,P=0.027),WHR(r=-0.253,P=0.007),BFP(r=-0.419,P=0.011),Fins(r=-0.295,P=0.017) and HOMA-IR(r=-0.175,P=0.046).Conclusion:Vaspin levels are closely associated with insulin resistance and obesity,may be involved in the development of insulin resistance and type 2 diabetes mellitus.
【Key words】 Newly diagnosed type 2 diabetes mellitus; Visceral adipose tissue derived serine protease inhibitor; Insulin resistance; Obesity
First-authors address:Huaian Affiliated Hospital of Xuzhou Medical University,Huaian 223002,China
doi:10.3969/j.issn.1674-4985.2017.34.031
脂肪組织作为胰岛素抵抗的始发部位,不仅仅能够储存和释放能量,还可以分泌多种脂肪细胞因子,包括脂联素、瘦素、内脂素、肿瘤坏死因子-α等[1-4]。其中,内脏脂肪源性丝氨酸蛋白酶抑制剂(visceral adipose tissue derived serine protease inhibitor,Vaspin)也是一种由脂肪细胞特异性表达和分泌且具有生物学活性的新型脂肪细胞因子[5-8]。有研究发现,Vaspin具有胰岛素增敏作用,与肥胖和胰岛素抵抗密切相关[9-11]。本研究就初诊2型糖尿病患者血清Vaspin水平与糖脂代谢参数进行分析,以探讨Vaspin在2型糖尿病发生中的作用,现报道如下。endprint
1 资料与方法
1.1 一般资料 选取2014年8月-2015年12月于本院就诊2型糖尿病患者116例为T2DM组,其中男64例,女52例,年龄(48.9±9.7)岁。纳入标准:符合1999年WHO制定的2型糖尿病诊断标准;病程≤6个月;抗谷氨酸脱羧酶抗体和抗胰岛素抗体均为阴性;空腹胰岛素(fasting insulin,Fins)≥5 mU/L;且无口服降糖药物及胰岛素使用史。排除标准:1型糖尿病、特殊类型糖尿病或合并糖尿病急慢性并发症患者;继发性肥胖患者;急慢性感染、肿瘤、心脑血管疾病和肝肾功能不全患者;怀孕、哺乳和长期服用避孕药患者。另随机选取同期于本院健康体检的正常人46例为对照组,其中男25例,女21例,年龄(47.2±10.2)岁。两组患者年龄、性别、身高、体重、血压比较差异均无统计学意义(P>0.05),具有可比性。患者均对本研究知情同意并签署知情同意书。
1.2 方法 统计两组患者的临床特征,包括年龄、性别、血压、身高、体重、腰围和臀围,并计算体重指数(body mass index,BMI)和腰臀比(waist-hip ratio,WHR),空腹10 h后于次日清晨留取静脉血,测量空腹血糖(fasting Plasma Glucose,FPG)、甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)、高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)、Fins、糖化血红蛋白(glycosylated hemoglobin,HbA1c)以及Vaspin浓度,口服75 g葡萄糖2 h后再次采血,测量餐后2 h血糖(2 hours postprandial blood glucose,2 h PPG)水平。血清Vaspin测量采用酶联免疫法,试剂盒由美国Creative Diagnostics公司生产,最低可测浓度为0.01 ng/mL,批内变异系数(CV)6.5%~8.7%,批间CV 5.8%~9.5%。胰岛素抵抗指数(HOMA-IR)=FPG×Fins/22.5。胰岛β细胞功能指数(HOMA-β)=Fins×20/(FPG-3.5)。体脂百分比(BFP)=1.2×BMI+0.23×年龄-16.2(男)或1.2×BMI+0.23×年龄-5.4(女)。分析血清Vaspin水平与BMI、WHR、BFP、Fins、HOMA-IR的关系。
1.3 统计学处理 采用SPSS 16.0软件对所得数据进行统计分析,计量资料用(x±s)表示,非正态分布数据经对数转换后再分析,组间比较采用t检验,组内比较采用配对t检验。以P<0.05为差异有统计学意义。血清Vaspin水平与变量之间关系采用Pearson相关分析。
2 结果
2.1 两组患者临床特征比较 两组患者BMI、WHR、BFP、SBP、DBP、TG、HDL-C、比较,差异均无统计学意义(P>0.05);T2DM组FPG、PPG、HbA1c、TC、LDL-C、Fins、HOMA-IR均高于对照组,HOMA-β低于对照组,比较差异均有统计学意义(P<0.05);T2DM组血清Vaspin水平低于对照组,但差异无统计学意义(P>0.05)。
2.2 不同亞组受试者血清Vaspin水平比较 按BMI水平将受试者分为2个亚组:正常体重(NW,BMI<25 kg/m2)和超重/肥胖(OB,BMI≥25 kg/m2)。分析后发现,T2DM组中正常体重受试者89例和超重/肥胖受试者27例的血清Vaspin水平分别为(1.37±0.26)ng/mL和(0.73±0.19)ng/mL(t=15.306,P<0.001);对照组中正常体重受试者36例和超重/肥胖受试者10例的血清Vaspin水平分别为(1.51±0.31)ng/mL和(0.77±0.23)ng/mL(t=9.192,P<0.001)。此外,T2DM组中男性和女性受试者的血清Vaspin水平分别为(0.87±0.25)ng/mL和(1.23±0.29)ng/mL(t=7.178,P<0.001);对照组中男性和女性受试者的血清Vaspin水平分别为(0.96±0.24)ng/mL和(1.32±0.28)ng/mL(t=4.697,P<0.001)。
2.3 血清Vaspin水平与各变量间的相关性分析 将受试者血清Vaspin水平与BMI、WHR、BFP、Fins、HOMA-IR进行Pearson相关分析发现,血清Vaspin水平与BMI(r=-0.312,P=0.027)、WHR(r=-0.253,P=0.007)、BFP(r=-0.419,P=0.011)、Fins(r=-0.295,P=0.017)和HOMA-IR(r=-0.175,P=0.046)呈负相关。
3 讨论
早在2005年,日本学者Hida等[12]首次从OLETE大鼠内脏脂肪组织中分离一种新型脂肪细胞因子,命名为Vaspin,Vaspin属于丝氨酸蛋白酶抑制剂(Serpin)超家族一员,由395个氨基酸组成,相对分子量约为45000,结构包含3个β折叠、9个α螺旋、以及1个反应位点环。本研究发现,两组患者中的OB受试者血清Vaspin水平均明显高于NW受试者(P<0.05),且Vaspin水平与BMI、WHR和BFP均呈负相关关系(P<0.05)。此前,Nakatsuka等[13]曾对OLETF大鼠进行动态观察发现,6周龄时大鼠内脏脂肪组织中无Vaspin mRNA的表达,但到30周龄时,随着OLETF大鼠的体重、体脂含量达到高峰,内脏脂肪组织中可以检测出高Vaspin mRNA表达,然而此后随着大鼠体重的下降,内脏脂肪组织中Vaspin mRNA表达表达逐渐减少。研究发现,给予运动干预治疗治疗8周后,伴随着体重指数和体脂百分比下降,血清Vaspin水平可出现明显升高[14]。Lu等[15]对接受减重手术治疗患者进行分析发现,减重手术后,随着体重下降,患者血清胰岛素和C肽浓度降低,胰岛素敏感性增加,胰岛素抵抗改善,血清Vaspin水平也随之逐渐降低,因此Vaspin水平与肥胖、体脂含量和体脂分布情况密切相关。endprint
本研究結果显示,两组患者中的女性受试者血清Vaspin水平均明显高于男性受试者(P<0.05),提示体内Vaspin分泌具有一定的性别差异。曾有研究发现,与年龄、BMI和WHR匹配的非多囊卵巢综合症(polycystic ovary syndrome,PCOS)患者相比,超重PCOS患者血清Vaspin和雌激素(estrogen,E2)水平均有不同程度升高[16]。而且通过使用不同剂量E2干预网膜脂肪细胞发现,E2能够增加Vaspin分泌,且呈剂量依赖性[17]。由此本研究推测雌激素有可能是导致Vaspin水平性别差异的原因之一。
本研究结果显示,血清Vaspin水平与FINS和HOMA-IR均呈负相关(P<0.05)。以往研究提示,给予肥胖ICR小鼠腹腔注射重组人Vaspin注射液后,进行葡萄糖耐量事件发现,与未注射Vaspin小鼠相比,注射Vaspin小鼠葡萄糖负荷后2 h血糖水平出现明显下降,但血清胰岛素浓度无明显增加,提示Vaspin或具有胰岛素增敏作用[18]。而且肥胖ICR小鼠经Vaspin注射治疗后,白色脂肪组织中瘦素、肿瘤坏死因子-α和抵抗素等基因表达下调,而脂联素和葡萄糖转运体-4基因表达上调,提示Vaspin的胰岛素增敏作用或通过对白色脂肪组织进行调控实现。此外临床研究显示,皮下脂肪组织中Vaspin mRNA表达水平与空腹胰岛素呈正相关[19],与胰岛素敏感性指数呈负相关[4]。本研究也发现,Vaspin水平与胰岛素抵抗密切相关,提示Vaspin或可能参与了胰岛素抵抗的发生发展。
综上所述,Vaspin与胰岛素抵抗、肥胖和体脂分布密切相关,或参与了胰岛素抵抗、肥胖和2型糖尿病的发生发展,Vaspin水平检测或可为临床评估糖尿病发病风险提供依据。
参考文献
[1] Feng R,Li Y,Wang C,et al.Higher vaspin levels in subjects with obesity and type 2 diabetes mellitus:a meta-analysis[J].Diabetes Res Clin Pract,2014,106(1):88-94.
[2] Asadi S,Goodarzi M T,Saidijam M,et al.Resveratrol attenuates visfatin and vaspin genes expression in adipose tissue of rats with type 2 diabetes[J].Iran J Basic Med Sci,2015,18(6):537-543.
[3] Yan M,Su B,Peng W,et al.Association of serum vaspin and adiponectin levels with renal function in patients with or without type 2 diabetes mellitus[J].J Diabetes Res,2014,2014:86 8732.
[4] Mm W Q,Fan J,Khor S,et al.Serum vaspin levels and vaspin mRNA expression in subcutaneous adipose tissue in women with gestational diabetes mellitus[J].Eur J Obstet Gynecol Reprod Biol,2014,182:98-101.
[5] Tasnim F,Faruque M O,Hassan Z,et al.Serum vaspin levels are associated with decreased insulin sensitivity in newly diagnosed type 2 diabetes mellitus in Bangladesh[J].Journal of Taibah University Medical Sciences,2015,10(3):327-332.
[6] Esteghamati A,Noshad S,Mousavizadeh M,et al.Response: association of vaspin with metabolic syndrome:the pivotal role of insulin resistance[J].Diabetes Metab J,2014,38(2):143-149.
[7] El-Mesallamy H O,Kassem D H,El-Demerdash E,et al.
Vaspin and visfatin/Nampt are interesting interrelated adipokines playing a role in the pathogenesis of type 2 diabetes mellitus[J].Metabolism,2011,60(1):63-70.
[8] Barzegari A,Amouzad M H.Effects of 8 weeks resistance training on plasma vaspin and lipid profile levels in adult men with type 2 diabetes[J].Caspian J Intern Med,2014,5(2):103-108.
[9] Li Z,Ma C,Li L,et al.Vaspin serum concentration in patients with type 2 diabetes and carotid plaque[J].J Int Med Res,2012,40(5):1670-1676.endprint
[10] Blüher M.Vaspin in obesity and diabetes: pathophysiological and clinical significance[J].Endocrine,2012,41(2):176-182.
[11] Esteghamati A,Noshad S,Mousavizadeh M,et al.Association of vaspin with metabolic syndrome:the pivotal role of insulin resistance[J].Diabetes Metab J,2014,38(2):143-149.
[12] Hida K,Wada J,Eguchi J,et al.Visceral adipose tissue-derived serine protease inhibitor:a unique insulin-sensitizing adipocytokine in obesity[J].Proc Natl Acad Sci USA,2005,102(30):10 610-10 615.
[13] Nakatsuka A,Wada J,Iseda I,et al.Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex[J].Circ Res,2013,112(9):771-780.
[14] Amouzad M H,Fadaei R A S,Abbaspour S A,et al.Effects of an eight-week resistance training on plasma vaspin concentrations,metabolic parameters levels and physical fitness in patients with type 2 diabetes[J].Cell J,2014,16(3):367-374.
[15] Lu H,Fouejeu Wamba P C,Lapointe M,et al.Increased vaspin levels are associated with beneficial metabolic outcome pre- and post-bariatric surgery[J].PLoS One,2014,9(10):e11 1002.
[16] Cakal E,Ustun Y,Engin-Ustun Y,et al.Serum vaspin and C-reactive protein levels in women with polycystic ovaries and polycystic ovary syndrome[J].Gynecol Endocrinol,2011,27(7):491-495.
[17] Akbarzadeh S,Ghasemi S,Kalantarhormozi M,et al.
Relationship among plasma adipokines,insulin and androgens level as well as biochemical glycemic and lipidemic markers with incidence of PCOS in women with normal BMI[J].Gynecol Endocrinol,2012,28(7):521-524.
[18] Gao F F,Liu G L,Zheng R X,et al.Correlation between vaspin concentration and insulin sensitivity in the visceral adipose tissue of young obese rats[J].Zhongguo Dang Dai Er Ke Za Zhi,2013,15(1):71-74.
[19] Shaker O G,Sadik N A.Vaspin gene in rat adipose tissue:relation to obesity-induced insulin resistance[J].Mol Cell Biochem,2013,373(1-2):229-239.
(收稿日期:2017-08-14) (本文編辑:董悦)endprint