NGAL及其受体与妊娠期糖尿病胰岛素抵抗关系的研究
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摘要
目的探讨妊娠期糖尿病(gestational diabetes mellitus, GDM)孕妇血清及皮下脂肪组织中性粒细胞明胶酶相关脂质运载蛋白(neutrophilgelatinase-associated lipocalin, NGAL)及其受体(NGALR)表达变化与胰岛素抵抗的关系。
方法采用半定量逆转录聚合酶链反应(RT-PCR)技术检测35例GDM孕妇(GDM组)及32例糖耐量正常孕妇(对照组)皮下脂肪组织中NGAL和NGALRmRNA表达水平,采用蛋白免疫印迹法(western-blot)检测两组孕妇皮下脂肪组织中NGAL和NGALR蛋白表达水平,采用酶联免疫吸附试验(ELISA)检测两组孕妇血清NGAL水平,并测定空腹血糖(FPG)、胰岛素(FINS)水平,计算稳态模型的胰岛素抵抗指(HOMA-IR)。两组各指标间的比较采用独立样本的t检验；指标间的相关性分析,采用直线相关分析法。
结果1、GDM组孕妇空腹血清NGAL、FPG、FINS水平及HOMA-IR均明显高于对照组,差异有显著性(P<0.01)。2、GDM组孕妇皮下脂肪组织NGALmRNA和蛋白表达水平为(0.92±0.25,5.32±1.37),明显高于对照组(0.57±0.14,3.49±0.72；P<0.01)。3、GDM组孕妇皮下脂肪组织中NGALRmRNA和蛋白表达水平为(0.61±0.18,3.77±0.84),对照组为(0.59±0.17,3.62±0.79),两组比较,差异无统计学意义(P>0.05)。4、GDM组孕妇血清NGAL水平与HOMA-IR呈明显正相关(r=0.521,P<0.01)；皮下脂肪组织NGALmRNA和蛋白表达水平与HOMA-IR呈明显正相关(r=0.486,0.332,P<0.05)；皮下脂肪组织中NGALRmRNA和蛋白表达水平与HOMA-IR无明显相关性(r=0.097,0.186,P>0.05)；皮下脂肪组织中NGALmRNA和蛋白表达水平与血清NGAL水平无明显相关性(r=0.127,0.083,p>0.05)
结论GDM孕妇血清中NGAL高水平的变化及皮下脂肪组织中NGALmRNA和蛋白的表达升高,可能是GDM孕妇胰岛素抵抗的机制之一。皮下脂肪组织NGALR可能并不参与GDM胰岛素抵抗的病理生理过程。
Objective To investigate the correlation of the expressions of neutrophil gelatinase-associated lipocalin(NGAL) and neutrophil gelatinase-associated lipocalin receptor (NGALR) with the insulin resistance in gestational diabetes mellitus (GDM).
Method The expressions of NGAL massager RNA (mRNA) and NGALR mRNA in subcutaneous adipose tissue were determined by RT-PCR in 35 pregnant women with GDM(GDM group)and 32 pregnant women with normal glucose tolerance (control group),NGAL and NGALR protein expressions were measured by Western blot. ELISA was used to measure the levels of serum NGAL.Then measure the levels of fasting plasma glucose(FPG) and fasting insulin(FINS),calculate the Home model insulin resistance index(HOMA-IR).
Result 1.The serum concentrations of NGAL,FBG,FINS,and HOMA-IR in GDM group,were significantly higher than in control group (P<0.01).2.NGAL mRNA and protein expressions in subcutaneous adipose tissue in GDM group (0.92±0.25,5.32±1.37) were significantly higher than in control group(0.57±0.14,3.49±0.72;P<0.01).3.NGALR mRNA and protein expressions in subcutaneous adipose tissue in GDM group were (0.61±0.18,3.77±0.84),in control group were(0.59±0.17,3.62±0.79),There were no significant difference between the two groups (P>0.05).4.1n GDM group the serum concentration of NGAL was positively correlated with HOMA-IR (r=0.521,p<0.01); the NGALmRNA and protein in subcutaneous adipose tissue were also significantly associated with HOMA-IR (r=0.486,0.332,P<0.05);NGALR mRNA and protein were not associated with HOMA-IR(r=0.097,0.186,P>0.05);NGALmRNA and protein were not associated with the serum NGAL (r=0.127,0.083,P>0.05).
Conclusion The elevation of serum NGAL levels and high expression of NGALmRNA and protein in subcutaneous adipose tissue may contribute to insulin resistance in GDM women.NGALR in subcutaneous adipose tissue were not involved in IR with GDM.
方法采用半定量逆转录聚合酶链反应(RT-PCR)技术检测35例GDM孕妇(GDM组)及32例糖耐量正常孕妇(对照组)皮下脂肪组织中NGAL和NGALRmRNA表达水平,采用蛋白免疫印迹法(western-blot)检测两组孕妇皮下脂肪组织中NGAL和NGALR蛋白表达水平,采用酶联免疫吸附试验(ELISA)检测两组孕妇血清NGAL水平,并测定空腹血糖(FPG)、胰岛素(FINS)水平,计算稳态模型的胰岛素抵抗指(HOMA-IR)。两组各指标间的比较采用独立样本的t检验；指标间的相关性分析,采用直线相关分析法。
结果1、GDM组孕妇空腹血清NGAL、FPG、FINS水平及HOMA-IR均明显高于对照组,差异有显著性(P<0.01)。2、GDM组孕妇皮下脂肪组织NGALmRNA和蛋白表达水平为(0.92±0.25,5.32±1.37),明显高于对照组(0.57±0.14,3.49±0.72；P<0.01)。3、GDM组孕妇皮下脂肪组织中NGALRmRNA和蛋白表达水平为(0.61±0.18,3.77±0.84),对照组为(0.59±0.17,3.62±0.79),两组比较,差异无统计学意义(P>0.05)。4、GDM组孕妇血清NGAL水平与HOMA-IR呈明显正相关(r=0.521,P<0.01)；皮下脂肪组织NGALmRNA和蛋白表达水平与HOMA-IR呈明显正相关(r=0.486,0.332,P<0.05)；皮下脂肪组织中NGALRmRNA和蛋白表达水平与HOMA-IR无明显相关性(r=0.097,0.186,P>0.05)；皮下脂肪组织中NGALmRNA和蛋白表达水平与血清NGAL水平无明显相关性(r=0.127,0.083,p>0.05)
结论GDM孕妇血清中NGAL高水平的变化及皮下脂肪组织中NGALmRNA和蛋白的表达升高,可能是GDM孕妇胰岛素抵抗的机制之一。皮下脂肪组织NGALR可能并不参与GDM胰岛素抵抗的病理生理过程。
Objective To investigate the correlation of the expressions of neutrophil gelatinase-associated lipocalin(NGAL) and neutrophil gelatinase-associated lipocalin receptor (NGALR) with the insulin resistance in gestational diabetes mellitus (GDM).
Method The expressions of NGAL massager RNA (mRNA) and NGALR mRNA in subcutaneous adipose tissue were determined by RT-PCR in 35 pregnant women with GDM(GDM group)and 32 pregnant women with normal glucose tolerance (control group),NGAL and NGALR protein expressions were measured by Western blot. ELISA was used to measure the levels of serum NGAL.Then measure the levels of fasting plasma glucose(FPG) and fasting insulin(FINS),calculate the Home model insulin resistance index(HOMA-IR).
Result 1.The serum concentrations of NGAL,FBG,FINS,and HOMA-IR in GDM group,were significantly higher than in control group (P<0.01).2.NGAL mRNA and protein expressions in subcutaneous adipose tissue in GDM group (0.92±0.25,5.32±1.37) were significantly higher than in control group(0.57±0.14,3.49±0.72;P<0.01).3.NGALR mRNA and protein expressions in subcutaneous adipose tissue in GDM group were (0.61±0.18,3.77±0.84),in control group were(0.59±0.17,3.62±0.79),There were no significant difference between the two groups (P>0.05).4.1n GDM group the serum concentration of NGAL was positively correlated with HOMA-IR (r=0.521,p<0.01); the NGALmRNA and protein in subcutaneous adipose tissue were also significantly associated with HOMA-IR (r=0.486,0.332,P<0.05);NGALR mRNA and protein were not associated with HOMA-IR(r=0.097,0.186,P>0.05);NGALmRNA and protein were not associated with the serum NGAL (r=0.127,0.083,P>0.05).
Conclusion The elevation of serum NGAL levels and high expression of NGALmRNA and protein in subcutaneous adipose tissue may contribute to insulin resistance in GDM women.NGALR in subcutaneous adipose tissue were not involved in IR with GDM.
引文
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2. Yan Q W, Yang Q, Mody N, et al. The Adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance. Diabetes,2007,56:2533-2540.
3. Wang Y, Lam KS, Kraegen EW. et al. Lipocalin-2 is an inflammatory maker closely associated with obesity, insulin resistance, hyperglycemia in humans. Clinical Chemi stry,2007,53:34-41.
4. Devireddy LR, Gazin C, Zhu XC,et al. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell,2005,123:1293-1305.
5. Yang J, Goetz D, Li JY, etal. An iron delivery pathway mediated by a lipocalin. Molecular Cell,2002,10:1045-1056.
6.乐杰.妇产科学7版.北京：人民卫生出版社,2008：151-154.
7. Wang LH, Li HW, Wang J, et al. C/EBP ζ targets to neutrophil gelatinase-associated lipocalin (NGAL) as a repressor for metastasis of MDA-MB-231 cells. Biochim Biophys Acta,2011,1813:1803-1813.
8. Cui L, Xu LY, Shen ZY, et al. NGALR is overexpressed and regulated by hypomethylation in Esophageal squamous Cell Carcinoma. Clin Cancer Res,2008,14:7674-7681.
9. Barden TP, HC Knowles:Diagnosis of diabetes in pregnancy. Clin Obstet Gynecol, 1981,24:3-19.
10. Agardh CD, Aberg A, Norden NE. Glucose levels and insulin secretion during a 75g glucose challenge test in normal pregnancy. J Intern Med,1996,240:303-309.
11. Catalano PM, Tyzbir ED, Wolfe RR, et al. Sims EAH:Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes. Am J Physiol,1993, 264:E60-E67.
12. Homko C, Sivan E, Chen X, et al. Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J Clin Endocrinol Metab,2001,86:568-573.
13. Zimmer DM, Golichowsk AM, Karn CA, et al.'Glucose and amino acid turnover in untreated gestational diabetes. Diabetes Care,1996:29:591-596.
14. smimakis KV, Martinez A, Blatman KH, et al. Early pregnancy insuljn resistance and subsequent gestational diabetes mellitus. Diabetes Care,2005,28:1207-1208.
15. Kjeldsen L, Johnsen AH, Sengelφv H, et al. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem,1993,268: 10425-10432.
16. Law IK, Xu A, Lam KS et al. Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity. Diabetes,2010,59:872-882.
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