浆细胞膜糖蛋白-1与妊娠期糖尿病发病关系的研究
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摘要
目的检测浆细胞膜糖蛋白(PC-1)及胰岛素受体酪氨酸激酶(IRTK)在妊娠期糖尿病(GDM)孕妇、正常孕妇及非孕对照妇女骨骼肌中的表达及活性，探讨二者与妊娠期糖尿病发病的关系。
方法采用Western blot的方法测定了20例GDM孕妇(GDM组)、20例糖耐量正常孕妇(正常妊娠组)及12例糖耐量正常非孕妇女(对照组)骨骼肌组织PC-1、胰岛素受体的表达水平；采用免疫沉淀及ELISSA的方法分别测定胰岛素刺激前后骨骼肌组织胰岛素受体酪氨酸磷酸化程度及IRTK活性；采用葡萄糖氧化酶法及放射免疫法测定空腹血葡萄糖(FPG)及空腹血胰岛素(FINS)水平，计算胰岛素抵抗指数(HOMA-IR)。
结果
1)GDM组FPG、FINS、HOMA-IR(5.61±0.78mmol／L、15.12±5.31 mU／L、1.21±0.52)均明显高于正常妊娠组(4.43±0.46 mmol／L、10.56±3.07 mU／L、0.80±0.31)(P＜0.01)，正常妊娠组FINS、HOMA-IR明显高于对照组(7.56±2.31 mU／L、0.47±0.26)(P＜0.01)。
2)GDM组PC-1表达水平(1.22±0.02)明显高于正常妊娠组(0.71±0.03)(P＜0.01)，正常妊娠组明显高于对照组(0.43±0.02)(P＜0.01)。
3)GDM组胰岛素受体含量、胰岛素受体基础酪氨酸磷酸化程度及其酪氨酸激酶基础活性(0.59±0.03、0.14±0.03、2.33±0.19)与正常妊娠组(0.61±0.05、0.15±0.02、2.36±0.26)，正常妊娠组与对照组(0.63±0.06、0.16±0.04、2.39±0.35)比较，差异均无显著性(P＞0.05)。
4)胰岛素刺激后的胰岛素受体酪氨酸磷酸化程度及IRTK活性比较，GDM组(0.17±0.04、2.86±0.47)明显低于正常妊娠组(0.24±0.02、3.84±0.53)(P＜0.01)，正常妊娠组明显低于对照组(0.31±0.03、4.87±0.56)(P＜0.01)。
5)正常妊娠组、GDM组PC-1表达水平与HOMA-IR呈明显正相关(r=0.611、0.734，P＜0.01)，与胰岛素刺激后胰岛素受体酪氨酸激酶活性成负相关(r=-0.652、-0.723，P＜0.01)。
结论
1)妊娠期糖尿病患者骨骼肌组织中存在PC-1的高表达。
2)骨骼肌组织PC-1高表达可能是妊娠期糖尿病患者胰岛素抵抗的分子机制之一。
3)PC-1可能通过抑制胰岛素受体酪氨酸磷酸化及IRTK活性发挥作用。
Objective To investigate the relationship between plasma cell membrane glycoprotein-l(PC-1) in skeletal muscle from women with GDM and the etiology of gestational diabetes mellitus.
Methods The expression of PC-1 and insulin receptor in skeletal muscle were determined by western blot from patients with GDM(GDM group, n=20),normal pregnant women (normal pregnancy group,n=20)and nonpregnant women(control group, n=12), the expression of insulin receptor tyrosine phosphorylation and the activity of insulin receptor tyrosine kinase (IRTK) before and after insulin stimulation in skeletal muscle of the three groups were determined by immunoprecipitation and ELISSA.Fasting plasma glucose (FPG) and fasting insulin (FINS) were measured by oxidized assay and immunoradioassay. Insulin resistant index(HOMA-IR)was calculated according to FPG and FINS.
Results
1) The levels of FPG, FINS, HOMA-IR in GDM group(5.61±0.78 mmol/L、15.12±5.31 mU/L、1.21±0.52) were significantly higher than those in normal pregnancy group (4.43±0.46 mmol/L、10.56±3.07 mU/L、0.80±0.31)(P＜0.01).The levels of FINS and HOMA-IR in normal pregnancy group were significantly higher than those in control group (7.56±2.31 mU/L、0.47±0.26) (P＜0.01).
2) PC-1 content in GDM group (1.22±0.02) was higher than that in normal pregnancy group (0.71±0.03) ,PC-1 content in normal pregnancy group was higher than that in control group (0.43±0.02) (P＜0.01).
3) No significant differences were evident in insulin receptor content , basal insulin receptor tyrosine phosphorylation ,basal insulin receptor tyrosine kinase activity in GDM group (0.59±0.03、0.14±0.03、2.33±0.19), normal pregnancy group (0.61±0.05、0.15±0.02、2.36±0.26) and control group (0.63±0.06、0.16±0.04、2.39±0.35) (P＞0.05).
4) After insulin stimulation, insulin receptor tyrosine phosphorylation and insulin receptor tyrosine kinase activity increased in all subjects but were lower in GDM group (0.17±0.04、2.86±0.47) compared with normal pregnancy group (0.24±0.02, 3.84±0.53) and control group (0.31±0.03, 4.87±0.56) (P＜0.01).
5) PC-1 content was positively correlated with HOMA-IR(r=0.611、0.734, P＜0.01) and negtively correlated with IRTK activity (r=-0.652、-0.723, P＜0.01) in normal pregnancy group and GDM group.
Conclusions
1) PC-1 content in skeletal muscle of GDM overexpresses.
2) Overexpressed PC-1 in skeletal muscle may be one of the cellular mechanism for insulin resistance of GDM.
3) PC-1 may produce the effect by inhibiting insulin receptor tyrosine phosphorylation and the activity of insulin receptor tyrosine kinase.
方法采用Western blot的方法测定了20例GDM孕妇(GDM组)、20例糖耐量正常孕妇(正常妊娠组)及12例糖耐量正常非孕妇女(对照组)骨骼肌组织PC-1、胰岛素受体的表达水平；采用免疫沉淀及ELISSA的方法分别测定胰岛素刺激前后骨骼肌组织胰岛素受体酪氨酸磷酸化程度及IRTK活性；采用葡萄糖氧化酶法及放射免疫法测定空腹血葡萄糖(FPG)及空腹血胰岛素(FINS)水平，计算胰岛素抵抗指数(HOMA-IR)。
结果
1)GDM组FPG、FINS、HOMA-IR(5.61±0.78mmol／L、15.12±5.31 mU／L、1.21±0.52)均明显高于正常妊娠组(4.43±0.46 mmol／L、10.56±3.07 mU／L、0.80±0.31)(P＜0.01)，正常妊娠组FINS、HOMA-IR明显高于对照组(7.56±2.31 mU／L、0.47±0.26)(P＜0.01)。
2)GDM组PC-1表达水平(1.22±0.02)明显高于正常妊娠组(0.71±0.03)(P＜0.01)，正常妊娠组明显高于对照组(0.43±0.02)(P＜0.01)。
3)GDM组胰岛素受体含量、胰岛素受体基础酪氨酸磷酸化程度及其酪氨酸激酶基础活性(0.59±0.03、0.14±0.03、2.33±0.19)与正常妊娠组(0.61±0.05、0.15±0.02、2.36±0.26)，正常妊娠组与对照组(0.63±0.06、0.16±0.04、2.39±0.35)比较，差异均无显著性(P＞0.05)。
4)胰岛素刺激后的胰岛素受体酪氨酸磷酸化程度及IRTK活性比较，GDM组(0.17±0.04、2.86±0.47)明显低于正常妊娠组(0.24±0.02、3.84±0.53)(P＜0.01)，正常妊娠组明显低于对照组(0.31±0.03、4.87±0.56)(P＜0.01)。
5)正常妊娠组、GDM组PC-1表达水平与HOMA-IR呈明显正相关(r=0.611、0.734，P＜0.01)，与胰岛素刺激后胰岛素受体酪氨酸激酶活性成负相关(r=-0.652、-0.723，P＜0.01)。
结论
1)妊娠期糖尿病患者骨骼肌组织中存在PC-1的高表达。
2)骨骼肌组织PC-1高表达可能是妊娠期糖尿病患者胰岛素抵抗的分子机制之一。
3)PC-1可能通过抑制胰岛素受体酪氨酸磷酸化及IRTK活性发挥作用。
Objective To investigate the relationship between plasma cell membrane glycoprotein-l(PC-1) in skeletal muscle from women with GDM and the etiology of gestational diabetes mellitus.
Methods The expression of PC-1 and insulin receptor in skeletal muscle were determined by western blot from patients with GDM(GDM group, n=20),normal pregnant women (normal pregnancy group,n=20)and nonpregnant women(control group, n=12), the expression of insulin receptor tyrosine phosphorylation and the activity of insulin receptor tyrosine kinase (IRTK) before and after insulin stimulation in skeletal muscle of the three groups were determined by immunoprecipitation and ELISSA.Fasting plasma glucose (FPG) and fasting insulin (FINS) were measured by oxidized assay and immunoradioassay. Insulin resistant index(HOMA-IR)was calculated according to FPG and FINS.
Results
1) The levels of FPG, FINS, HOMA-IR in GDM group(5.61±0.78 mmol/L、15.12±5.31 mU/L、1.21±0.52) were significantly higher than those in normal pregnancy group (4.43±0.46 mmol/L、10.56±3.07 mU/L、0.80±0.31)(P＜0.01).The levels of FINS and HOMA-IR in normal pregnancy group were significantly higher than those in control group (7.56±2.31 mU/L、0.47±0.26) (P＜0.01).
2) PC-1 content in GDM group (1.22±0.02) was higher than that in normal pregnancy group (0.71±0.03) ,PC-1 content in normal pregnancy group was higher than that in control group (0.43±0.02) (P＜0.01).
3) No significant differences were evident in insulin receptor content , basal insulin receptor tyrosine phosphorylation ,basal insulin receptor tyrosine kinase activity in GDM group (0.59±0.03、0.14±0.03、2.33±0.19), normal pregnancy group (0.61±0.05、0.15±0.02、2.36±0.26) and control group (0.63±0.06、0.16±0.04、2.39±0.35) (P＞0.05).
4) After insulin stimulation, insulin receptor tyrosine phosphorylation and insulin receptor tyrosine kinase activity increased in all subjects but were lower in GDM group (0.17±0.04、2.86±0.47) compared with normal pregnancy group (0.24±0.02, 3.84±0.53) and control group (0.31±0.03, 4.87±0.56) (P＜0.01).
5) PC-1 content was positively correlated with HOMA-IR(r=0.611、0.734, P＜0.01) and negtively correlated with IRTK activity (r=-0.652、-0.723, P＜0.01) in normal pregnancy group and GDM group.
Conclusions
1) PC-1 content in skeletal muscle of GDM overexpresses.
2) Overexpressed PC-1 in skeletal muscle may be one of the cellular mechanism for insulin resistance of GDM.
3) PC-1 may produce the effect by inhibiting insulin receptor tyrosine phosphorylation and the activity of insulin receptor tyrosine kinase.
引文
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38 Dong H, Maddux BA, Altomonte J, etal. Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes. 2005,54(2):367-372.
39 Stefanovic V, Antic S. Plasma cell membrane glycoprotein 1 (PC-1): a marker of insulin resistance in obesity, uremia and diabetes mellitus. Clin Lab. 2004, (5-6): 271-278.
40 MadduxBA, GoldfineID. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha subunit [J]. Diabetes, 2000, 49:13-19.
41 Stefanovic V, Antic S, latkovic M, etal. Reversalof increased lymphocyte PC-1 activity in patients with type 2 diabetes treated with metformin [J]. Diabetes MetabRes Rev, 1999,15:400-404.
42 Kim JK, Fillmore JJ, Sunshine MJ, etal. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest. 2004 ,114(6):823-827.
43 Dey D, Basu D, RoySS, etal. Involvement of novel PKC isoforms in FFA induced defects in insulin signaling. Mol Cell Endocrinol. 2006 ,246(1-2):60-64.
44 Patiag D, Gray S, Idris I, etal. Effects of tumour necrosis factor-alpha and inhibition of protein kinase C on glucose uptake in L6 myoblasts. Clin Sci (Lond). 2000 ,99(4): 303-307.
45 Liu YF, Herschkovitz A, Boura-Halfon S, etal. Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance. Mol Cell Biol. 2004 ,24(21):9668-9681.
46 Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood). 2005 ,230(9):593-605.
47 Gual P, Le Marchand-Brustel Y, Tanti JE. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005, 87(1):99-109.
48 Liu J, Kimura A, Baumann CA, etal. APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol Cell Biol. 2002 ,22(11):3599-3609.
49 Ljzerman RG, Voordouw JJ, Van Weissenbruch MM, etal. TNF-alpha levels are associated with skin capillary recruitment in humans: a potential explanation for the relationship between TNF-alpha and insulin resistance. Clin Sci (Lond). 2006 ,110(3): 361-368.
50 Kinalski M, Kuzmicki M, Telejko B, etal. Tumor necrosis factor-alpha system in patients with gestational diabetes. Przegl Lek. 2006,63(4):173-175.
51 Nakamori Y, Emoto M, Fukuda N, etal. Myosin motor Myolc and its receptor NEMO/IKK-gamma promote TNF-alpha-induced serine307 phosphorylation of IRS-1. J Cell Biol. 2006 ,173(5): 665-671.
52 Hennige AM, Stefan N, Kapp K, etal. Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. FASEB J. 2006 ,20 (8):1206-1208.
53 Cseh K, Baranyi E, Melczer Z, etal. The pathophysiological influence of leptin and the tumor necrosis factor system on maternal insulin resistance: negative correlation with anthropometric parameters of neonates in gestational diabetes. Gynecol Endocrinol. 2002 ,16(6):453-460.
54 McLachlan KA, JenkinS A, Alford FP, etal. Do adiponectin, TNFalpha, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diabetes Metab Res Rev. 2006 ,22(2):131-138.
55 Tan YJ, Fan ZT, Yang HX. Role of urotensin II gene in the genetic susceptibility to gestational diabetes mellitus in northern Chinese women. Zhonghua Fu Chan Ke Za Zhi. 2006 ,41(11):732-735.
56 Goldfine ID, Muddux BA, Youngren JF, etal. Role of PC-1 in the etiology of insulin resistance. Ann N Y Acad Sci. 1999 ,892:204-22.
57 Maddux BA, Goldfine ID Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Diabetes. 2000 Jan;49(1):13-19.
58 Kumakura S, Maddux BA, Sung CK. Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post -receptor site[J].J Cell Biochem, 1998, 68:366-377.
59 Abate N, Carulli L, Cabo-Chan A Jr, Chandalia M, Snell PG, Grundy SM. Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. J Clin Endocrinol Metab. 2003 Dec;88 (12):5927-5934.
60 Shao J, Catalano PM, Yamashita H, Ruyter I, Smith S, Youngren J, Friedman JE. Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. Diabetes. 2000 ,49(4):603-610.
61 Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab. 2002, 282(3): E522-533.
62 Gonzatez C, Alonso A, Femandez R, etal. Regulation of insulin receptor substrate-1 in the liver, skeletal muscle and adipose tissue of rats throughout pregnancy. Gynecol Endocrinol. 2003, 17(3): 187-197.
63 Sulochana KN, Rajesh M, Ramakrishnan S. Insulin receptor tyrosine kinase activity in monocytes of type 2 diabetes mellitus patients receiving oral L-lysine. Indian J Biochem Biophys, 2001, 38(5): 331-334.
64 Itani SI, Zhou Q, Pories WJ, etc. Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes, 2000, 49(8): 1353-1358.
65 邓华聪，葛倩，刘金波等．2型糖尿病患者胰岛素受体酪氨酸激酶活性变化机制的探讨．中华内分泌代谢杂志，2006，22(1)：30-33．
66 Elmendorf JS. Fractionation analysis of the subcellular distribution of GLUT-4 in 3T3-L1 adipocytes. Methods Mol Med. 2003, 83: 105-111.
67 Lacasa D, Boute N, Issad T. Interaction of the insulin receptor with the receptor-like protein tyrosine phosphatases PTPalpha and PTPepsilon in living cells. Mol Pharmocal, 2005, 67(4): 1206-1213.
68 Karlsson M, Thom H, Parpal S, etal. Insulin induces translocation of glucose transporter GLUT4 to plasma membrane caveolae in adipocytes. FASEB J. 2002, 16(2): 249-251.
69 Chiappe De, Cingolani GE, Caldiz CI. Insulin resistance and GLUT-4 glucose transporter in adipocytes from hypertensive rats. Metabolism. 2004, 53(3): 382-387.
70 Ericsson A, Hamark B, Powell TL, etal. Glucose transporter isoform 4 is expressed in the syncytiotrophoblast of first trimester human placenta. Hum Reprod. 2005, 20(2): 521-530.
71 Harmon AW, Patel YM. Naringenin inhibits phosphoinositide 3-kinase activity and glucose uptake in 3T3-L1 adipoeytes. Biochem Biophys Res Commun. 2003, 305(2): 229-234.
72 Nadler ST, Stoehr JP, Rabaglia ME, etal. Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice. Am J Physiol Endocrinol Metab. 2001, 281(6): 1249-1254.
73 Pirola L, Bonnafous S, Johnston AM, etal. Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. J Biol Chem. 2003, 278(18): 15641-15651.
74 Shao J, Yamashita H, Qiao L, etal. Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. Diabetes. 2002 , 51(1):19-29.
2 Catalano PM,Kirwan JP, Haugel-de Mouzon S, etal. Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. J Nutr. 2003 ,133(5):1674S-1683S.
3 Shaat N, Groop L. Genetics of gestational diabetes mellitus. Curr Med Chera. 2007,14(5):569-583.
4 Akbay E, TirasMB, Yetkin I, etal. . Insulin secretion and insulin sensitivity in normal pregnancy and gestatioal diabetes mellitus. Gynecol Endocrinol, 2003, 17 ( 2 ) : 137 -142.
5 Smimakis KV, Martinez A, Blatman KH,etal. Early pregnancy insulin resistance and subsequent gestational diabetes mellitus. Diabetes Care. 2005 ,28(5):1207-1208.
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8 Friedman JE, Ishizuka T, Shao J, etal. Impaired Glucose Transport and Insulin Receptor Tyrosine Phosphorylation in Skeletal Muscle From Obese Women With Gestational Diabetes. Diabetes , 1999,48(9):1807 - 1814.
9 Lappas M, Yee K, Permezel M, etal. Release and regulation of leptin, resistin and adiponectin from human placenta, fetal membranes, and maternal adipose tissue and skeletal muscle from normal and gestational diabetes mellitus-complicated pregnancies. J Endocrinol. 2005 ,186(3):457-465.
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15 Kinalski M, Kuzmicki M, Telejko B, etal. Tumor necrosis factor-alpha system in patients with gestational diabetes. Przegl Lek. 2006, 63(4):173-175.
16 Cseh K, Baranyi E, Melczer Z, etal. The pathophysiological influence of leptin and the tumor necrosis factor system on maternal insulin resistance: negative correlation with anthropometric parameters of neonates in gestational diabetes. Gynecol Endocrinol. 2002 ,16(6):453-460.
17 Kinalski M, Telejko B, Kuzmicki M. Tumor necrosis factor alpha system and plasma adiponectin concentration in women with gestational diabetes. Horm Metab Res. 2005,37(7):450-454.
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19 Teno S, Iwamoto Y. Glycoprotein PC-1. Nippon Rinsho. 2002 ,60 (Suppl 7):621-625.
20 Stefanovic V,Antic S. Plasma cell membrane glycoprotein 1 (PC-1): a marker of insulin resistance in obesity, uremia and diabetes mellitus. Clin Lab.
2004, 50(5-6): 271-278.
21 Abate N, Carulli L, Cabo-Chan A Jr. Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. J Clin Endocrinol Metab. 2003, 88(12), 5927-5934.
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24 Maddux BA, Goldfine ID Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Diabetes. 2000, 49(1):13-19.
25 Shao J, Catalano PM, Yamashita H, Ruyter L, Smith S, Youngren J, Friedman JE. Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. Diabetes. 2000, 49(4): 603-610.
26 Orcy RB, BruM I, da Silva RS, etal. Insulin receptor tyrosine kinase activity and substrate 1 (IRS-1) expression in human myometrium and leiomyoma. Eur J Obstet Gynecol Reprod Biol. 2005, 123(1): 107-110.
27 Jiang L, Liu C, Wang WQ, etal. Leprechaunism: an inherited insulin resistance syndrome caused by the defect of insulin receptor. Zhonghua Nei Ke Za Zhi. 2006, 45(9): 730-733.
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29 Capeau J. Insulin signaling: mechanisms altered in insulin resistance. Med Sci (Paris). 2005, 21Spec No: 34-39.
30 Youngren JF, Goldfine ID, Pratley RE, etal. Decreased muscle insulin receptor kinase correlates with insulin resistance in normoglycemic Pima Indians. Am J Physiol. 1997, 273(2 Pt 1): E276-283.
31 Sulochana KN, Rajesh M, Ramakrishnan S. Insulin receptor tyrosine kinase activity in monocytes of type 2 diabetes mellitus patients receiving oral L-lysine. Indian J Biochem Biophys, 2001, 38(5): 331-334.
32 Itani SI, Zhou Q, Pories WJ, etc. Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes, 2000, 49(8): 1353-1358.
33 Lacasa D, Boute N, Issad T. Interaction of the insulin receptor with the receptor-like protein tyrosine phosphatases PTPalpha and PTPepsilon in living cells. Mol Pharmocal, 2005, 67(4): 1206-1213.
34 邓华聪，葛倩，刘金波等．2型糖尿病患者胰岛素受体酪氨酸激酶活性变化机制的探讨．中华内分泌代谢杂志，2006，22(1)：30-33．
35 Jacob KK, Whittaker J, Stanley FM. Insulin receptor tyrosine kinase activity and phosphorylation of tyrosines 1162 and 1163 are required for insulin-increased prolactin gene expression. Mol Cell Endocrinol. 2002, 186(1): 7-16.
36 Tomazic M, Janez A, Sketelj A, etc. Comparison of alterations in insulin signalling pathway in adipocytes from Type Ⅱ diabetic pregnant women and women with gestational diabetes mellitus. Diabetologia, 2002, 45(4): 502-508.
37 Kumakura S, Maddux BA, Sung CK. Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post -receptor site[J]. J Cell Biochem, 1998, 68: 366-377.
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4 Lappas M, Yee K, Permezel M, etal. Release and regulation of leptin, resistin and adiponectin from human placenta, fetal membranes, and maternal adipose tissue and skeletal muscle from normal and gestational diabetes mellitus-complicated pregnancies. J Endocrinol. 2005 ,186(3):457-465.
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8 Smimakis KV, Martinez A, Blatman KH, etal. Early pregnancy insulin resistance and subsequent gestational diabetes mellitus. Diabetes Care. 2005 , 28(5): 1207-1208.
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19 Mamabolo RL, Alberts M, Levitt NS, etal. Prevalence of gestational diabetes mellitus and the effect of weight on measures of insulin secretion and insulin resistance in third-trimester pregnant rural women residing in the Central Region of Limpopo Province, South Africa. Diabet Med. 2007 Jan 29; [Epub ahead of print] .
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26 Tomazic M, Janez A, Kocijancic A, etal. Comparison of alterations in insulin signalling pathway in adipocytes from Type II diabetic pregnant women and women with gestational diabetes mellitus. Diabetologia. 2002, 45(4):502-508.
27 Ohne Y, Toyoshima Y, Kato H. Disruption of the availability of amino acids induces a rapid reduction of serine phosphorylation of insulin receptor substrate-1 in vivo and in vitro. Biosci Biotechnol Biochem. 2005,69(5):989-998.
28 Su X, Lodhi IJ, Saltiel AR, etal. Insulin-stimulated Interaction between insulin receptor substrate 1 and p85alpha and activation of protein kinase B/Akt require Rab5. J Biol Chem. 2006 , 281(38):27982-27990.
29 Bai L, Wang Y, Fan J, etal. Dissecting multiple steps of GLUT4 trafficking and identifying the sites of insulin action. Cell Metab. 2007, 5(1):47-57.
30 Gonzalez E, McGraw TE. Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane. Mol Biol Cell. 2006,17(10):4484-4493.
31 Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood). 2005 ,230(9):593-605. Review
32 Leinninger GM, Backus C, Uhler MD, Lentz SI, Feldman EL. Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. FASEB J. 2004 Oct;18 (13): 1544-6. Epub 2004 Aug 19
33 Wang C, Wang L, Yang Z. Role of protein tyrosine phosphatase 1B in the type 2 diabetes and obesity. Yi Chuan. 2004, 26(6):941-946.
34 Zabolotny JM, Kim YB, Peroni 0D. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. Proc Natl Acad Sci U S A. 2001 ,98(9):5187-5192.
35 Elchebly M, Payette P, Michaliszyn E, etal. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1β gene[J]. Science, 1999, 283:1544-1548.
36 Ropelle ER, Pauli JR, Prada PO. Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J Physiol. 2006 , 577(Pt 3):997-1007.
37 Teno S, Iwamoto Y. Glycoprotein PC-1. Nippon Rinsho. 2002 ,60 (Suppl 7):621-625.
38 Dong H, Maddux BA, Altomonte J, etal. Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes. 2005,54(2):367-372.
39 Stefanovic V, Antic S. Plasma cell membrane glycoprotein 1 (PC-1): a marker of insulin resistance in obesity, uremia and diabetes mellitus. Clin Lab. 2004, (5-6): 271-278.
40 MadduxBA, GoldfineID. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha subunit [J]. Diabetes, 2000, 49:13-19.
41 Stefanovic V, Antic S, latkovic M, etal. Reversalof increased lymphocyte PC-1 activity in patients with type 2 diabetes treated with metformin [J]. Diabetes MetabRes Rev, 1999,15:400-404.
42 Kim JK, Fillmore JJ, Sunshine MJ, etal. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest. 2004 ,114(6):823-827.
43 Dey D, Basu D, RoySS, etal. Involvement of novel PKC isoforms in FFA induced defects in insulin signaling. Mol Cell Endocrinol. 2006 ,246(1-2):60-64.
44 Patiag D, Gray S, Idris I, etal. Effects of tumour necrosis factor-alpha and inhibition of protein kinase C on glucose uptake in L6 myoblasts. Clin Sci (Lond). 2000 ,99(4): 303-307.
45 Liu YF, Herschkovitz A, Boura-Halfon S, etal. Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance. Mol Cell Biol. 2004 ,24(21):9668-9681.
46 Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood). 2005 ,230(9):593-605.
47 Gual P, Le Marchand-Brustel Y, Tanti JE. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005, 87(1):99-109.
48 Liu J, Kimura A, Baumann CA, etal. APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol Cell Biol. 2002 ,22(11):3599-3609.
49 Ljzerman RG, Voordouw JJ, Van Weissenbruch MM, etal. TNF-alpha levels are associated with skin capillary recruitment in humans: a potential explanation for the relationship between TNF-alpha and insulin resistance. Clin Sci (Lond). 2006 ,110(3): 361-368.
50 Kinalski M, Kuzmicki M, Telejko B, etal. Tumor necrosis factor-alpha system in patients with gestational diabetes. Przegl Lek. 2006,63(4):173-175.
51 Nakamori Y, Emoto M, Fukuda N, etal. Myosin motor Myolc and its receptor NEMO/IKK-gamma promote TNF-alpha-induced serine307 phosphorylation of IRS-1. J Cell Biol. 2006 ,173(5): 665-671.
52 Hennige AM, Stefan N, Kapp K, etal. Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. FASEB J. 2006 ,20 (8):1206-1208.
53 Cseh K, Baranyi E, Melczer Z, etal. The pathophysiological influence of leptin and the tumor necrosis factor system on maternal insulin resistance: negative correlation with anthropometric parameters of neonates in gestational diabetes. Gynecol Endocrinol. 2002 ,16(6):453-460.
54 McLachlan KA, JenkinS A, Alford FP, etal. Do adiponectin, TNFalpha, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diabetes Metab Res Rev. 2006 ,22(2):131-138.
55 Tan YJ, Fan ZT, Yang HX. Role of urotensin II gene in the genetic susceptibility to gestational diabetes mellitus in northern Chinese women. Zhonghua Fu Chan Ke Za Zhi. 2006 ,41(11):732-735.
56 Goldfine ID, Muddux BA, Youngren JF, etal. Role of PC-1 in the etiology of insulin resistance. Ann N Y Acad Sci. 1999 ,892:204-22.
57 Maddux BA, Goldfine ID Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Diabetes. 2000 Jan;49(1):13-19.
58 Kumakura S, Maddux BA, Sung CK. Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post -receptor site[J].J Cell Biochem, 1998, 68:366-377.
59 Abate N, Carulli L, Cabo-Chan A Jr, Chandalia M, Snell PG, Grundy SM. Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. J Clin Endocrinol Metab. 2003 Dec;88 (12):5927-5934.
60 Shao J, Catalano PM, Yamashita H, Ruyter I, Smith S, Youngren J, Friedman JE. Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. Diabetes. 2000 ,49(4):603-610.
61 Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab. 2002, 282(3): E522-533.
62 Gonzatez C, Alonso A, Femandez R, etal. Regulation of insulin receptor substrate-1 in the liver, skeletal muscle and adipose tissue of rats throughout pregnancy. Gynecol Endocrinol. 2003, 17(3): 187-197.
63 Sulochana KN, Rajesh M, Ramakrishnan S. Insulin receptor tyrosine kinase activity in monocytes of type 2 diabetes mellitus patients receiving oral L-lysine. Indian J Biochem Biophys, 2001, 38(5): 331-334.
64 Itani SI, Zhou Q, Pories WJ, etc. Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes, 2000, 49(8): 1353-1358.
65 邓华聪，葛倩，刘金波等．2型糖尿病患者胰岛素受体酪氨酸激酶活性变化机制的探讨．中华内分泌代谢杂志，2006，22(1)：30-33．
66 Elmendorf JS. Fractionation analysis of the subcellular distribution of GLUT-4 in 3T3-L1 adipocytes. Methods Mol Med. 2003, 83: 105-111.
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