Effect of Insulin Interventional Therapy on Hindlimb Ischemia of Rats with Diabetic_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Yingnan ¹ , XUE Junqiang ¹ , GAO Ping ² , RAN Jipeng ¹

1.Department of Vascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China;;
2.Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China;

Corresponding author：

Keywords：

Insulin; Diabetic; Hindlimb ischemia; Angiogenesis; Vascular endothelial growth factor

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ObjectiveTo study the effect of exogenous insulin on inducing angiogenesis and the expression of vascular endothelial growth factor (VEGF) of hindlimb ischemia of rats with diabetic. MethodsThe hindlimb ischemic model of diabetic rat was established by the ligation of femoral blood vessels of hindlimb in twenty healthy male SD rats and which were divided into model group (n=10) and treatment group (n=10). Another 10 normal rats were selected as control group. Then the expression of VEGF protein and capillary density of muscle tissues of rat hindlimb were detected by Western blot analysis and alkaline phosphatase (APK) stain method, respectively. ResultsThe differences of body weight and blood glucose level of rats before operation and on day 7 after operation were not significant in the control group (P gt;0.05). The body weight of rat was significantly lower on day 7 after operation than that before operation in the model group (P lt;0.05), while the difference of blood glucose level of rats was not significant in the model group (P gt;0.05). The body weight and blood glucose level of rat significantly decreased in the treatment group on day 7 after subcutaneous injection of insulin as compared with the level before operation (P lt;0.05). Compared with the control group, the body weight decreased and blood glucose level increased in the model group and treatment group, and the difference was significant (P lt;0.05, P lt;0.01). The body weight of rat in the treatment group was not different from that in the model group (P gt;0.05), but the blood glucose level of rat on day 7 after operation in the treatment group was significantly lower than that in the model group (P lt;0.05). The relative expression of VEGF protein of muscle tissues of ischemic hindlimbs in the treatment group (155.06±10.26) was significantly higher than that in the model group (94.30±11.23), P lt;0.05, while no expression was found in the control group. The capillary density of muscle tissues of right hindlimb in the control group was significantly higher than that in the model group or treatment group (P lt;0.05), and furthermore, which was higher in the treatment group than that in the model group (P lt;0.05). The difference of capillary density of muscle tissues of left hindlimb was not different among three groups (P gt;0.05). The capillary density of muscle tissues of right hindlimb was not different from that of left hindlimb in the control group (P gt;0.05) and which was significantly lower than that of left hindlimb in the model group or treatment group (P lt;0.05). ConclusionInsulin may increase the expression of VEGF protein in ischemic muscle tissue of diabetic rats and protect the ischemic muscle.

Citation： ZHANG Yingnan ,XUE Junqiang,GAO Ping,RAN Jipeng. Effect of Insulin Interventional Therapy on Hindlimb Ischemia of Rats with Diabetic. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(4): 391-395. doi: Copy

1.	刘仁贵, 赵纪春. 糖尿病并发下肢血管病变的发病机理及治疗进展 [J]. 中国普外基础与临床杂志, 2006, 13(6): 676679.
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3.	张宪生, 邹英华, 王维亮. 纤维蛋白原与糖尿病下肢动脉缺血性病变的关系 [J]. 中国普外基础与临床杂志, 2005, 12(4): F005.
4.	Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association [J]. Circulation, 2007, 115(1): 114126.
5.	王欣, 张强, 张宏伟, 等. 晚期糖基化终产物受体在糖尿病大鼠自体移植静脉中的表达及氨基胍的干预作用 [J]. 中国普外基础与临床杂志, 2008, 15(6): 390395.
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7.	Murohara T, Asahara T, Silver M, et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia [J]. J Clin Invest, 1998, 101(11): 25672578.
8.	乔海兵, 邢开宇. 改良碱性磷酸酶染色法 [J]. 实用医技杂志, 2006, 13(6): 10111012.
9.	Abaci A, Oˇguzhan A, Kahraman S, et al. Effect of diabetes mellitus on formation of coronary collateral vessels [J]. Circulation, 1999, 99(17): 22392242.
10.	Benjamin LE. Glucose, VEGFA and diabetic complications [J]. Am J Pathol, 2001, 158(4): 11811184.
11.	陶蕊, 徐蓉, 段俊丽, 等. 高血糖状态对缺血后血管新生影响的机制研究 [J]. 上海交通大学学报(医学版), 2008, 28(5): 492496.
12.	Dandona P, Mohanty P, Chaudhuri A, et al. Insulin infusion in acute illness [J]. J Clin Invest, 2005, 115(8): 20692072.
13.	Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients [J]. J Clin Invest, 2005, 115(8): 22772286.
14.	马卫国, 朱本章. 胰岛素抗炎作用研究进展 [J]. 国外医学内分泌学分册, 2004, 24(3): 194196.
15.	Garg R, Chaudhuri A, Munschauer F, et al. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy [J]. Stroke, 2006, 37(1): 267273.
16.	Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes [J]. J Clin Invest, 2005, 115(5): 11111119.
17.	Hansson GK. Inflammation, atherosclerosis, and coronary artery disease [J]. N Engl J Med, 2005, 352(16): 16851695.
18.	赵春华. 干细胞原理、技术与临床 [M]. 北京: 化学工业出版社, 2006: 177178.
19.	陈毅, 刘丹萍. 三种细胞因子体外联合诱导兔骨髓间充质干细胞向血管内皮细胞的分化 [J]. 中国组织工程研究与临床康复, 2008, 12(21): 40934096.
20.	刘元标. 血管内皮生长因子与血管新生 [J]. 中国康复医学杂志, 2004, 19(5): 396400.
21.	Yamagishi S, Abe R, Jinnouchi Y, et al. Pigment epitheliumderived factor inhibits vascular endothelial growth factorinduced vascular hyperpermeability both in vitro and in vivo [J]. Int Med Res, 2007, 35(6): 896899.
22.	Takeshita S, Isshiki T, Ochiai M, et al. Endotheliumdependent relaxation of collateral microvessels after intramuscular gene transfer of vascular endothelial growth factor in a rat model of hindlimb ischemia [J]. Circulation, 1998, 98(13): 12611263.
23.	Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’kinase/Akt signal transduction pathway. Requirement for Flk1/KDR activation [J]. J Biol Chem, 1998, 273(46): 3033630343.
24.	Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells [J]. J Exp Med, 2001, 193(9): 10051014.
25.	吴星火, 杨述华, 王晶, 等. 胰岛素对脊髓损伤后血管内皮生长因子的表达及血管再生的影响 [J]. 创伤外科杂志, 2006, 8(5): 452455.
26.	Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors [J]. FASEB J, 1999, 13(1): 922.
27.	Jiang ZY, He Z, King BL, et al. Characterization of multiple signaling pathways of insulin in the regulation of vascular endothelial growth fact or expression in vascular cells and angiogenesis [J]. J Biol Chem, 2003, 278(34): 3196431971.
28.	Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factordependent retinal neovascularization by insulinlike growth factor1 receptor [J]. Nat Med, 1999, 5(12): 13901395.

1. 刘仁贵, 赵纪春. 糖尿病并发下肢血管病变的发病机理及治疗进展 [J]. 中国普外基础与临床杂志, 2006, 13(6): 676679.
2. 许樟荣. 糖尿病足病变研究进展 [J]. 中国医师杂志, 2004, 6(1): 14.
3. 张宪生, 邹英华, 王维亮. 纤维蛋白原与糖尿病下肢动脉缺血性病变的关系 [J]. 中国普外基础与临床杂志, 2005, 12(4): F005.
4. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association [J]. Circulation, 2007, 115(1): 114126.
5. 王欣, 张强, 张宏伟, 等. 晚期糖基化终产物受体在糖尿病大鼠自体移植静脉中的表达及氨基胍的干预作用 [J]. 中国普外基础与临床杂志, 2008, 15(6): 390395.
6. 沈亚非, 徐焱成. 链脲佐菌素诱导试验实验性糖尿病大鼠模型建立的研究 [J]. 实用诊断与治疗杂志, 2005, 19(2): 7980.
7. Murohara T, Asahara T, Silver M, et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia [J]. J Clin Invest, 1998, 101(11): 25672578.
8. 乔海兵, 邢开宇. 改良碱性磷酸酶染色法 [J]. 实用医技杂志, 2006, 13(6): 10111012.
9. Abaci A, Oˇguzhan A, Kahraman S, et al. Effect of diabetes mellitus on formation of coronary collateral vessels [J]. Circulation, 1999, 99(17): 22392242.
10. Benjamin LE. Glucose, VEGFA and diabetic complications [J]. Am J Pathol, 2001, 158(4): 11811184.
11. 陶蕊, 徐蓉, 段俊丽, 等. 高血糖状态对缺血后血管新生影响的机制研究 [J]. 上海交通大学学报(医学版), 2008, 28(5): 492496.
12. Dandona P, Mohanty P, Chaudhuri A, et al. Insulin infusion in acute illness [J]. J Clin Invest, 2005, 115(8): 20692072.
13. Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients [J]. J Clin Invest, 2005, 115(8): 22772286.
14. 马卫国, 朱本章. 胰岛素抗炎作用研究进展 [J]. 国外医学内分泌学分册, 2004, 24(3): 194196.
15. Garg R, Chaudhuri A, Munschauer F, et al. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy [J]. Stroke, 2006, 37(1): 267273.
16. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes [J]. J Clin Invest, 2005, 115(5): 11111119.
17. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease [J]. N Engl J Med, 2005, 352(16): 16851695.
18. 赵春华. 干细胞原理、技术与临床 [M]. 北京: 化学工业出版社, 2006: 177178.
19. 陈毅, 刘丹萍. 三种细胞因子体外联合诱导兔骨髓间充质干细胞向血管内皮细胞的分化 [J]. 中国组织工程研究与临床康复, 2008, 12(21): 40934096.
20. 刘元标. 血管内皮生长因子与血管新生 [J]. 中国康复医学杂志, 2004, 19(5): 396400.
21. Yamagishi S, Abe R, Jinnouchi Y, et al. Pigment epitheliumderived factor inhibits vascular endothelial growth factorinduced vascular hyperpermeability both in vitro and in vivo [J]. Int Med Res, 2007, 35(6): 896899.
22. Takeshita S, Isshiki T, Ochiai M, et al. Endotheliumdependent relaxation of collateral microvessels after intramuscular gene transfer of vascular endothelial growth factor in a rat model of hindlimb ischemia [J]. Circulation, 1998, 98(13): 12611263.
23. Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’kinase/Akt signal transduction pathway. Requirement for Flk1/KDR activation [J]. J Biol Chem, 1998, 273(46): 3033630343.
24. Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells [J]. J Exp Med, 2001, 193(9): 10051014.
25. 吴星火, 杨述华, 王晶, 等. 胰岛素对脊髓损伤后血管内皮生长因子的表达及血管再生的影响 [J]. 创伤外科杂志, 2006, 8(5): 452455.
26. Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors [J]. FASEB J, 1999, 13(1): 922.
27. Jiang ZY, He Z, King BL, et al. Characterization of multiple signaling pathways of insulin in the regulation of vascular endothelial growth fact or expression in vascular cells and angiogenesis [J]. J Biol Chem, 2003, 278(34): 3196431971.
28. Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factordependent retinal neovascularization by insulinlike growth factor1 receptor [J]. Nat Med, 1999, 5(12): 13901395.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect of Insulin Interventional Therapy on Hindlimb Ischemia of Rats with Diabetic

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