【作者】 马方；

【导师】 赵宝珍；

【作者基本信息】 第二军医大学 ， 影像医学与核医学， 2010， 博士

【摘要】 背景：糖尿病(diabetes mellitus, DM)是目前人类健康的第三位杀手,已发展为一种世界范围内威胁人类健康的重要疾病。糖尿病肾损害(diabetic nephropathy, DN)、肢端坏疽是常见而严重的微血管病变,也是糖尿病患者致死、致残的常见原因。早期微血管病变是可逆的、功能性的改变,早期干预能阻止或延缓肾脏损害的进展,因此提供早期诊断微血管病变的依据成为医学领域学者面临的重要课题,对于肾脏微血管病变的研究也成为关注的热点。肾损害的发生、发展常引起血流灌注的改变或与血流灌注改变有关,因而如能寻找有效评价其血流灌注的方法,正确评估肾血流灌注对判断肾功能的状态、肾损害的严重程度及其转归有重要意义。研究证实,超声造影是近年来兴起的一种评价血流灌注的新方法,由于新型造影剂SonoVue的微泡小于红细胞,可顺利经过肺循环,经外周静脉注射后随血流可达到肾实质毛细血管网,增强并显示肾内微小血管的血流信号,有利于观察肾的血流灌注情况,具有能实时显像、无电离辐射、可多次重复检查、价格相对低廉等优点,且有更好的空间和时间分辨力。超声造影剂微泡的血流动力学与红细胞基本相似,通过研究造影剂微泡在肾脏的灌注及排泄规律,分析造影时间一强度曲线,可在一定程度上定量分析肾脏的血流灌注特点。e-Flow技术是基于传统能量多普勒技术的新一代血流成像模式,与彩色多普勒相比,该技术对极低速度血流的敏感度明显增加,“外溢”伪像减少,清晰度增加,因此可真实地显示肢端末梢微小血管的血流充盈状态,提供较传统彩色多普勒和能量多普勒技术更敏感的血流信息。本研究内容分为五部分,前三部分为动物实验,采用超声造影与形态学对比研究,观察自发性糖尿病(Goto-Kakisaki Wistar Rats, GK)大鼠肾脏的血流灌注变化和组织病理学改变,四、五部分为临床研究,采用超声造影、e-Flow成像新技术,探索糖尿病肾损害和肢端微血管病变的发生发展规律,为临床早期诊断微血管病变提供依据。目的：研究自发性糖尿病(GK)大鼠早期肾脏组织病理学特点,以及随病程进展的动态变化规律,为探讨2型糖尿病肾脏血流灌注变化以及糖尿病肾损害的早期诊断提供形态学基础。方法：①自发性糖尿病(GK)雄性大鼠30只,按周龄分为3组,4周龄、12周龄、20周龄每组各10只。另选周龄与GK大鼠相匹配的Wistar雄性大鼠30只作为对照。②采用尾部光电测压法测量收缩压。③心腔取血,测血糖、尿素氮、肌酐、总胆固醇、甘油三酯等项血生化指标。④膀胱穿刺取尿,BCA法测定尿蛋白浓度。SDS-PAGE电泳法分析尿蛋白成分。⑤肾脏取材后,常规石蜡制片、电镜制片,分别行光学显微镜、电子显微镜观察。结果：①各周龄GK大鼠血糖均高于其相应的对照组,差异均有统计学意义(P<0.01)。组间差异亦有统计学意义(P<0.01)。②12周龄、20周龄GK大鼠尿蛋白、肾重量、肾长径、总胆固醇高于其相应的对照组(P<0.05),且随着周龄增加逐渐增高,组间差异均有统计学意义(P<0.01)。③12周龄GK大鼠肾实质厚度、肾皮质厚度高于其对照组(P<0.01),组间差异均有统计学意义(P<0.01)。④光镜下可见12周龄GK大鼠肾小球出现玻璃样变、硬化,局部液化坏死；间质小血管硬化,玻璃样变,炎性细胞浸润,肾小管水样变性。20周龄GK大鼠则可见多个肾小球出现局限性或全部玻璃样变,硬化萎缩,部分视野内肾小球几乎消失；肾小球毛细血管壁增厚,局部硬化,玻璃样变,肾小球系膜基质及胶原成分增多,基底膜增厚,间质小血管硬化,玻璃样变,管腔狭窄,部分毛细血管丛局灶性坏死；肾小球球囊纤维化,入球小动脉闭锁,肾小管内出现蛋白管型。⑤电镜下见12周龄大鼠肾小球囊壁上皮细胞线粒体肿胀,粗面内质网扩张；少数足细胞缺失,形态异常,细胞间隙模糊融合。肾小管上皮细胞有部分破环的线粒体,呈空泡样结构,溶酶体增多。20周龄GK大鼠则表现为肾小球塌陷,血管袢与肾小球囊壁距离增宽。内皮细胞肿胀,细胞器减少,线粒体肿胀,嵴缺失。系膜区扩张,系膜细胞增生,细胞肿胀,血管腔变窄或闭塞。足细胞肿胀,足突部分或广泛融合或消失,基底膜不均匀增厚。肾小管上皮细胞肿胀,微绒毛变短、变少,排列紊乱,细胞器减少,线粒体空泡样结构增多,大溶酶体增多,肾小管坏死。4周龄GK大鼠、各对照组Wistar大鼠肾脏无上述病理改变。结论：自发性糖尿病(GK)大鼠4周龄时即出现高血糖,12周出现肾小球增大、局灶性硬化、系膜区扩张、肾小球毛细血管基底膜增厚和肾小管变性等典型的肾损害病理学变化,且随病程延长呈进行性加重。这些形态学异常可能是早期肾小球高滤过的病理学基础。自发性糖尿病大鼠是研究2型糖尿病肾损害的理想模型。目的：探讨自发性糖尿病大鼠肾内微血管密度的变化规律,及其与2型糖尿病发生、发展的相关关系,为肾脏血流灌注的研究提供形态学基础。方法：雄性GK大鼠4周龄、12周龄、20周龄各10只,周龄相匹配的Wistar大鼠各10只作为对照组,用免疫组化法染色。每只大鼠标本选5张切片,每张切片分别对皮质区和髓质区各随机采集18个视野。图像分析系统对皮质区和髓质区微血管密度分别进行定量分析。另在每张切片皮质区随机选取5个肾小球,采用不规则方式分割,对肾小球毛细血管密度、肾小球面积和周长进行分析。结果：肾皮质间质微血管密度：不同周龄的GK大鼠与同周龄对照组比较,差异均无统计学意义(P>0.05)。对照组间差异无统计学意义(P>0.05)。GK大鼠组间差异有统计学意义(P<0.05)。肾髓质微血管密度：不同周龄GK大鼠均较同周龄对照组减少,差异有统计学意义(P<0.05-P<0.01),GK大鼠组间差异有统计学意义(P<0.01),对照组间差异无统计学意义(P>0.05)。肾小球微血管密度：20周龄GK大鼠较同周龄对照组减少,差异有统计学意义(P<0.01)。GK大鼠组间、对照组间差异均有统计学意义(P<0.01-P<0.05)。肾小球平均周长：4周龄GK大鼠大于同周龄对照组,差异有统计学意义(P=0.01)。12周龄、20周龄GK大鼠与同周龄对照组差异无统计学意义(P>0.05)。GK组间、对照组间差异均有统计学意义(P<0.01-P<0.05)。结论：GK大鼠存在肾微血管稀少的现象,因微血管稀少发生在糖尿病形成之后,并随糖尿病程的延长逐渐明显,推测它可能是糖尿病引起的一种继发性改变。幼年GK大鼠的肾髓质微血管稀少,提示微血管稀少的现象也可能与遗传因素有关。目的：探讨自发性2型糖尿病大鼠(GK)肾实质血流灌注特点及变化规律,为临床糖尿病肾损害的早期诊断和干预提供理论依据。方法：自发性2型糖尿病雄性大鼠(GK)30只,按周龄分为3组,4周龄10只,12周龄10只,20周龄10只。Wistar雄性大鼠30只,按周龄分为3组,4周龄10只,12周龄10只,20周龄10只作为对照。经股静脉插管,团注法快速注射超声造影剂SonoVue,剂量为0.028ml／100g体重。实时观察实验大鼠肾实质显影情况,观察并存储注射造影剂后0-5min的动态图像,时间—强度曲线(time intensity curve, TIC)分析肾实质的灌注特点。结果：①各组实验大鼠肾脏在注射造影剂后快速增强,肾动脉-皮质-锥体-肾静脉依次显影。②肾实质灌注的时间—强度曲线形态为单峰式,上升支陡峭,下降支较平坦。各周龄GK大鼠肾实质灌注的时间-强度曲线整体形态较其对照组宽大,随着糖尿病大鼠周龄的增加更加明显。③4周龄GK大鼠肾实质灌注的参数与其对照组相比较,上升段曲线下面积增大(P<0.05)。12周龄、20周龄GK大鼠肾实质灌注的时间-强度曲线的上升支斜率减小,达峰时间延长,上升段曲线下面积、曲线下总面积增大,差异均有统计学意义(P<0.05)。糖尿病大鼠组间差异有统计学意义(P<0.05)。结论：实时超声造影增强显像可以有效地观察自发性糖尿病大鼠肾实质血流灌注特点及变化规律,自发性糖尿病大鼠早期即存在肾实质微循环的灌注异常。目的：探讨实时超声造影增强显像及定量分析技术评价糖尿病肾损害肾脏血流灌注改变的临床价值。方法：选取对照组(健康成人21例)、早期肾损害组(CKD1-2期)19例、晚期肾损害组(CKD4-5期)14例,所有受检者造影前1天检测血清肌酐(Cr)、尿素氮(BUN)等血液生化指标。检查时经肘静脉团注SonoVue (0.03 ml/kg)行肾脏实时超声造影增强显像,观察并存储注射造影剂后0-5 min的动态图像,观察肾皮质的灌注过程,选择拟合度(Goodness of Fitness Index, GOF)85%以上的灌注曲线,应用定量分析软件对时间—强度曲线(TIC)进行脱机分析,分别计算3组基础强度(Basic intensity,BI),强度增量(A1),下降支斜率(Sloperate of descending curve, A2),上升支斜率(Sloperate of ascending curve, A3)、显影时间(Arriving Time, AT)、达峰时间(time to peak intensity, TTP)、造影剂平均通过时间(mean trasit time, MTT)、峰值强度(peak intensity, PI)、曲线下总面积(area under the curve, AUC),包括上升段曲线下面积AUC1与下降段曲线下面积AUC2。对以上检测结果进行统计学分析,并进行达峰时间、曲线下面积与肾小球滤过率GFR的相关性检验。结果：①各组肾脏在团注造影剂后肾动脉—皮质—锥体—肾静脉依次显影,早期肾损害组和晚期肾损害组肾皮质显影速度较对照组减慢。②各组肾皮质灌注的时间—强度曲线形态为一非对称的单峰曲线,有明显的上升支、顶峰、下降支。上升支陡峭,下降支较平坦。早期肾损害组的灌注曲线较对照组上升支平缓,至波峰后保持数秒平台期后缓慢下降。晚期肾损害组与对照组和早期肾损害组比较,上升支平缓,波峰减低。③早期肾损害组显影时间、达峰时间较对照组延长(P<0.05-P<0.01)。上升段曲线下面积、下降段曲线下面积和曲线下总面积均有增大趋势,但差异无统计学意义(P>0.05)。强度增量A1、峰值强度PI减低(P<0.05)。晚期肾损害组显影时间、达峰时间较对照组延长(P<0.05-P<0.01),上升段曲线下面积AUC1、下降段曲线下面积AUC2和曲线下总面积AUC减小(P<0.05),强度增量A1、峰值强度PI减低(P<0.05-P<0.01)。与早期肾损害组比较,晚期肾损害组上升段曲线下面积AUC1、下降段曲线下面积AUC2和曲线下总面积AUC明显减小(P<0.01)、显影时间AT延长(P<0.01);达峰时间TTP有延长趋势。AUC与肾小球滤过率GFR呈高度正相关(r=0.472,P=0.01),达峰时间TTP与GFR无相关关系(r=0.262,P=0.177)。结论：超声造影技术可较敏感地反映糖尿病肾损害肾血流灌注的变化特点,有望成为一种评价肾脏血流动力学及血流灌注的改变,提示早期肾损害,评估病变程度,反映肾小球滤过率、提供肾损害分级标准,预测预后的精确、无创、简便、敏感地临床实用技术。目的：研究指、趾腹小动脉和甲床微动脉的结构及血流动力学参数,评价糖尿病患者手指、足趾端微循环状态。方法：73例2型糖尿病患者按病程由短到长分为3组,正常对照组40例。采用e-flow成像显示末节指、趾腹小动脉和甲床微动脉,获得多普勒指标,用血管像素比估算血管数量。结果：①大部分的指、趾甲床动脉走行方向与手指、足趾平行,纵行的动脉间有横行的动脉支穿插吻合。②糖尿病Ⅱ、Ⅲ组末节手指腹、足趾腹和甲床内微小动脉稀少,血流频谱呈高阻波形。③糖尿病Ⅰ组手指甲床动脉、足趾甲床动脉和足趾腹动脉舒张期血流速度(EDV)低于对照组(P<0.05),阻力指数(RI)高于对照组(P<0.05-P<0.01)。足趾甲床动脉平均血管像素比低于对照组(P<0.05)。④糖尿病Ⅱ、Ⅲ组手指甲床动脉、足趾甲床动脉及手指腹动脉、足趾腹动脉收缩期最大流速(PSV)、EDV、平均血管像素比低于对照组(P<0.01-P<0.05),RI高于对照组(P<0.01)。⑤糖尿病各组及对照组足趾甲床动脉和足趾腹动脉PSV、EDV、平均血管像素比低于同组手指相同指标(P<0.01),RI高于同组手指相同指标(P<0.05-P<0.01)。结论糖尿病早期(病程5年内)即可出现指、趾端微血管血流动力学改变,晚期血管数量减少。肢端末梢微血管受损早于肢端缺血症状的出现。趾端血管损害出现较指端更早,程度更重。e-Flow可作为评价肢端早期微血管病变的有效方法。更多还原

【Abstract】 Background Diabetic nephropathy and acral gangrene are severe microvascular changes in Diabetes mellitus (DM), as well as the common causes of mortality and morbidity. Early microvascular changes are functional and usually reversible. As early intervention can prevent or delay the progression of kidney impairment, early vascular investigation may provide clue for early diagnosis and treatment, so studies on microvascular pathologic changes has become an importan subject.The development and progression of kidney impairment and acral gangrene often lead to changes in blood perfusion or prefusion-related changes. It is therefore important to evaluate tissue blood perfusion correctly because it is of great significance for judging the status of tissue function, severity of impairment and reversion.Studies have confirmed that contrast-enhanced ultrasonography (CEUS) is a new technique for evaluating blood perfusion. As the new contrast agent SonoVue contains microbubbles that are smaller than red blood cells, they can reach the capillary network of renal parenchyma, thus enhancing and displaying blood flow signals of intra-renal microvessels, and facilitating blood perfusion in the kidneys. CEUS is characterized by real time, non-ionizing radiation, repeatability, low cost, and high space and time resolution. To some extent, we could learn the characteristics of renal blood perfusion by studying perfusion and elimination of the microbubbles in the kidneys, and by analysing contrast time-intensity curves (TIC).e-Flow technique is a new blood flow detection scheme based on conventional energy Doppler technique. It has a significantly higher sensitivity to extremely low blood flow and better imaging, thus able to truely display blood filling of peripheral microvessels and providing more sensitive blood flow information as compared with the colored Doppler and energry Doppler techniques.The present study was divided in five parts,the first three parts are animal experiments designed to observe the changes of renal blood perfusion in GK rats and pathologic changes by comparing CEUS and histomorphologic findings.The fourth and fifth part are the clinical sdudies to investigate facts in the occurence and progression of microvessels lesions of kidney and acra in DM patients. Objective To study early pathologic changes in kidney tissue of Goto-Kakizaki (GK) diabetes prone rats and facts of dynamic change with progression of the disease so as to provide a morphologic basis for early diagnosis and intervention of early renal blood perfusion and impairment in type 2 DM patients.Methods①Based on ages,30 GK male rats were equally divided to 4-week,12-and 20-week groups. Thirty age-matched Wistar male rats were used as the control.②Systolic pressure was measured by tail volume photoelectric manometry.③Blood from the cardiac cavity was measured for glucose, blood urea nitrogen (BUN), creatinine (CR), total cholesterol (TC) and triglyceride (TG).④Urine taken by bladder puncture was measured for protein concentration by BCA, and protein composition by SDS-PAGE electrophoresis.⑤Kideny specimens were paraffin-embedded routinely, prepared electromicroscopically, and study under optical microscopy and electronic microscopy.Results①The blood glucose levels of GK rats in each group are higher than their corresponding control groups (P<0.01).②Urine protein, kidney weight, and length of 12-and 20-week GK rats were higher than those of the corresponding control groups (P<0.05), and this tendency increased gradually while the age in increased in each group. There was statistical differences between the three DM groups (P<0.01).③The thickness of the renal parencyma and cortex of the 12-week GK rats was significantly higher than that of the corresponding control group (P<0.01), The differences between the three DM groups were significant (P<0.01).④Optical microscopy in the 12-week GK rats revealed hyalinization, sclerosis, inflammatory cell infiltration. In the 20-week GK rats, there are local or complete hyalinization and sclerotic atrophy of multiple glomerula, and absence of glomerula in some visual fields; increased composition of glomerular mesangial matrix and collagen; thickening of the basement membrane; hardening, hyalinization and luminal stenosis of interstitial small blood vessels; atresia of afferent glomerular arterioles.⑤Electronic microscopy in the 12-week GK rats revealed absence and abnormal morphology of some podocytes, with fuzzy fusion of inter-cellular space. In the 20-week GK rats, we can see collapse of renal glomerula, swelling of epothelial cells, decrease in organelles, swelling of mitochondria, and absence of crests; expansion, proliferation and swelling of mesangial cells, and stenosis or obstruction of lumens; swelling of podocytes, partial or extensive fusion or disappearance of foot processes, and uneven thickening of the basement membrane.Conclusion Hyperglycemia occurred in 4-week GK rats, and typical pathologic changes of kidney impairment occurred in 12-week group. The impairments include: enlargement and focal sclerosis of renal glomerula, expansion of mesangial mesangial areas, thickening of glomerular capillary basement membranes which deteriorated with the course of disease prolonging. These morphologic abnormalities may be the pathogenic basis of early glomerular hyperfiltration. GK rats is an ideal animal model for studying kidney impairment of tyep 2 DM.Objective To investigate changes in microvascular density in the kidney of GK rats and its correlation with the development and progression of type 2 DM in order to provide the morphological information for study in kidney perfusion.Methods The experimental animals and grouping criteria are the same as of part one. Kideny specimens were paraffin-embedded and sliced routinely and stained by immunohistochemistry.5 specimen sections from each rat, eighteen visual fields from each section were selected randomly in the cortex and medulla areas of each section. Microvascular density in these areas was analyzed quantitatively using an image analysis system. Five glomerula were selected randomly from the cortex in each section, separated irregularly, and analyzed for the density of glomerular capillaries, and the area and circumference of the glomerula.Results①The medulla microvascular density of the three GK groups was significantly lower than that of the three corresponding control groups (P<0.05-P<0.01). There was significant difference between the three GK groups (P<0.01), while there was no significant difference between the three control groups (P>0.05).②The glomerula microvascular density of the 20-week GK rats was significantly lower than that of the corresponding control group (P<0.01). There was significant difference between both the GK group and the control group (P<0.01-P<0.05).③The mean circumference of glomerulus of 4-week GK rats was significantly longer than that of the corresponding control group (P=0.01). There was significant difference both between the GK groups and between the control groups (P<0.01-P<0.05).Conclusion Renal microvascular sparsity was present in GK rats. As this phenomenon occurred after DM and became gradually apparent along with the progress of diabetes, we assume that it is a secondary change caused by DM. Medulla microvascular sparsity in young GK rats and may also be related to hereditary factors.Objective To explore changes of blood perfusion in renal parenchyma of spontaneously diabetic GK rats in an attempt to provide experimental clues for early diagnosis and intervention of diabetic kidney impairment in diabetic patients.Methods The experimental animals and grouping criteria are the same as of part one. Ultrasound contrast agent SonoVue was administered at a dose of 0.028ml/100g body weight by quick intravenous bolus injection through femoral vein cannulation. Imaging changes in the rat renal parenchyma were observed in real time, and dynamic images within 0-5min of contrast injection were observed and stored. The characteristics of blood perfusion in the renal parenchyma were analyzed using the time-intensity curve (TIC).Results①The kidney was quickly enhanced after injection of the contrast agent in all groups, and the renal artery, cortex, renal vein were displayed in sequence;②TIC of the renal parenchyma was a single-peak type with a steep ascending stair and a flat descending stair. The overall shape of TIC of the DM groups was wider than that of the control groups. With increase in age, TIC became progressively wider;③The slope rate of the ascending curve in 4-,12-and 20-week GK rats became smaller, the time to peak (TTP) was prolonged, and the area under the ascending curve and the total area under the curve were increased. The differences were statistically significant (P<0.05). The total area under the curve increased with the age of the diabetic rats increasing. There were significant differences between the groups (P<0.05).Conclusion Real-time contrast-enhanced ultrasonography can effectively display changes of blood perfusion in renal parenchyma of spontaneously diabetic GK rats, indicating that abnormal blood perfusion of renal parenchymal microcirculation already exists in the early stage of spontaneous diabetes.Objective To investigate the clinical importance of real-time gray-scale contrast-enhanced ultrasonography and quantitative analysis in assessing diabetes complicated kidney perfusion impairment.Methods 21 healthy adults were selected as the control.19patients with early kidney impairment (Chronic Kidney Disease, CKD 1-2) and 14 patients with late kidney impairment (CKD 4-5) were included in the study groups. Cr and BUN were detected one day before ultrasonographic examination in all subjects. SonoVue (0.03 ml/kg) was injected by intravenous bolus injection through the cubital vein for real-time gray-scale contrast-enhanced ultrasonographic examination. Dynamic images within 0-5min of contrast injection were observed and stored. The perfusion process of the renal cortex was observed. Using the quantitative analysis software, the outage time-intensity curves (TIC) with more than 85% goodness of fitness index (GOF) were chosen for analysis for basic intensity (BI), intensity increment (A1), slope rate of descending curve (A2), slope rate of ascending curve (A3), arriving time (AT), time to peak (TTP), mean transit time (MTT), peak intensity (PI), and area under the curve (AUC). The above results were statistically analyzed, and correlations between these parameters of TTP、AUC and GFR were also analyzed.Results①The renal artery-cortex-pyramid-renal vein was displayed in sequence after intravenous bolus injection of the contrast agent. AT of the renal cortex in the early and late kidney impairment groups was slower than that in the control group;②TIC of renal cortex perfusion presented as an asymmetric single-peak curve. Compared with the control group, the ascending curve of the early and late kidney impairment group was flat, and the peak was low.③Compared with the control group, AT and TTP of the early kidney impairment group were prolonged (P<0.05-P<0.01); AUC1, AUC2 and AUC were increased, though the differences were not statistically significant (P>0.05); Al and PI were decreased (P<0.05). Compared with the control group, AT and TTP of the late kidney impairment group were prolonged (P<0.05-P<0.01); AUC1, AUC2 and AUC were decreased (P<0.05); Al and PI were reduced (P<0.05-P<0.01). Compared with the early kidney impairment group, AUC1, AUC2 and AUC of the late kidney impairment group were increased significantly (P<0.01); AT was prolonged significantly (P<0.01); TTP was prolonged. AUC were positively correlated with GFR(r= 0.472, P=0.01),and TTP was not correlated with GFR((r=0.262, P=0.177).Conclusion Contrast-enhanced ultrasonography is sensitive to blood perfusion changes in diabetes-induced kidney impairment, and could possibly be a clinically practicable technique for the reflecting changes in haemodynamics and blood perfusion of kidney, due to early kidney impairment, evaluating the degree of affection; estimating filterability of renal glomerulm and providing grading standard for kidney impairment.Objective To study the anatomic structures and the hemodynamics parameters of small artery of digit tip or arteriole on nail bed; To evaluate the microcirculation in digit tip of 2 type diabetic. Methods The small arteries in digit tip and arteriole on nail bed of 73 case of diabetic divided into three groups according to the course of disease and 40 normal adults setup as a control group were imaged and their hemodynamics parameters were measured by e-flow imaging. The amount of arteries was assessed by calculating their pixel.Results①The way of most arteriole on nail bed were parallel with finger and toe and there are transverse branch among longitudinal arteries.②In the diabetes groupⅡ、Ⅲthere are less arteriole on nail bed of finger and toe and the blood flow frequency spectrum present a high block waveform..③In the diabetes group I,contrasted with control group,the EDV of small arteries in finger tip and toe tip and arteriole on nail bed of toe decreased (P<0.05) and RI increased remarkably (P<0.05/P<0.01);The average pixel of arteriole on nail bed of toe decreased (P<0.05).④In the diabetes groupⅡ、Ⅲ, the PSV、EDV、average pixel of small arteries in finger tip and toe tip and arteriole on nail bed are lower (P<0.01/P<0.05) and RI are higher (P<0.01)than that of control group.⑤PSV、EDV、average pixel of small artery and arteriole on nail bed of toe tip were lower (P<0.01)and RI were higher (P<0.01/P<0.05)than same mark of finger significantly in every groups of diabetes and control group.Conclusions The changes of homodynamic parameters of arteriole of digit tip can occur within 5 years after the diagnosis of diabetes. The amount of arteries reduced in advanced stage. The arteriole injury of the end of extremity happens earlier than ischemia symptom. The arteriole damage in toe tip occurs earlier and more severe than that in finger. E-flow can be used as an efficient method to evaluate early arteriole pathological changes in the end of extremity.更多还原