微循环障碍和糖尿病及其慢性并发症的关系
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摘要
第一部分皮肤微血管舒张功能测定方法的建立及在糖耐量正常人中的检测
目的：建立和优化无创伤性皮肤微血管舒张功能检测技术—毛细血管恢复试验并检测糖耐量正常人的微血管舒张功能。
方法：在毛细血管显微镜下，观察受试者皮肤甲襞微血管加压致反应性充血后毛细血管密度的变化，用毛细血管恢复率作为测定微血管舒张功能的指标。选取糖耐量正常人53例，其中9例在不同日先后做2次微血管舒张功能检查，间隔时间大于7天，控制条件一样。在同日做微循环检查时，分别选择不同的加压时间(1分钟，4分钟，8分钟)比较毛细血管恢复率的变化情况。
结果：阻断毛细血管血流1min后，毛细血管恢复率仅为(21.3士7.0)％，明显低于阻断时间为4min或8min组。而阻断4min后测定的毛细血管恢复率和阻断8min后测定值基本相似，没有统计学差异。毛细血管恢复率的变异系数(CV)值为18.7±2.0％。3例平均年龄为(65.6±6.7)岁的糖耐量正常者微血管舒张功能检测结果显示，平均毛细血管密度基础值为(37.5±8.2)支／mm~2，峰值为(50.3±9.6)支／mm~2，毛细血管恢复率为(37.50±6.8)％，男女之间没有明显差异。年龄与毛细血管恢复率呈负相关(r=-0.413，P＜0.05)。
结论：阻断血流时间设定为4min能够较好较快的反映微血管舒张功能。因此，本课题选择了阻断4min作为试验方案。毛细血管恢复试验操作简便，重复性高、稳定性好，是比较理想的研究微血管舒张功能的新方法。初步对糖耐量正常者做了微血管舒张功能的检测，年龄与毛细血管恢复率呈负相关。
第二部分社区2型糖尿病人群中微血管舒张功能检测及和慢性并发症的关系
目的：测定社区2型糖尿病人群的皮肤微血管舒张功能，观察其影响因素以及和慢性并发症之间的关系。
方法：对上海市中心城区的社区2型糖尿病患者共367人进行了微血管舒张功能的检测，同时检查了尿白蛋白肌酐比、小瞳孔眼底成像、外周神经系统检查和颈动脉B超，按有无慢性并发症及并发症种类的多少分组，比较毛细血管恢复率(％)的差异，并对各种慢性并发症的危险因素进行分析。
结果：2型糖尿病人平均年龄为(66.0±10.9)岁，平均毛细血管恢复率为(29.6±12.3)％。年龄、糖尿病病程、收缩压、糖化血红蛋白和毛细血管恢复率密切相关(P＜0.05)。伴有糖尿病微血管并发症患者的毛细血管恢复率和毛细血管密度峰值都明显低于对照组(P＜0.05)。与＞30％的水平相比，毛细血管恢复率在20-30％组及＜20％组是糖尿病视网膜病变的独立危险因素(OR：5.78，95％CI：2.064-16.184；OR：21.267，95％CI：7.180-62.989)，校正了年龄、性别、糖尿病病程、HbA1c和收缩压混杂因素后，仍有统计学意义(adjusted OR：1.013，95％CI：1.006-1.020；adJusted OR：1.023，95％CI：1.015-1.030)。毛细血管恢复率20-30％组及＜20％组也是白蛋白尿的独立危险因素(adjusted OR：1.007；95％CI：1.003-1.011；adjusted OR：1.015；95％CI：1.010-1-020)。此外，毛细血管恢复率＜200％组是糖尿病外周神经病变的危险因素之一(OR：5.188；95％CI：2.201-12.23])。随着糖尿病微血管并发症种类的增多，毛细血管恢复率呈明显递减趋势(39.5±11.5 vs 27.8±9.4 vs 20.9±9.3 vs 15.1±5.0，P_(trend)＜0.05)。伴有颈动脉斑块病变患者的毛细血管恢复率、毛细血管密度峰值和基础值都低于无斑块病变者，但无统计学差异(P＞0.05)。
结论：毛细血管恢复率是糖尿病视网膜病变、白蛋白尿和外周神经病变的独立危险因素，并且随着微血管并发症种类的增多呈明显递减趋势，但与大血管病变的关系不明显。检测微血管舒张功能，有助于早期观察糖尿病微血管并发症的发生和严重程度。
第三部分2型糖尿病大鼠肠系膜微循环的改变及其发病机制的探讨
目的：观察2型糖尿病大鼠肠系膜微血管和微血流的变化，脂质过氧化产物水平以及抗氧化酶表达的改变。
方法：选取2型糖尿病大鼠(Otsuka long-evans tokushima fatty，OLETF)33只，非糖尿病大鼠(long-evans tokushima otsuka，LETO)7只，全麻状态下，使用带电脑图像处理装置的微循环活体观察电视显微镜进行活体肠系膜微循环观察。检测微血管分支数目、微动脉及微静脉口径、微静脉中沿壁滚动与贴壁黏附的白细胞数、微动脉边流和轴流的宽度、内皮细胞厚度等。实验结果经电视录像记录后用图像处理系统定量测定。ELISA方法测定大鼠尿8-iso-PGF2a水平，同时RT-PCR和Western Blot方法检测抗氧化酶的表达差异。
结果：OLETF大鼠肠系膜微血管分支数LETO大鼠减少24.5％(P＜0.01)，微血管分支数与血糖水平呈负相关(r=-0.44，P＜0.05)。OLETF大鼠的微动脉边流宽度小于对照组，边流与管径的比值显著减少(P＜0.01)，沿壁滚动与贴壁黏附白细胞明显增加(P＜0.01)。OLETF大鼠尿8-iso-PGF2a水平明显升高(P＜0.05)，而SOD_2和过氧化氢酶的表达两组之间没有明显差异。
结论：2型糖尿病大鼠肠系膜微循环出现明显微血流形态、结构和功能障碍；同时，糖尿病大鼠体内的氧化应激水平增强，与微循环障碍相互作用，形成恶性循环，这些变化可能共同导致了糖尿病微血管并发征的发生发展。
Part One: Establish the method to test dysfunction of skin vasodilation and study on the microcirculation function in individuals with normal glucose tolerance
Objective: To investigate the reproducibility of the capillary recruitment and the influence of occlusion time on postocclusive skin reactive hyperemia using computerized videophotometric capillaroscopy and to measure microcirculation function in individuals with normal glucose tolerance.
Methods: We estimated baseline capillary density by counting the number of continuously erythrocyte-perfused capillaries and used postocclusive reactive hyperemia to estimate the functional reserve. Postocclusive capillary recruitment was calculated by dividing the increase in density by the baseline density. 53 individuals with normal glucose tolerance were enrolled and analyzed. Nailfold capillaries in finger skin were recorded before and after 1, 4 or 8 minutes of arterial occlusion with a digital cuff in 9 individuals to investigate the influence of different occlusion time. Duplicate measurements were performed in 9 individuals on 2 separate days to determine the day-to-day coefficient of variation of postocclusive capillary recruitment.
Results: The percent increase of capillary density was only (21.3±7.0) % when the occlusion time was 1 minute, lowed than those with the occlusion time of 4 and 8 minutes. There was no difference in the percent increase between 4 or 8 minutes occlusion. The average age of non-diabetic subjects was (65.6±6.7) years old. The average baseline capillary density was (37.5±8.2) /mm~2, with an average peak capillary density of (50.3±9.6) /mm~2. The average percent increase was (37.50±6.8) %, and there was no difference between male and female subjects. Age was statistically associated with percent increase(r=0.413, P＜0.05). The day-to-day coefficient of variation of postocclusive capillary recruitment was 18.7±2.0%.
Conclusion: Capillary recruiment is an ideal method to measure the microcirculation dysfunction because of high reproducibility and stability. We selected 4 minutes as the occlusion time for its convenience and precise. We performed Capillary recruitment in individuals with normal glucose tolerance and found that age was associated with the percent increase of capillary density.
Part Two: Study on the microcirculation dysfunction in type 2 diabetic patients and its relation with diabetic complications
Objective: To measure microcirculation function in type 2 diabetic patients and to analyze its relation with diabetic complications.
Methods: 367 type 2 diabetic patients in Shanghai downtown were enrolled and categorized into several groups, those with diabetic retinopathy or not, those with albuminuria or not, those with diabetic peripheral neuropathy or not, and those with carotid artery plaque or not. We examined the capillary recruitment, the randomized morning urinary albumin creatinine ratio, the digitally stored fundus images, the carotid artery intima media thickness and carotid plaque by the Doppler, and compared the percentage increase of capillary density among these groups.
Results: The average age of diabetic patients was (66.0±10.9) years old. The average percentage increase of capillary density was (29.6±12.3) %. Age, diabetes duration, HbAlc, and systolic blood pressure were statistically associated with the percent increase of capillary density (P＜0.05). The percentage increases of capillary density in those with diabetic retinopathy, albuminuria, and peripheral neuropathy were significantly decreased as compared of those of controls. There was no significant difference between patients with diabetic macrovascular complications and controls. The percentage increase of capillary density of 20-30% or＜20% was an independent risk factor of diabetic retinopathy (adjusted OR: 1.013, 95%CI: 1.006-1.020; adjusted OR: 1.023, 95%CI: 1.015-1.030) and albuminuria (adjusted OR: 1.007; 95%CI: 1.003-1.011; adjusted OR: 1.015; 95%CI: 1.010-1.020). Also, the percent increase of＜20% was an independent risk factor of diabetic peripheral neuropathy (adjusted OR: 5.188; 95%CI: 2.201 -12.231).
Conclusion: The percentage increase of capillary density was an independent risk factor of diabetic retinopathy, albuminuria, and diabetic peripheral neuropathy. There was no significant relation between dysfunction of microcirculation and diabetic macrovascular complications. Measurement of capillary recruitment might help us to observe the occurrence and progression of diabetic microvascular complications.
Part Three: Study on the changes of mesentery microcirculation in type 2 diabetic rats and the possible mechanism
Objective: To study the dysfunction of microvessels and micro-blood-flow in mesentery microcirculation of type 2 diabetic rats.
Methods: Thirty-three OLETF (otsuka long-evans tokushima fatty) type 2 diabetic rats and seven LETO (long-evans tokushima otsuka) non-diabetic control rats were used in the study. After general anesthesia, a video microscope with image analysis system was used to observe the mesentery microcirculation in diabetic rats and controls. The microvascular number, diameter of arterioles and venules, number of rolling and sticking leukocytes on the surface of venules endothelium, width of marginal flow and axial flow in the arterioles, and thickness of endothelium were measured. The results were analysed quantitatively with the video microscopic image analysis system. Semi-quantitative RT-PCR and Western blotting were performed to verify the differential expression of some important antioxidative enzymes.
Results: Compared with control rats, the microvascular number in the mesentery of diabetic rats was reduced by 24.5 % (P＜0.01), which was inversely correlated to blood glucose level (r=-0.44, P＜0.05). The width of marginal flow in diabetic rats was decreased, and the ratio of width of marginal flow to width of arteriole reduced significantly (P＜0.01). The rolling and sticking leukocyte number adhered to the endothelium in the venule was increased significantly (P＜0.01). Results of RT-PCR and Western blotting showed no significantly different expression of SOD2 and catalase between OLETF and LETO rats. Meanwhile, the level of urine 8-iso-PGF2a was significantly increased in OLETF rats(P＜0.05).
Conclusions: The overt microvascular abnormality and micro-blood-flow dysfunction was shown in mesentery microcirculation of diabetic rats. Meanwhile, the level of oxidative stress in diabetic rats was increased, acting with microcirculation dysfunction to make a vacious cycle, which together might contribute to the development of diabetes and its complications. They were the pathogenetic basis of microangiopathy and various complications in diabetic rats.
目的：建立和优化无创伤性皮肤微血管舒张功能检测技术—毛细血管恢复试验并检测糖耐量正常人的微血管舒张功能。
方法：在毛细血管显微镜下，观察受试者皮肤甲襞微血管加压致反应性充血后毛细血管密度的变化，用毛细血管恢复率作为测定微血管舒张功能的指标。选取糖耐量正常人53例，其中9例在不同日先后做2次微血管舒张功能检查，间隔时间大于7天，控制条件一样。在同日做微循环检查时，分别选择不同的加压时间(1分钟，4分钟，8分钟)比较毛细血管恢复率的变化情况。
结果：阻断毛细血管血流1min后，毛细血管恢复率仅为(21.3士7.0)％，明显低于阻断时间为4min或8min组。而阻断4min后测定的毛细血管恢复率和阻断8min后测定值基本相似，没有统计学差异。毛细血管恢复率的变异系数(CV)值为18.7±2.0％。3例平均年龄为(65.6±6.7)岁的糖耐量正常者微血管舒张功能检测结果显示，平均毛细血管密度基础值为(37.5±8.2)支／mm~2，峰值为(50.3±9.6)支／mm~2，毛细血管恢复率为(37.50±6.8)％，男女之间没有明显差异。年龄与毛细血管恢复率呈负相关(r=-0.413，P＜0.05)。
结论：阻断血流时间设定为4min能够较好较快的反映微血管舒张功能。因此，本课题选择了阻断4min作为试验方案。毛细血管恢复试验操作简便，重复性高、稳定性好，是比较理想的研究微血管舒张功能的新方法。初步对糖耐量正常者做了微血管舒张功能的检测，年龄与毛细血管恢复率呈负相关。
第二部分社区2型糖尿病人群中微血管舒张功能检测及和慢性并发症的关系
目的：测定社区2型糖尿病人群的皮肤微血管舒张功能，观察其影响因素以及和慢性并发症之间的关系。
方法：对上海市中心城区的社区2型糖尿病患者共367人进行了微血管舒张功能的检测，同时检查了尿白蛋白肌酐比、小瞳孔眼底成像、外周神经系统检查和颈动脉B超，按有无慢性并发症及并发症种类的多少分组，比较毛细血管恢复率(％)的差异，并对各种慢性并发症的危险因素进行分析。
结果：2型糖尿病人平均年龄为(66.0±10.9)岁，平均毛细血管恢复率为(29.6±12.3)％。年龄、糖尿病病程、收缩压、糖化血红蛋白和毛细血管恢复率密切相关(P＜0.05)。伴有糖尿病微血管并发症患者的毛细血管恢复率和毛细血管密度峰值都明显低于对照组(P＜0.05)。与＞30％的水平相比，毛细血管恢复率在20-30％组及＜20％组是糖尿病视网膜病变的独立危险因素(OR：5.78，95％CI：2.064-16.184；OR：21.267，95％CI：7.180-62.989)，校正了年龄、性别、糖尿病病程、HbA1c和收缩压混杂因素后，仍有统计学意义(adjusted OR：1.013，95％CI：1.006-1.020；adJusted OR：1.023，95％CI：1.015-1.030)。毛细血管恢复率20-30％组及＜20％组也是白蛋白尿的独立危险因素(adjusted OR：1.007；95％CI：1.003-1.011；adjusted OR：1.015；95％CI：1.010-1-020)。此外，毛细血管恢复率＜200％组是糖尿病外周神经病变的危险因素之一(OR：5.188；95％CI：2.201-12.23])。随着糖尿病微血管并发症种类的增多，毛细血管恢复率呈明显递减趋势(39.5±11.5 vs 27.8±9.4 vs 20.9±9.3 vs 15.1±5.0，P_(trend)＜0.05)。伴有颈动脉斑块病变患者的毛细血管恢复率、毛细血管密度峰值和基础值都低于无斑块病变者，但无统计学差异(P＞0.05)。
结论：毛细血管恢复率是糖尿病视网膜病变、白蛋白尿和外周神经病变的独立危险因素，并且随着微血管并发症种类的增多呈明显递减趋势，但与大血管病变的关系不明显。检测微血管舒张功能，有助于早期观察糖尿病微血管并发症的发生和严重程度。
第三部分2型糖尿病大鼠肠系膜微循环的改变及其发病机制的探讨
目的：观察2型糖尿病大鼠肠系膜微血管和微血流的变化，脂质过氧化产物水平以及抗氧化酶表达的改变。
方法：选取2型糖尿病大鼠(Otsuka long-evans tokushima fatty，OLETF)33只，非糖尿病大鼠(long-evans tokushima otsuka，LETO)7只，全麻状态下，使用带电脑图像处理装置的微循环活体观察电视显微镜进行活体肠系膜微循环观察。检测微血管分支数目、微动脉及微静脉口径、微静脉中沿壁滚动与贴壁黏附的白细胞数、微动脉边流和轴流的宽度、内皮细胞厚度等。实验结果经电视录像记录后用图像处理系统定量测定。ELISA方法测定大鼠尿8-iso-PGF2a水平，同时RT-PCR和Western Blot方法检测抗氧化酶的表达差异。
结果：OLETF大鼠肠系膜微血管分支数LETO大鼠减少24.5％(P＜0.01)，微血管分支数与血糖水平呈负相关(r=-0.44，P＜0.05)。OLETF大鼠的微动脉边流宽度小于对照组，边流与管径的比值显著减少(P＜0.01)，沿壁滚动与贴壁黏附白细胞明显增加(P＜0.01)。OLETF大鼠尿8-iso-PGF2a水平明显升高(P＜0.05)，而SOD_2和过氧化氢酶的表达两组之间没有明显差异。
结论：2型糖尿病大鼠肠系膜微循环出现明显微血流形态、结构和功能障碍；同时，糖尿病大鼠体内的氧化应激水平增强，与微循环障碍相互作用，形成恶性循环，这些变化可能共同导致了糖尿病微血管并发征的发生发展。
Part One: Establish the method to test dysfunction of skin vasodilation and study on the microcirculation function in individuals with normal glucose tolerance
Objective: To investigate the reproducibility of the capillary recruitment and the influence of occlusion time on postocclusive skin reactive hyperemia using computerized videophotometric capillaroscopy and to measure microcirculation function in individuals with normal glucose tolerance.
Methods: We estimated baseline capillary density by counting the number of continuously erythrocyte-perfused capillaries and used postocclusive reactive hyperemia to estimate the functional reserve. Postocclusive capillary recruitment was calculated by dividing the increase in density by the baseline density. 53 individuals with normal glucose tolerance were enrolled and analyzed. Nailfold capillaries in finger skin were recorded before and after 1, 4 or 8 minutes of arterial occlusion with a digital cuff in 9 individuals to investigate the influence of different occlusion time. Duplicate measurements were performed in 9 individuals on 2 separate days to determine the day-to-day coefficient of variation of postocclusive capillary recruitment.
Results: The percent increase of capillary density was only (21.3±7.0) % when the occlusion time was 1 minute, lowed than those with the occlusion time of 4 and 8 minutes. There was no difference in the percent increase between 4 or 8 minutes occlusion. The average age of non-diabetic subjects was (65.6±6.7) years old. The average baseline capillary density was (37.5±8.2) /mm~2, with an average peak capillary density of (50.3±9.6) /mm~2. The average percent increase was (37.50±6.8) %, and there was no difference between male and female subjects. Age was statistically associated with percent increase(r=0.413, P＜0.05). The day-to-day coefficient of variation of postocclusive capillary recruitment was 18.7±2.0%.
Conclusion: Capillary recruiment is an ideal method to measure the microcirculation dysfunction because of high reproducibility and stability. We selected 4 minutes as the occlusion time for its convenience and precise. We performed Capillary recruitment in individuals with normal glucose tolerance and found that age was associated with the percent increase of capillary density.
Part Two: Study on the microcirculation dysfunction in type 2 diabetic patients and its relation with diabetic complications
Objective: To measure microcirculation function in type 2 diabetic patients and to analyze its relation with diabetic complications.
Methods: 367 type 2 diabetic patients in Shanghai downtown were enrolled and categorized into several groups, those with diabetic retinopathy or not, those with albuminuria or not, those with diabetic peripheral neuropathy or not, and those with carotid artery plaque or not. We examined the capillary recruitment, the randomized morning urinary albumin creatinine ratio, the digitally stored fundus images, the carotid artery intima media thickness and carotid plaque by the Doppler, and compared the percentage increase of capillary density among these groups.
Results: The average age of diabetic patients was (66.0±10.9) years old. The average percentage increase of capillary density was (29.6±12.3) %. Age, diabetes duration, HbAlc, and systolic blood pressure were statistically associated with the percent increase of capillary density (P＜0.05). The percentage increases of capillary density in those with diabetic retinopathy, albuminuria, and peripheral neuropathy were significantly decreased as compared of those of controls. There was no significant difference between patients with diabetic macrovascular complications and controls. The percentage increase of capillary density of 20-30% or＜20% was an independent risk factor of diabetic retinopathy (adjusted OR: 1.013, 95%CI: 1.006-1.020; adjusted OR: 1.023, 95%CI: 1.015-1.030) and albuminuria (adjusted OR: 1.007; 95%CI: 1.003-1.011; adjusted OR: 1.015; 95%CI: 1.010-1.020). Also, the percent increase of＜20% was an independent risk factor of diabetic peripheral neuropathy (adjusted OR: 5.188; 95%CI: 2.201 -12.231).
Conclusion: The percentage increase of capillary density was an independent risk factor of diabetic retinopathy, albuminuria, and diabetic peripheral neuropathy. There was no significant relation between dysfunction of microcirculation and diabetic macrovascular complications. Measurement of capillary recruitment might help us to observe the occurrence and progression of diabetic microvascular complications.
Part Three: Study on the changes of mesentery microcirculation in type 2 diabetic rats and the possible mechanism
Objective: To study the dysfunction of microvessels and micro-blood-flow in mesentery microcirculation of type 2 diabetic rats.
Methods: Thirty-three OLETF (otsuka long-evans tokushima fatty) type 2 diabetic rats and seven LETO (long-evans tokushima otsuka) non-diabetic control rats were used in the study. After general anesthesia, a video microscope with image analysis system was used to observe the mesentery microcirculation in diabetic rats and controls. The microvascular number, diameter of arterioles and venules, number of rolling and sticking leukocytes on the surface of venules endothelium, width of marginal flow and axial flow in the arterioles, and thickness of endothelium were measured. The results were analysed quantitatively with the video microscopic image analysis system. Semi-quantitative RT-PCR and Western blotting were performed to verify the differential expression of some important antioxidative enzymes.
Results: Compared with control rats, the microvascular number in the mesentery of diabetic rats was reduced by 24.5 % (P＜0.01), which was inversely correlated to blood glucose level (r=-0.44, P＜0.05). The width of marginal flow in diabetic rats was decreased, and the ratio of width of marginal flow to width of arteriole reduced significantly (P＜0.01). The rolling and sticking leukocyte number adhered to the endothelium in the venule was increased significantly (P＜0.01). Results of RT-PCR and Western blotting showed no significantly different expression of SOD2 and catalase between OLETF and LETO rats. Meanwhile, the level of urine 8-iso-PGF2a was significantly increased in OLETF rats(P＜0.05).
Conclusions: The overt microvascular abnormality and micro-blood-flow dysfunction was shown in mesentery microcirculation of diabetic rats. Meanwhile, the level of oxidative stress in diabetic rats was increased, acting with microcirculation dysfunction to make a vacious cycle, which together might contribute to the development of diabetes and its complications. They were the pathogenetic basis of microangiopathy and various complications in diabetic rats.
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