二甲双胍对糖尿病大鼠全层皮肤缺损创面愈合的作用及其机制

王宝宏; 张艳冰; 张先平; 李玉婷; 伍智慧; 扈容英; 赵诗乐; 蒋宏娜; 姚雨薇; 董俭达

doi:10.3760/cma.j.cn501225-20231219-00253

二甲双胍对糖尿病大鼠全层皮肤缺损创面愈合的作用及其机制

doi: 10.3760/cma.j.cn501225-20231219-00253

1.
宁夏医科大学基础医学院，银川　　750004
2.
西安市胸科医院病理科，西安　　710100
3.
宁夏医科大学总医院皮肤科，银川　　750004
4.
宁夏医科大学临床医学院，银川　　750004

基金项目:

国家自然科学基金地区科学基金项目 82060155

宁夏自然科学基金 2022AAC03162

国家级大学生创新创业训练计划 201810752006, 202210752007

自治区级大学生创新创业训练计划 S202310752026, S202310752009

宁夏回族自治区科技创新团队 NXKJT2019010

详细信息

通讯作者:
董俭达，Email：20010025@nxmu.edu.cn

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出版历程
- 收稿日期: 2023-12-19

Effects and mechanism of metformin on the wound healing of full-thickness skin defects in diabetic rats

1.
School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, China
2.
Department of Pathology, Xi'an Chest Hospital, Xi'an 710100, China
3.
Department of Dermatology, General Hospital, Ningxia Medical University, Yinchuan 750004, China
4.
School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, China

Funds:

Regional Science Fund Project of National Natural Science Foundation of China 82060155

Ningxia Natural Science Foundation 2022AAC03162

National College Student Innovation and Entrepreneurship Training Program 201810752006, 202210752007

Autonomous Region-Level College Student Innovation and Entrepreneurship Training Program S202310752026, S202310752009

Ningxia Hui Autonomous Region Science and Technology Innovation Team of China NXKJT2019010

More Information

Corresponding author: Dong Jianda, Email: 20010025@nxmu.edu.cn

摘要

摘要: 目的探讨二甲双胍对糖尿病大鼠全层皮肤缺损创面愈合的作用及其机制。方法该研究为实验研究。将18只8周龄雄性SD大鼠按照完全随机分组法分为对照组、糖尿病组及糖尿病+二甲双胍组，每组6只。将后2组大鼠制成糖尿病模型，然后在18只大鼠背部各制备4个直径5 mm的圆形全层皮肤缺损创面。仅在糖尿病+二甲双胍组大鼠创面涂抹二甲双胍F-127水凝胶。观察伤后7、13 d创面愈合情况并计算创面愈合率。收集伤后7、13 d创面组织，行苏木精-伊红染色，检测再上皮化表皮长度，计算表皮和真皮创面直径变化率；行免疫组织化学染色后，检测角蛋白10和增殖细胞核抗原（PCNA）的相对表达；行蛋白质印迹法检测角蛋白10和PCNA的蛋白表达。最后1个实验样本数为3，其余实验样本数均为8。分析3组大鼠创面组织中角蛋白10、PCNA相对表达与创面愈合率间的相关性，创面组织中角蛋白10相对表达和PCNA相对表达间的相关性。结果伤后7 d，糖尿病组与糖尿病+二甲双胍组大鼠创面愈合率分别为81.48%（77.89%，85.53%）、93.04%（92.51%，94.24%），均明显低于对照组的100%（97.17%，100%），Z值分别为2.37、-3.36，P<0.05；糖尿病+二甲双胍组大鼠创面愈合率明显高于糖尿病组（Z=3.45，P<0.05）。伤后13 d，对照组与糖尿病+二甲双胍组大鼠创面愈合率均为100%（100%，100%），均明显高于糖尿病组的94.47%（90.68%，99.82%），Z值分别为2.90、-2.90，P<0.05。伤后7 d，对照组和糖尿病+二甲双胍组大鼠表皮创面直径变化率均明显高于糖尿病组（Z值分别为3.36、-2.74，P<0.05）。3组大鼠伤后7、13 d真皮创面直径变化率均相近（P>0.05）。对照组、糖尿病+二甲双胍组大鼠伤后13 d创面再上皮化表皮长度均明显长于糖尿病组（Z值分别为3.34、-2.64，P<0.05）。糖尿病组大鼠伤后7、13 d创面组织中角蛋白10的相对表达均明显高于对照组（Z值分别为-3.36、-3.26，P<0.05）和糖尿病+二甲双胍组（Z值分别为3.36、3.15，P<0.05），糖尿病+二甲双胍组大鼠伤后7 d创面组织中角蛋白10相对表达明显低于对照组（Z=3.05，P<0.05）；糖尿病组大鼠伤后7、13 d创面组织中PCNA相对表达均明显低于对照组（Z值均为3.36，P<0.05）和糖尿病+二甲双胍组（Z值均为-3.36，P<0.05）。对照组和糖尿病+二甲双胍组大鼠伤后7 d创面组织中角蛋白10蛋白表达及糖尿病+二甲双胍组大鼠伤后13 d创面组织中角蛋白10蛋白表达均明显低于糖尿病组（P<0.05），对照组和糖尿病+二甲双胍组大鼠伤后7 d创面组织中PCNA蛋白表达均明显高于糖尿病组（P<0.05）。对照组和糖尿病+二甲双胍组大鼠创面组织中角蛋白10相对表达和创面愈合率均呈显著正相关（r值分别为0.78、0.71，P<0.05），糖尿病+二甲双胍组大鼠创面组织中PCNA相对表达和创面愈合率呈显著负相关（r=-0.60，P<0.05），糖尿病组和糖尿病+二甲双胍组大鼠创面组织中PCNA相对表达与角蛋白10相对表达均呈显著负相关（r值分别为-0.41、-0.49，P<0.05）。结论糖尿病大鼠全层皮肤缺损创面延迟愈合并伴有创面组织KC中的角蛋白10上调及PCNA下调。二甲双胍通过下调创面组织KC中的角蛋白10表达和上调PCNA表达，促进糖尿病大鼠全层皮肤缺损创面愈合，且创面愈合率与角蛋白10的表达呈正相关，与PCNA的表达呈负相关。
- 二甲双胍 /
- 糖尿病 /
- 细胞增殖 /
- 细胞分化 /
- 角质形成细胞 /
- 创面修复
Abstract: Objective To investigate the effects and mechanism of metformin on the wound healing of full-thickness skin defects in diabetic rats. Methods This study was an experimental study. Eighteen 8-week-old male Sprague Dawley rats were divided into control group, diabetes group, and diabetes+metformin group according to complete random grouping method, with 6 rats in each group. The latter two groups of rats were used to create diabetic models, and then four circular full-thickness skin defect wounds with a diameter of 5 mm were made on the back of 18 rats. Metformin F-127 hydrogel was applied only to the wounds of rats in diabetes+metformin group. The wound healing status on post injury day (POD) 7 and 13 was observed and the wound healing rate was calculated. The wound tissue on POD 7 and 13 was collected for hematoxylin-eosin staining to measure the length of re-epithelialized epidermis and calculate the change rates in diameters of epidermal and dermal wounds, for immunohistochemical staining to detect the relative expressions of keratin 10 and proliferating cell nuclear antigen (PCNA), and for Western blotting to detect the protein expressions of keratin 10 and PCNA. The sample size in all the above experiments was 8 except that in the last experiment was 3. The correlations between the relative expressions of keratin 10 and PCNA in wound tissue in three groups of rats and their wound healing rates, and the correlation between the relative expressions of keratin 10 and PCNA in wound tissue were analyzed. Results On POD 7, the wound healing rates of rats in diabetes group and diabetes+metformin group were 81.48% (77.89%, 85.53%) and 93.04% (92.51%, 94.24%), which were significantly lower than 100% (97.17%, 100%) in control group (with Z values of 2.37 and -3.36, respectively, P<0.05); the wound healing rate of rats in diabetes+metformin group was significantly higher than that in diabetes group (Z=3.45, P<0.05). On POD 13, the wound healing rates of rats in control group and diabetes+metformin group were both 100% (100%, 100%), which were significantly higher than 94.47% (90.68%, 99.82%) in diabetes group (with Z values of 2.90 and -2.90, respectively, P<0.05). On POD 7, the change rates in epidermal wound diameter of rats in control group and diabetes+metformin group were significantly higher than that in diabetes group (with Z values of 3.36 and -2.74, respectively, P<0.05). The change rates in dermal wound diameter of rats in the three groups were similar on POD 7 and 13 (P>0.05). The lengths of re-epithelialized epidermis of rats in control group and diabetes+metformin group on POD 13 were significantly longer than that in diabetes group (with Z values of 3.34 and -2.64, respectively, P<0.05). The relative expressions of keratin 10 in wound tissue of rats in diabetes group on POD 7 and 13 were significantly higher than those in control group (with Z values of -3.36 and -3.26, respectively, P<0.05) and diabetes+metformin group (with Z values of 3.36 and 3.15, respectively, P<0.05), and the relative expression of keratin 10 in wound tissue of rats in diabetes+metformin group on POD 7 was significantly lower than that in control group (Z=3.05, P<0.05); the relative expressions of PCNA in wound tissue of rats in diabetes group on POD 7 and 13 were significantly lower than those in control group (with both Z values of 3.36, P<0.05) and diabetes+metformin group (with both Z values of -3.36, P<0.05). The protein expressions of keratin 10 in wound tissue of rats in control group and diabetes+metformin group on POD 7 as well as that in diabetes+metformin group on POD 13 were significantly lower than those in diabetes group (P<0.05), and the protein expressions of PCNA in wound tissue of rats in control group and diabetes+metformin group on POD 7 were significantly higher than that in diabetes group (P<0.05). There was a significant positive correlation between the relative expression of keratin 10 in wound tissue and the wound healing rate in control group and diabetes+metformin group of rats (with r values of 0.78 and 0.71, respectively, P<0.05), there was a significant negative correlation between the relative expression of PCNA in wound tissue and the wound healing rate in diabetes+metformin group of rats (r=-0.60, P<0.05), and there was a significant negative correlation between the relative expressions of PCNA and keratin 10 in wound tissue of rats in diabetes group and diabetes+metformin group (with r values of -0.41 and -0.49, respectively, P<0.05). Conclusions The diabetic rats with full-thickness skin defect wound exhibit delayed healing, accompanied by up-regulation of keratin 10 and down-regulation of PCNA in keratinocytes in the wound tissue. Metformin can promote wound healing in diabetic rats with full-thickness skin defects by down-regulating keratin 10 expression and up-regulating PCNA expression in keratinocytes in the wound tissue, and the wound healing rate was positively correlated with the expression of keratin 10 and negatively correlated with the expression of PCNA.
- Metformin /
- Diabetes mellitus /
- Cell proliferation /
- Cell differentiation /
- Keratinocytes /
- Wound repair
王宝宏：酝酿和设计实验、实施研究、采集数据、整理数据、统计分析、撰写论文、修改论文；张艳冰：酝酿和设计实验、解释和分析数据、统计分析、修改论文；张先平、李玉婷、伍智慧、扈容英：采集数据、修改论文；赵诗乐、蒋宏娜、姚雨薇：采集数据、整理数据；董俭达：研究指导、修改论文、经费支持

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1 3组全层皮肤缺损大鼠伤后各时间点创面愈合情况。1A、1B、1C.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后7 d创面愈合情况，图1A、1C创面面积小于图1B；1D、1E、1F.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后13 d创面愈合情况，图1D、1F创面已完全愈合，图1E部分创面尚未完全愈合

注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶

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2 3组全层皮肤缺损大鼠伤后各时间点表皮和真皮创面愈合情况苏木精-伊红×2。2A、2B、2C.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后7 d创面愈合情况，图2A、2C真皮和表皮创面直径均小于图2B；2D、2E、2F.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后13 d创面愈合情况，图2D、2F创面均已完全愈合，图2E部分创面尚未完全愈合

注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；绿色箭头之间的直线距离为表皮创面直径，红色箭头之间的直线距离为真皮创面直径

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3 3组全层皮肤缺损大鼠伤后各时间点创面组织中角蛋白10表达（棕黄色）二氨基联苯胺-苏木精×10。3A、3B、3C.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后7 d情况，图3A、3C角蛋白10表达均较图3B降低；3D、3E、3F.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后13 d情况，图3D、3F角蛋白10表达均较图3E降低

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4 3组全层皮肤缺损大鼠伤后各时间点创面组织中PCNA的表达（棕黄色）二氨基联苯胺-苏木精×10。4A、4B、4C.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后7 d情况，图4A、4C中PCNA表达均较图4B增高；4D、4E、4F.分别为对照组、糖尿病组、糖尿病+二甲双胍组伤后13 d情况，图4D、4F中PCNA表达均较图4E增高

注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；PCNA为增殖细胞核抗原

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5 蛋白质印迹法检测的3组全层皮肤缺损大鼠伤后各时间点创面组织中角蛋白10和PCNA的蛋白表达。5A.伤后7 d的角蛋白10；5B.伤后13 d的角蛋白10；5C.伤后7 d的PCNA；5D.伤后13 d的PCNA

注：条带上方1、2、3分别表示对照组、糖尿病组和糖尿病+二甲双胍组；对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；PCNA为增殖细胞核抗原

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表1 3组全层皮肤缺损大鼠伤后各时间点创面愈合率比较[%，M（Q₁，Q₃）]

表1. Comparison of the wound healing rates in three groups of rats with full-thickness skin defects at various time points after injury

组别	创面数（个）	7 d	13 d
对照组	8	100（97.17，100）	100（100，100）
糖尿病组	8	81.48（77.89，85.53）	94.47（90.68，99.82）
糖尿病+二甲双胍组	8	93.04（92.51，94.24）	100（100，100）
H值		3.45	14.93
P值		<0.001	<0.001
Z₁值		2.37	2.90
P₁值		0.018	0.004
Z₂值		-3.36	0
P₂值		<0.001	>0.999
Z₃值		3.45	-2.90
P₃值		<0.001	0.004
注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；各组各时间点创面数均为8个；Z₁值、P₁值和Z₂值、P₂值分别为糖尿病组、糖尿病+二甲双胍组与对照组各时间点比较所得，Z₃值、P₃值为糖尿病组与糖尿病+二甲双胍组各时间点比较所得

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表2 3组全层皮肤缺损大鼠伤后各时间点表皮创面直径变化率比较[%，M（Q₁，Q₃）]

表2. Comparison of epidermal wound diameter change rates in 3 groups of rats with full-thickness skin defects at various time points after injury

组别	创面数（个）	7 d	13 d
对照组	8	99.20（98.50，99.70）	100（99.70，100）
糖尿病组	8	71.00（59.00，78.70）	87.90（75.30，100）
糖尿病+二甲双胍组	8	96.60（81.00，100）	99.80（98.50，100）
H值		13.14	3.84
P值		0.001	0.147
Z₁值		3.36	—
P₁值		<0.001	—
Z₂值		0.73	—
P₂值		0.461	—
Z₃值		-2.74	—
P₃值		0.006	—
注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；各组各时间点创面数均为8个；Z₁值、P₁值和Z₂值、P₂值分别为糖尿病组、糖尿病+二甲双胍组与对照组各时间点比较所得，Z₃值、P₃值为糖尿病组与糖尿病+二甲双胍组各时间点比较所得；“—”表示无此项

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表3 3组全层皮肤缺损大鼠伤后各时间点真皮创面直径变化率比较[%，M（Q₁，Q₃）]

表3. Comparison of dermal wound diameter change rates in 3 groups of rats with full-thickness skin defects at various time points after injury

组别	创面数（个）	7 d	13 d
对照组	8	72.40（68.50，74.00）	73.00（71.30，74.70）
糖尿病组	8	67.40（56.40，68.60）	66.40（51.70，74.40）
糖尿病+二甲双胍组	8	69.60（65.60，70.40）	73.50（65.40，75.00）
H值		4.74	2.08
P值		0.094	0.354
注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；各组各时间点创面数均为8个

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表4 3组全层皮肤缺损大鼠伤后各时间点创面再上皮化表皮长度比较[μm，M（Q₁，Q₃）]

表4. Comparison of epidermal re-epithelialization lengths of wounds in 3 groups of rats with full-thickness skin defects at various time points after injury

组别	创面数（个）	7 d	13 d
对照组	8	4.92（4.81，5.00）	5.00（4.94，5.00）
糖尿病组	8	2.45（1.56，5.00）	4.06（1.52，4.60）
糖尿病+二甲双胍组	8	5.00（5.00，5.00）	5.00（4.76，5.00）
H值		5.90	13.36
P值		0.052	0.001
Z₁值		—	3.34
P₁值		—	<0.001
Z₂值		—	0.28
P₂值		—	0.783
Z₃值		—	-2.64
P₃值		—	0.007
注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；各组各时间点创面数均为8个；Z₁值、P₁值和Z₂值、P₂值分别为糖尿病组、糖尿病+二甲双胍组与对照组各时间点比较所得，Z₃值、P₃值为糖尿病组与糖尿病+二甲双胍组各时间点比较所得；“—”表示无此项

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表5 3组全层皮肤缺损大鼠伤后各时间点创面组织中角蛋白10和PCNA的相对表达比较[M（Q₁，Q₃）]

表5. Comparison of the relative expressions of keratin 10 and PCNA in wound tissue in 3 groups of rats with full-thickness skin defects at various time points after injury

组别	各时间点创面数（个）	7 d		13 d
组别	各时间点创面数（个）	角蛋白10	PCNA	角蛋白10	PCNA
对照组	8	0.83（0.50，1.01）	1.86（1.56，2.13）	0.71（0.60，0.93）	2.37（1.96，2.54）
糖尿病组	8	3.46（2.64，5.74）	1.02（0.95，1.09）	5.15（3.15，6.51）	0.56（0.39，0.88）
糖尿病+二甲双胍组	8	0.11（0.06，0.21）	2.11（1.99，2.15）	0.49（0.36，0.81）	2.34（2.05，2.56）
H值		19.57	16.64	14.51	15.41
P值		<0.001	<0.001	<0.001	<0.001
Z₁值		-3.36	3.36	-3.26	3.36
P₁值		<0.001	<0.001	0.001	<0.001
Z₂值		3.05	-1.68	1.16	-0.32
P₂值		0.023	0.093	0.248	0.753
Z₃值		3.36	-3.36	3.15	-3.36
P₃值		<0.001	<0.001	0.002	<0.001
注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；PCNA为增殖细胞核抗原；Z₁值、P₁值和Z₂值、P₂值分别为糖尿病组、糖尿病+二甲双胍组与对照组各时间点各指标比较所得，Z₃值、P₃值为糖尿病组与糖尿病+二甲双胍组各时间点各指标比较所得

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表6 3组全层皮肤缺损大鼠伤后各时间点创面组织中角蛋白10和PCNA的蛋白表达比较（x¯±s）

表6. Comparison of the protein expressions of keratin 10 and PCNA in wound tissue in three groups of rats with full-thickness skin defects at various time points after injury

组别	各时间点创面数（个）	7 d		13 d
组别	各时间点创面数（个）	角蛋白10	PCNA	角蛋白10	PCNA
对照组	3	0.62±0.24	1.16±0.12	0.63±0.23	1.26±0.36
糖尿病组	3	1.01±0.12	0.46±0.17	1.21±0.40	0.74±0.19
糖尿病+二甲双胍组	3	0.56±0.10	0.97±0.16	0.33±0.24	1.14±0.22
F值		6.58	16.89	6.73	3.12
P值		0.031	0.003	0.029	0.118
P₁值		0.026	0.001	0.055	—
P₂值		0.710	0.171	0.262	—
P₃值		0.016	0.007	0.011	—
注：对照组大鼠不进行药物干预；糖尿病组、糖尿病+二甲双胍组大鼠均制成糖尿病模型，前一组不进行药物干预，后一组在创面涂抹二甲双胍F-127水凝胶；角蛋白10和增殖细胞核抗原（PCNA）蛋白表达的处理因素主效应，F值分别为14.42、3.43，P值分别为<0.001、0.055；时间因素主效应，F值分别为0.03、17.45，P值分别为0.002、0.001；两者交互作用，F值分别为3.12、1.10，P值分别为0.041、0.387；P₁值、P₂值分别为糖尿病组、糖尿病+二甲双胍组与对照组各时间点各指标比较所得，P₃值为糖尿病组与糖尿病+二甲双胍组各时间点各指标比较所得；“—”表示无此项