Relationships of Skin AGEs and Serum CN-1
with Microvascular Complications in Type 2 Diabetes Mellitus

doi:10.12114/j.issn.1007-9572.2021.02.134

Abstract

Abstract: Background

Hyperglycemia plays a significant role in the development and progression of diabetic complications. While carnosine is a putative scavenger of advanced glycation end products (AGEs) , its availability in tissue is limited by the activity of serum carnosinase-1 (CN-1) . So far, the correlations of skin AGEs and serum CN-1 concentration with type 2 diabetes mellitus (T2DM) , and microvascular complications in T2DM are still unclear.

Objective

To investigate the relationships of skin AGEs, and serum CN-1 with microvascular complications in T2DM to evaluate the predictive values of skin AGEs and serum CN-1 for diabetic complications.

Methods

A total of 134 inpatients with T2DM were recruited from the Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University between January and March 2021.Their clinical data were collected. Pearson correlation analysis and Spearman rank correlation analysis were used to examine the correlation between skin AGEs and serum CN-1, and the correlations of skin AGEs and serum CN-1 with demographic and serological data, diabetic microvascular complications and other diseases. The influencing factors of skin AGEs and serum CN-1 were investigated by multiple linear regression analysis.

Results

Out of all subjects, there were 13 (9.7%) cases of diabetic retinopathy (DR) , 38 (28.4%) cases of diabetic nephropathy (DN) , 56 (41.8%) cases of diabetic peripheral neuropathy (DPN) , and 79 (59.0%) cases of diabetic peripheral vascular disease. The skin AGEs level was (80.2 ±10.6) and serum CN-1 concentration was (6.9±3.4) μg/L on average. Correlation analyses demonstrated that gender, age, and DR were positively correlated with skin AGEs (P<0.05) , but estimated glomerular filtration rate (eGFR) and CN-1 were negatively correlated with skin AGEs (P<0.05) . Multiple linear regression analysis revealed that gender (B=7.630) , age (B=0.408) and DR (B=7.183) were associated with skin AGEs (P<0.05) . Correlation analyses showed that serum CN-1 was increased with age or with the increase in diastolic blood pressure (DBP) (P<0.05) , while it decreased with the decline of skin AGEs (P<0.05) .

Conclusion

Both skin AGEs and serum CN-1 may have no obvious correlation with most diabetic microvascular complications, such as DN, DPN and diabetic peripheral vascular disease. But different from serum CN-1, skin AGEs may significantly correlated with DR.

Key words: Diabetes mellitus, type 2, Advanced glycation end products, Carnosine, Carnosinase-1, Diabetic nephropathies, Diabetic retinopathy, Diabetic peripheral vascular disease

摘要： 背景

高血糖在糖尿病并发症发生、发展中起重要作用。尽管肌肽是晚期糖基化终末产物（AGEs）的潜在清除剂，但其在组织中的有效性受血清肌肽酶-1（CN-1）活性的限制。目前2型糖尿病患者皮肤AGEs与血清CN-1的相关性及其与糖尿病微血管并发症的关系尚未明确。

目的

探究2型糖尿病患者皮肤AGEs、血清CN-1与糖尿病微血管并发症的关系，以评估皮肤AGEs和血清CN-1预测糖尿病并发症的临床价值。

方法

选取2021年1—3月在安徽医科大学第一附属医院内分泌科住院的2型糖尿病患者134例为研究对象，收集患者的临床资料。采用Pearson相关分析和Spearman秩相关分析探究皮肤AGEs与血清CN-1的相关性，皮肤AGEs、血清CN-1分别与一般资料、糖尿病微血管并发症及其他疾病、实验室检查指标的相关性，采用多元线性回归分析探究皮肤AGEs、血清CN-1变化的影响因素。

结果

134例患者中糖尿病视网膜病变（DR）13例（9.7%）、糖尿病肾病（DN）38例（28.4%）、糖尿病周围神经病变（DPN）56例（41.8%）、糖尿病周围血管病变79例（59.0%），皮肤AGEs（80.2±10.6），血清CN-1（6.9±3.4）μg/L。相关性分析结果显示，性别、年龄、DR与皮肤AGEs呈正相关（P<0.05），估算肾小球滤过率（eGFR）、CN-1与皮肤AGEs呈负相关（P<0.05）。多元线性回归分析结果显示，性别（B=7.630）、年龄（B=0.408）、DR（B=7.183）是皮肤AGEs的影响因素（P<0.05）。相关性分析结果显示，年龄、舒张压（DBP）与血清CN-1呈正相关（P<0.05），皮肤AGEs与血清CN-1呈负相关（P<0.05）。

结论

皮肤AGEs、血清CN-1与大部分糖尿病微血管并发症（DN、DPN及糖尿病周围血管病变）间无明显相关关系；与血清CN-1不同，皮肤AGEs与DR存在相关性。

关键词: 糖尿病, 2型, 晚期糖基化终末产物, 肌肽, 肌肽酶-1, 糖尿病肾病, 糖尿病视网膜病变, 糖尿病周围血管病变

CLC Number:

R587.1

YANG Guang, XU Xin, ZHANG Yu, XU Juan, JIANG Shujuan, XIA Li, ZHANG Yang, WANG Yikun, LI Zhongsheng, ZHANG Shiqi.

Relationships of Skin AGEs and Serum CN-1 with Microvascular Complications in Type 2 Diabetes Mellitus [J]. Chinese General Practice, 2022, 25(09): 1082-1087.

杨光,徐新,张宇等. 2型糖尿病患者皮肤晚期糖基化终末产物和血清肌肽酶-1与糖尿病微血管并发症的关系研究[J]. 中国全科医学, 2022, 25(09): 1082-1087. DOI: 10.12114/j.issn.1007-9572.2021.02.134.

Figures/Tables 5

References 30

[1]	KLEIN R，KLEIN B E，MOSS S E，et al. The Wisconsin epidemiologic study of diabetic retinopathy. Ⅱ. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years[J]. Arch Ophthalmol，1984，102(4):520-526. DOI：10.1001/archopht.1984.01040030398010.
[2]	NASS N，BARTLING B，NAVARRETE SANTOS A，et al. Advanced glycation end products，diabetes and ageing[J]. Z Gerontol Geriatr，2007，40(5):349-356. DOI：10.1007/s00391-007-0484-9.
[3]	HOFMANN B，JACOBS K，NAVARRETE SANTOS A，et al. Relationship between cardiac tissue glycation and skin autofluorescence in patients with coronary artery disease[J]. Diabetes Metab，2015，41(5):410-415. DOI：10.1016/j.diabet.2014.12.001.
[4]	PARADELA-DOBARRO B，AGRA R M，ÁLVAREZ L，et al. The different roles for the advanced glycation end products axis in heart failure and acute coronary syndrome settings[J]. Nutr Metab Cardiovasc Dis，2019，29(10):1050-1060. DOI：10.1016/j.numecd.2019.06.014.
[5]	CHOU P S，WU M N，YANG C C，et al. Effect of advanced glycation end products on the progression of Alzheimer's disease[J]. J Alzheimers Dis，2019，72(1):191-197. DOI：10.3233/JAD-190639.
[6]	AUBERT C E，MICHEL P L，GILLERY P，et al. Association of peripheral neuropathy with circulating advanced glycation end products，soluble receptor for advanced glycation end products and other risk factors in patients with type 2 diabetes[J]. Diabetes Metab Res Rev，2014，30(8):679-685. DOI：10.1002/dmrr.2529.
[7]	BIERHAUS A，FLEMING T，STOYANOV S，et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy[J]. Nat Med，2012，18(6):926-933. DOI：10.1038/nm.2750.
[8]	BROWNLEE M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature，2001，414(6865):813-820. DOI：10.1038/414813a.
[9]	VAN PUYVELDE K，METS T，NJEMINI R，et al. Effect of advanced glycation end product intake on inflammation and aging：a systematic review[J]. Nutr Rev，2014，72(10):638-650. DOI：10.1111/nure.12141.
[10]	SHEETZ M J，KING G L. Molecular understanding of hyperglycemia's adverse effects for diabetic complications[J]. JAMA，2002，288(20):2579-2588. DOI：10.1001/jama.288.20.2579.
[11]	BOLDYREV A A，ALDINI G，DERAVE W. Physiology and pathophysiology of carnosine[J]. Physiol Rev，2013，93(4):1803-1845. DOI：10.1152/physrev.00039.2012.
[12]	BANDO K，SHIMOTSUJI T，TOYOSHIMA H，et al. Fluorometric assay of human serum carnosinase activity in normal children，adults and patients with myopathy[J]. Ann Clin Biochem，1984，21(Pt 6):510-514. DOI：10.1177/000456328402100613.
[13]	PETERS V，JANSEN E E，JAKOBS C，et al. Anserine inhibits carnosine degradation but in human serum carnosinase （CN1） is not correlated with histidine dipeptide concentration[J]. Clin Chim Acta，2011，412(3/4):263-267. DOI：10.1016/j.cca.2010.10.016.
[14]	LIU Y，ZHANG L，ZHU L，et al. Non-invasive method for detecting skin autofluorescence of advanced glycation end products[C]//2009 2nd International Conference on Biomedical Engineering and Informatics. October 17-19，2009，Tianjin，China. IEEE，2009：1-3. DOI：10.1109/BMEI.2009.5305228.
[15]	JANUSZEWSKI A S，SACHITHANANDAN N，KARSCHIMKUS C，et al. Non-invasive measures of tissue autofluorescence are increased in Type 1 diabetes complications and correlate with a non-invasive measure of vascular dysfunction[J]. Diabet Med，2012，29(6):726-733. DOI：10.1111/j.1464-5491.2011.03562.x.
[16]	MULDER D J，VAN HAELST P L，GRAAFF R，et al. Skin autofluorescence is elevated in acute myocardial infarction and is associated with the one-year incidence of major adverse cardiac events[J]. Neth Heart J，2009，17(4):162-168. DOI：10.1007/BF03086239.
[17]	LUTGERS H L，GERRITS E G，GRAAFF R，et al. Skin autofluorescence provides additional information to the UK Prospective Diabetes Study （UKPDS） risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus[J]. Diabetologia，2009，52(5):789-797. DOI：10.1007/s00125-009-1308-9.
[18]	MONNIER V M，SUN W J，GAO X Y，et al. Skin collagen advanced glycation endproducts （AGEs） and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes[J]. Cardiovasc Diabetol，2015，14:118. DOI：10.1186/s12933-015-0266-4.
[19]	WANG Y K，ZHU L，ZHANG L，et al. A portable system for noninvasive assessment of advanced glycation end-products using skin fluorescence and reflectance spectrum[J]. J Appl Spectrosc，2012，79(3):431-436. DOI：10.1007/s10812-012-9619-x.
[20]	MOLDOGAZIEVA N T，MOKHOSOEV I M，MEL'NIKOVA T I，et al. Oxidative stress and advanced lipoxidation and glycation end products （ALEs and AGEs） in aging and age-related diseases[J]. Oxid Med Cell Longev，2019，2019:3085756. DOI：10.1155/2019/3085756.
[21]	SIMM A，MÜLLER B，NASS N，et al. Protein glycation - Between tissue aging and protection[J]. Exp Gerontol，2015，68:71-75. DOI：10.1016/j.exger.2014.12.013.
[22]	KANDA A，DONG Y，NODA K，et al. Advanced glycation endproducts link inflammatory cues to upregulation of galectin-1 in diabetic retinopathy[J]. Sci Rep，2017，7(1):16168. DOI：10.1038/s41598-017-16499-8.
[23]	MOORE T C，MOORE J E，KAJI Y，et al. The role of advanced glycation end products in retinal microvascular leukostasis[J]. Invest Ophthalmol Vis Sci，2003，44(10):4457-4464. DOI：10.1167/iovs.02-1063.
[24]	STERNBERG M，M'BEMBA J，URIOS P，et al. Skin collagen pentosidine and fluorescence in diabetes were predictors of retinopathy progression and creatininemia increase already 6years after punch-biopsy[J]. Clin Biochem，2016，49(3):225-231. DOI：10.1016/j.clinbiochem.2015.10.011.
[25]	PFISTER F，RIEDL E，WANG Q，et al. Oral carnosine supplementation prevents vascular damage in experimental diabetic retinopathy[J]. Cell Physiol Biochem，2011，28(1):125-136. DOI：10.1159/000331721.
[26]	YOSHIOKA K. Skin autofluorescence is a noninvasive surrogate marker for diabetic microvascular complications and carotid intima-media thickness in Japanese patients with type 2 diabetes：a cross-sectional study[J]. Diabetes Ther，2018，9(1):75-85. DOI：10.1007/s13300-017-0339-3.
[27]	ZHANG S Q，ALBRECHT T，RODRIGUEZ-NIÑO A，et al. Carnosinase concentration，activity，and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy[J]. Amino Acids，2019，51(4):611-617. DOI：10.1007/s00726-018-02692-0.
[28]	RODRIGUEZ-NIÑO A，GANT C M，BRAUN J D，et al. Detection of carnosinase-1 in urine of healthy individuals and patients with type 2 diabetes：correlation with albuminuria and renal function[J]. Amino Acids，2019，51(1):17-25. DOI：10.1007/s00726-018-2602-y.
[29]	KAMEI J，OHSAWA M，MIYATA S，et al. Preventive effect of L-carnosine on changes in the thermal nociceptive threshold in streptozotocin-induced diabetic mice[J]. Eur J Pharmacol，2008，600(1/2/3):83-86. DOI：10.1016/j.ejphar.2008.10.002.
[30]	ADELMANN K，FREY D，RIEDL E，et al. Different conformational forms of serum carnosinase detected by a newly developed sandwich ELISA for the measurements of carnosinase concentrations[J]. Amino Acids，2012，43(1):143-151. DOI：10.1007/s00726-012-1244-8.

指标	r（r_s）值	P值
性别	0.273^a	<0.01
年龄	0.392	<0.01
BMI	-0.158	0.07
糖尿病病程	0.143^a	0.11
SBP	0.054	0.55
DBP	-0.167	0.06
HbA_1c	-0.068	0.44
FC-P	-0.013^a	0.89
ACR	0.100^a	0.26
eGFR	-0.382	<0.01
DR	0.195^a	0.03
DPN	0.031^a	0.75
DN	0.005^a	0.95
糖尿病周围血管病变	0.120^a	0.18
CN-1	-0.222	0.02
冠心病	0.067^a	0.46
高血压	0.131^a	0.14
脑卒中	0.116^a	0.19
血脂异常	-0.054^a	0.54

指标	r（r_s）值	P值
性别	0.273^a	<0.01
年龄	0.392	<0.01
BMI	-0.158	0.07
糖尿病病程	0.143^a	0.11
SBP	0.054	0.55
DBP	-0.167	0.06
HbA_1c	-0.068	0.44
FC-P	-0.013^a	0.89
ACR	0.100^a	0.26
eGFR	-0.382	<0.01
DR	0.195^a	0.03
DPN	0.031^a	0.75
DN	0.005^a	0.95
糖尿病周围血管病变	0.120^a	0.18
CN-1	-0.222	0.02
冠心病	0.067^a	0.46
高血压	0.131^a	0.14
脑卒中	0.116^a	0.19
血脂异常	-0.054^a	0.54

变量	赋值
性别	男=1，女=0
年龄	实测值
eGFR	实测值
DR	是=1，否=0
CN-1	实测值

变量	赋值
性别	男=1，女=0
年龄	实测值
eGFR	实测值
DR	是=1，否=0
CN-1	实测值

变量	非标准化系数		β	t值	P值
变量	B	SE	β	t值	P值
性别	7.630	1.734	0.356	4.400	<0.01
年龄	0.408	0.094	0.447	4.330	<0.01
DR	7.183	2.851	0.209	2.519	0.013
eGFR	-0.053	0.043	-0.127	-1.241	0.217
CN-1	-0.205	0.273	-0.061	-0.750	0.455