ABSTRACT OBJECTIVE To investigate the distribution of nine (9) urine biomarkers in people living with type 2 diabetes mellitus (T2DM), with or without microvascular complications. METHODS In

total, 407 people with T2DM were enrolled from 2021 to 2022. According to diabetic retinopathy (DR) and urinary albumin-creatinine ratio (UACR), the 407 people were divided into four (4)

groups, DR(–)UACR(–), DR(+)UACR(–), DR(–)UACR(+), and DR( + )UACR(+). In addition, 112 healthy volunteers were enrolled during the same period. The nine (9) urine markers included

α1-microglobulin (u-α1MG), immunoglobulin G (u-IgG), neutrophil gelatinase-associated lipid carrier protein (u-NGAL), cystatin C (u-CysC), retinol-binding protein (u-RBP), β2-microglobulin

u-NAG/Cr biomarker level showed a significant difference between healthy participants and people with T2DM. In the DR(–)UACR(–)group, u-Trf/Cr showed the highest positive rate (21.37%),

followed by u-IgG/Cr (14.52%); u-NAG/Cr (10.48%); u-β2MG/Cr (4.44%); u-CysC/Cr (4.03%); u-NGAL/Cr (4.03%); u-RBP/Cr (2.82%); u-α1MG/Cr (2.42%); 17.34% of people with T2DM showed multiple

biomarkers positive (≥2 biomarkers). The positive rates of one biomarker (21.33%) and two biomarkers (18.67%) in people who have less than five (5) years of T2DM were almost close to those

of the DR(–)UACR(–) group (21.37%, and 12.10%, respectively). CONCLUSION Renal tubule biomarkers may be used as an indicator in the early detection and monitoring of renal injury in diabetes

mellitus. The u-NAG biomarker should be measured for the people with T2DM of the first-time diagnosis. SIMILAR CONTENT BEING VIEWED BY OTHERS ASSESSING THE DIAGNOSTIC UTILITY OF URINARY

ALBUMIN-TO-CREATININE RATIO AS A POTENTIAL BIOMARKER FOR DIABETIC PERIPHERAL NEUROPATHY IN TYPE 2 DIABETES MELLITUS PATIENTS Article Open access 08 November 2024 URINARY NON-ALBUMIN

PROTEIN-CREATININE RATIO IS AN INDEPENDENT PREDICTOR OF MORTALITY IN PATIENTS WITH TYPE 2 DIABETES: A RETROSPECTIVE COHORT STUDY Article Open access 08 May 2024 ASSOCIATION OF URINARY

CREATININE EXCRETION AND BODY MASS INDEX WITH DIABETIC RETINOPATHY IN PATIENTS WITH TYPE 2 DIABETES Article Open access 26 July 2024 INTRODUCTION Diabetic kidney disease (DKD) is one of the

most common microvascular complications of diabetes mellitus (DM). The prevalence of DKD is reported to be about 20–40% worldwide with an increasing trend [1]. As it is deemed the main cause

of end-stage renal disease (ESRD) and increases the risk of death [2, 3], early detection and intervention are crucial [4, 5]. Although renal biopsy is often considered the gold diagnostic

standard, it is also very invasive [6]. Urinary albumin-creatinine ratio (UACR) plays an important role in the early screening of DKD. However, studies proved that even in DM patients with

normoalbuminuria, there also was a progressive decrease in eGFR [7]. Diabetic retinopathy (DR) is another microvascular complication of DM and is considered an important sign of diabetic

kidney disease [8]. At the same time, some people living with DKD are not accompanied by DR [9]. There is also increasing attention on renal tubulointerstitial injury, which may occur

earlier than glomerular damage [5, 10, 11]. In this study, we assessed the detectability and distribution of 9 urine biomarkers in people living with type 2 diabetes mellitus (T2DM), with or

without microvascular complications, aiming to discover their added utility in the earlier detection of kidney damage in addition to DR and UACR. METHODS STUDY PARTICIPANTS Between February

2021 and December 2022, 407 people with T2DM were enrolled by continuous and convenient sample collection at the Endocrinology Department of Civil Aviation General Hospital, Beijing, China.

Inclusion criteria are (1) satisfaction with the WHO diagnostic criteria for diabetes in 2021 [12], (2) 18–80 years old, and (3) completion of the examination of the retina. Exclusion

criteria are any known acute and chronic kidney diseases, allergies, connective tissue diseases, infections, tumors, ketoacidosis, and heart failure. At the same time, 112 healthy subjects

aged 18 to 80 years from the physical examination department were also enrolled to establish a normal range of any urine biomarkers. This study was conducted in accordance with the

principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Civil Aviation General Hospital (2022-L-K-53). Informed consent was obtained from all subjects.

MATERIALS AND METHODS DR was evaluated by an ophthalmologist based on the slit lamp examination and fundus photograph of the retina, according to reported guidelines [13, 14]. Urine samples

of participants were collected on the second morning after fasting. All urine samples were analyzed with an automatic biochemical analyzer (Hitachi P modular). The urine markers included:

α1-Microglobulin (u-α1MG), immunoglobulin G (u-IgG), microalbumin (u-Alb), neutrophil gelatinase-associated lipid carrier protein (u-NGAL), cysteine protease inhibitor C (u-CysC),

retinol-binding protein (u-RBP), β2-Microglobulin (u-β2MG), N-acetyl-β-D-glucosaminidase (u-NAG), transferrin (u-Trf), collagen type IV (u-Col), and urine creatinine (Cr). It has been

recognized that these biomarkers are associated with certain functions of a kidney. For example, UACR, u-Trf/Cr, and u-IgG/Cr are deemed markers of glomerular barriers. U-α1 MG/Cr, u-β2

MG/Cr, u-RBP/Cr, and u-CysC/Cr are deemed as markers of renal tubular reabsorption. U-NGAL/Cr and u-NAG/Cr are deemed markers of renal tubular epithelial cell injury. U-Col/Cr is deemed as a

marker of glomerular and tubular basement membrane. As DKD can damage glomerular barriers, the renal tubular reabsorption, renal tubular cells, and the membrane, the above-listed biomarkers

can show any abnormal situation of these functions, which may serve as an early indicator of DKD. The biomarker assays were supplied by Beijing Leadman Biochemistry Co. Ltd, and the

calibration of the testing kits has been reported in another publication [15]. The performance of the 9 urine biomarkers assays was presented in Table 1. After centrifugation, the

supernatant of urine was analyzed, and all the concentrations were calibrated by urine creatinine. STATISTICAL ANALYSIS As all variables do not follow the normal distribution, a

Mann-Whitney, or Kruskal-Wallis rank sum test was used to compare groups, and a pairwise comparison was conducted with the Benjamini-Hochberg method. Categorical variables were expressed in

terms of the number of subjects and their corresponding percentages, and an χ2 test or exact probability method was used for comparisons between groups. Statistical significance was defined

as _p_ < 0.05. The data analysis was conducted using Stata 12.0 and R software. RESULTS DISTRIBUTION OF NINE URINE BIOMARKERS IN HEALTHY INDIVIDUALS In the 112 healthy individuals, the

nine (9) urine biomarkers showed skewed distributions. The quantiles at the 2.5th, 25th, 50th, 75th, and 97.5th percentiles are presented in Table 2. The level of 97.5 percentile was taken

as the upper reference limit for each biomarker. It was considered positive if the concentration was above the upper reference limit. For UACR, the cut-off value was set at >30 mg/g [16].

THE PROPORTION OF MICROVASCULAR COMPLICATIONS IN 407 PEOPLE WITH T2DM Among the 407 people with T2DM, 248 individuals (61%) were in the group of DR(-)UACR(-), 100 individuals (25%) were in

the group of DR(–)UACR( + ), 37 individuals (9%) were in the group of DR( + )UACR(–), and 22 individuals (5%) were in the group of DR( + )UACR(+). Figure 1 illustrates a pie chart showing

the distribution of people with T2DM. The clinical characteristics of the enrolled population are shown in Supplementary Tables 1, 2. COMPARISON OF URINE BIOMARKERS AMONG DIFFERENT GROUPS

DISTRIBUTION OF URINARY BIOMARKERS AMONG DIFFERENT GROUPS Figure 2 shows the levels of glomerular and tubular injury biomarkers in each group and according to different microvascular

complications. The DR( + )UACR(+) group has a much higher level than any other group with regard to every biomarker. Compared with the levels of healthy volunteers, the DR(-)UACR(-) group

showed a significantly higher level for u-NAG/Cr, indicating that u-NAG is an earlier marker for tubular damage. Besides, the UACR(-) group showed an increasing trend for u-α1 MG/Cr and

u-NAG/Cr, with or without retinopathy. For the DR(+) group, u-RBP/Cr showed a higher level than those of the DR(-) group with the same level of UACR, which might be a potential marker for

retinopathy. THE POSITIVE RATES OF THE URINE BIOMARKERS AMONG DIFFERENT GROUPS Table 3 shows the positive rates of the nine (9) urine biomarkers among different groups. The positive rates of

eight (8) urine biomarkers were significantly higher in the UACR(+) group than those of the UACR(–) group, except for u-NGAL/Cr among DR(–) subjects. Among DR(+) subjects, only the

detection rates of u-Trf/Cr, u-IgG/Cr, and u-NAG/Cr were significantly higher in the UACR(+) group than in the UACR(–) group. Among the DR(–)UACR(–) group, the u-Trf/Cr showed the highest

positive rate (21.37%), followed by u-IgG/Cr (14.52%); u-NAG/Cr (10.48%); u-β2MG/Cr (4.44%); u-CysC/Cr (4.03%); u-NGAL/Cr (4.03%); u-RBP/Cr (2.82%); u-α1MG/Cr (2.42%); and u-Col/Cr (0.00%).

Except for u-β2MG/Cr, u-RBP/Cr, and u-CysC/Cr, there were no significant differences among the three groups in 189 subjects living with T2DM (Supplementary Table 3). The positive rate of

u-NAG/Cr was 11.27% in the non-hypertension group among the DR(-)UACR(-) group (Supplementary Table 4). MULTIPLE POSITIVE RATES OF URINE BIOMARKERS IN T2DM PATIENTS Among people of the

DR(–)UACR(–) group, 21.37% were positive for only one marker, and 17.34% showed multiple positives (≥2 biomarkers). Among the individuals with a diabetes duration of less than 5 years,

21.33% were positive for only one urine biomarker. The top three urine biomarkers that have high positive rates were u-Trf/Cr, u-NAG/Cr, and u-IgG/Cr. The DR(–)UACR(–) group surprisingly

showed the same three urine biomarkers with high positive rates. (Fig. 3, Supplementary Fig. 1). DISCUSSION The first finding of our research was the distribution of microvascular

complications in diabetes in the outpatient population. Among the enrolled outpatient population, about 61% of the people fall into the group DR(–)UACR(–), 9% fall into the group DR( + 

)UACR(–), 25% fall into the group DR(–)UACR(+), and 5% fall into the group of DR( + )UACR(+). In these outpatient populations, about 14% of DR(+) people showed significant differences in the

measured value or positive rate of urine markers regardless of the development of retinopathy, suggesting that the occurrence of retinopathy and kidney damage in people with diabetes may

not be closely associated with each other at least in certain patients. While some studies pointed out that DR and DKD might have been accompanied by and influenced each other [17, 18], our

study showed a sizable portion of people with T2DM may develop the two conditions independently from each other. Our second finding was that even in the patients having both negative values

in DR and UACR, the positive detection rate of u-NAG/Cr reached 10.48%. It has been recognized that urinary NAG, which is located on the lysosome of renal tubular epithelial cells, can

reflect the structural damage of renal tubular epithelial cells [19]. People with T2DM often have an elevated level of u-NAG/Cr possibly due to the overload burden of re-absorption, the

local inflammation injury and hypoxia, etc. These conditions might happen before the glomerular damage. A previous study also showed that the u-NAG level was proportional to non-albumin

proteinuria levels in T2DM patients with DKD even before the onset of overt albuminuria [20]. In the UACR positive group, the u-NAG/Cr positive rate was close to 40%, indicating that the

effect of diabetes on the glomeruli and tubules was independent, rather than in concert, and varied from person to person. This finding strongly suggests that it is important to include

renal tubular-related markers in the early screening of DKD. Further studies about the susceptibility of people with T2DM to glomerular or tubular injury are needed, and appropriate early

intervention strategies also need further investigation. Our third finding was that the positive rates of u-IgG/Cr were high even in the people with both negative values in DR and UACR.

Previous research suggests that the increase in urinary IgG reflects the serious damage to the glomerular basement membrane [21]. The increase in a urinary IgG excretion rate seems to

suggest a decrease in the estimated glomerular filtration rate (eGFR), which may be a marker of disease progression [22]. However, some other studies have reported that urinary IgG can rise

before the occurrence of microalbuminuria or in normal albuminuria in people with diabetes [23,24,25], which is consistent with our results. It is possible that the increase in urinary IgG

excretion may be due to selective damage to the glomerular pore size and increased intraglomerular water pressure caused by hyperglycemia [26]. As urine IgG has a higher sensitivity than

that of microalbuminuria in reflecting changes in renal hemodynamics and inflammation [27], our finding suggests that urinary IgG can also be used as an early marker of diabetic kidney

injury. Our study also showed several abnormal increases in other urine proteins, including both glomerular and tubular relative biomarkers. The data shows that urinary renal tubular

reabsorption biomarkers (such as u-α1MG/Cr, u-β2MG/Cr, u-RBP/Cr, and u-CysC/Cr) increased in the DR and UACR double negative group. This result suggests that the proximal tubule reabsorption

function may be decreased in the early stage of diabetes, which can cause a large amount of low molecular weight proteins to be present in the urine [7]. The detection rates of tubular

epithelial cell injury biomarkers (u-NGAL/Cr and u-NAG/Cr) were 4.03% and 10.48% respectively. The development of inflammation, stress, and increased reabsorption burden caused by high

glucose could worsen renal tubular lesions. These biomarkers could help to evaluate the extent of renal tubular injury [28, 29]. The management and prognosis based on these biomarkers could

be clinically significant and are worthy of further investigation. We finally found that the positive rates for certain biomarkers did not show significant differences in patients having

different years of diabetes. In both the group of diabetes with less than 5 years and other groups, it is observed that the top three biomarkers that have high positive rates were u-TRF/Cr,

u-NAG/Cr, and u-IgG/Cr. This is true even in the DR(-)UACR (-) group. (See Fig. 3, Supplementary Fig. 1) As the onset of type 2 diabetes is difficult to pinpoint precisely, it is advisable

to initiate annual testing for albuminuria and tubular injury markers at the time of diabetes diagnosis [16]. However, tubular markers might not have been frequently measured in the present

clinical work, causing their clinical significance to be underappreciated to certain degrees. We suggest that different panels of tubular biomarkers should be used for diagnosing people

living with T2DM at different diabetes duration for various purposes, to evaluate DKD more completely. The study has several limitations. Firstly, it was a cross-sectional study that adopted

continuous and convenient recruitment, and we provided the distribution of nine (9) urinary biomarkers only in people living with T2DM in a stable chronic condition. Secondly, due to

limited conditions, we did not collect detailed medication information of the participants, such as their medication history. The eGFR and HbA1c results were collected for only a small

number of participants. As a result, we were unable to thoroughly discuss any correlation among eGRF, HbA1c, and the results of nine (9) biomarkers in this study. Thirdly, we didn’t

determine the range of the sample size for this study. When planning this study, we set up a minimum threshold and then tried to enroll as many participants as possible within the period. In

addition, this is a single-center study. In summary, diabetes retinopathy and renal lesions can be independent, and even a seemingly normal UACR could not rule out retinopathy. It is

necessary to add renal tubule markers to the screening list of DKD, to fill in the gap in UACR-negative people living with T2DM. Early detection of renal tubular biomarkers is critical for

adjusting treatment strategies, safeguarding kidney functions, and improving prognosis. Detection of both glomerular and tubule biomarkers is recommended in efforts to detect DKD in the

early stages. DATA AVAILABILITY All data included in this study are shown in this article or supplementary information, any further request is available by contacting the corresponding

authors. CHANGE HISTORY * _ 24 SEPTEMBER 2024 The title of the methodology was written firstly as ‘Methods and methods’. It was changed to ‘Methods’ _ REFERENCES * Aldemir O, Turgut F, Gokce

C. The association between methylation levels of targeted genes and albuminuria in patients with early diabetic kidney disease. Ren Fail. 2017;39:597–601. Article  PubMed  PubMed Central 

CAS  Google Scholar  * Cefalu, William T, Berg, Gebel E, Saraco, Mindy, et al. Microvascular complications and foot care: standards of medical care in diabetes-2019. Diabetes Care.

2019;42:S124–S138. (42-Suppl.1). Article  Google Scholar  * Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for

2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. Article  PubMed  Google

Scholar  * Yamazaki T, Mimura I, Tanaka T, Nangaku M. Treatment of diabetic kidney disease: current and future. Diabetes Metab J. 2021;45:11–26. Article  PubMed  PubMed Central  Google

Scholar  * Jiang X, Zhang Q, Wang H-B, Cui X-F, Liu R. Associations of urinary, glomerular, and tubular markers with the development of diabetic kidney disease in type 2 diabetes patients. J

Clin Lab Anal. 2018;32:e22191. Article  PubMed  Google Scholar  * Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical manifestations of kidney disease among US

adults with diabetes, 1988–2014. JAMA. 2016;316:602–10. Article  PubMed  PubMed Central  Google Scholar  * Chen C, Wang C, Hu C, Han Y, Zhao L, Zhu X, et al. Normoalbuminuric diabetic

kidney disease. Front Med. 2017;11:310–8. Article  PubMed  Google Scholar  * Heyman SN, Raz I, Dwyer JP, Sibony RW, Lewis JB, Abassi Z. Diabetic proteinuria revisited: updated physiologic

perspectives. Cells. 2022;11:2917. Article  PubMed  PubMed Central  CAS  Google Scholar  * Kishore L, Kaur N, Singh R. Distinct biomarkers for early diagnosis of diabetic nephropathy. Curr

Diabetes Rev. 2017;13:598–605. Article  PubMed  CAS  Google Scholar  * Ix JH, Shlipak MG. The promise of tubule biomarkers in kidney disease: a review. Am J Kidney Dis. 2021;78:719–27.

Article  PubMed  PubMed Central  CAS  Google Scholar  * Fufaa GD, Weil EJ, Nelson RG, Hanson RL, Bonventre JV, Sabbisetti V, et al. Association of urinary KIM-1, L-FABP, NAG and NGAL with

incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. Diabetologia. 2015;58:188–98. Article  PubMed  CAS  Google Scholar  * Association AD. 2.

Classification and diagnosis of diabetes: standards of medical care in diabetes-2021. Diabetes care. 2021;44:S15–S33. Article  Google Scholar  * Faselis C, Katsimardou A, Imprialos K,

Deligkaris P, Kallistratos M, Dimitriadis K. Microvascular complications of type 2 diabetes mellitus. Curr Vasc Pharmacol. 2020;18:117–24. Article  PubMed  CAS  Google Scholar  * Wong TY,

Sun J, Kawasaki R, Ruamviboonsuk P, Gupta N, Lansingh VC, et al. Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screening, follow-up,

referral, and treatment based on resource settings. Ophthalmology 2018;125:1608–22. Article  PubMed  Google Scholar  * Zhang C, Xu S, Wang X. Performance evaluation of the reagents for 10

markers of renal injury in urine. Chin J Clin Lab Sci. 2022;40:763–7. CAS  Google Scholar  * Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Lernmark Å, et al. Guidelines and

recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2023;69:808–68. Article  PubMed  Google Scholar  * Ting DSW, Cheung GCM, Wong TY.

Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review. Clin Exp Ophthalmol. 2016;44:260–77. Article  PubMed  Google Scholar

  * Mima A. A narrative review of diabetic kidney disease: previous and current evidence-based therapeutic approaches. Adv Ther. 2022;39:3488–500. Article  PubMed  Google Scholar  * An C,

Akankwasa G, Liu J, Wang D, Cheng G, Zhang J, et al. Urine markers of renal tubular injury in idiopathic membranous nephropathy: A cross sectional study. Clin Chim Acta. 2019;492:7–11.

Article  PubMed  CAS  Google Scholar  * Han E, Kim M-K, Lee Y-H, Kim HS, Lee B-W. Association between nonalbumin proteinuria and renal tubular damage of N-acetyl-β-d-glucosaminidase and its

clinical relevance in patients with type 2 diabetes without albuminuria. J Diabetes Complications. 2019;33:255–60. Article  PubMed  Google Scholar  * Djukanović L, Djordjević V, Ležaić V,

Cukuranović R, Marić I, Bukvić D, et al. Urinary protein patterns in patients with Balkan endemic nephropathy. Int Urol Nephrol. 2013;45:1661–9. Article  PubMed  Google Scholar  * Berg UB,

Bohman SO, Widstam-Attorps U. Renal histological changes in relation to renal function and urinary protein excretion in IgA nephropathy. Arch Dis Child. 1991;66:593–7. Article  PubMed 

PubMed Central  CAS  Google Scholar  * Narita T, Sasaki H, Hosoba M, Miura T, Yoshioka N, Morii T, et al. Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin,

transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients. Diabetes care. 2004;27:1176–81. Article  PubMed  CAS  Google Scholar  * Meng C, Chen J, Sun X, Guan S, Zhu H, Qin

Y, et al. Urine immunoglobin G greater Than 2.45 mg/L has a correlation with the onset and progression of diabetic kidney disease: a retrospective cohort study. J Personalized Med.

2023;13:452. Article  Google Scholar  * Narita T, Fujita H, Koshimura J, Meguro H, Kitazato H, Shimotomai T, et al. Glycemic control reverses increases in urinary excretions of

immunoglobulin G and ceruloplasmin in type 2 diabetic patients with normoalbuminuria. Horm Metab Res. 2001;33:370–8. Article  PubMed  CAS  Google Scholar  * Narita T, Kitazato H, Koshimura

J, Suzuki K, Murata M, Ito S. Effects of protein meals on the urinary excretion of various plasma proteins in healthy subjects. Nephron. 1999;81:398–405. Article  PubMed  CAS  Google Scholar

  * Narita T, Hosoba M, Kakei M, Ito S. Increased urinary excretions of immunoglobulin g, ceruloplasmin, and transferrin predict development of microalbuminuria in patients with type 2

diabetes. Diabetes Care. 2006;29:142–4. Article  PubMed  CAS  Google Scholar  * Li A, Yi B, Liu Y, Wang J, Dai Q, Huang Y, et al. Urinary NGAL and RBP are biomarkers of normoalbuminuric

renal insufficiency in type 2 diabetes mellitus. J Immunol Res. 2019;2019:5063089. Article  PubMed  PubMed Central  Google Scholar  * Zhang D, Ye S, Pan T. The role of serum and urinary

biomarkers in the diagnosis of early diabetic nephropathy in patients with type 2 diabetes. PeerJ. 2019;7:e7079. Article  PubMed  PubMed Central  Google Scholar  Download references

ACKNOWLEDGEMENTS We would like to thank Director Junting Duan and her colleagues in the Endocrine Department of the Civil Aviation General Hospital for their support and assistance. FUNDING

Funding for this work was provided by the Capital Health Development Research Special Project (Grant number: 2022-2-6031) and Civil Aviation Medicine Center (General Hospital) Scientific

Research Fund-funded Project (Grant number: 202224). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Clinical Laboratory, Civil Aviation General Hospital (Peking University Civil

Aviation School of Clinical Medicine), Beijing, China Chanyuan Zhang, Xiaoqian Wang, Jing Yang, Dongfang Qin, Yin Liang & Xuejing Wang * Civil Aviation Medicine Center, Civil Aviation

Administration of China (Civil Aviation General Hospital), Beijing, China Tiebing Liu Authors * Chanyuan Zhang View author publications You can also search for this author inPubMed Google

Scholar * Tiebing Liu View author publications You can also search for this author inPubMed Google Scholar * Xiaoqian Wang View author publications You can also search for this author

inPubMed Google Scholar * Jing Yang View author publications You can also search for this author inPubMed Google Scholar * Dongfang Qin View author publications You can also search for this

author inPubMed Google Scholar * Yin Liang View author publications You can also search for this author inPubMed Google Scholar * Xuejing Wang View author publications You can also search

for this author inPubMed Google Scholar CONTRIBUTIONS XJW is responsible for the design of this study and the revision of the article. XJW has full access to the data of the study and final

responsibility for the decision to submit for publication. CYZ is responsible for specimen collection, testing, data analysis, article writing, and revision. TBL is responsible for data

analysis and article revision. XQW, JY, DFQ, and YL are responsible for collecting specimens. CORRESPONDING AUTHOR Correspondence to Xuejing Wang. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional

affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION 41387_2024_310_MOESM2_ESM.TIF Supplementary Fig 1. Positive counts for only one of the nine urinary biomarkers in four

groups. A represents diabetes duration 10 years group, B represents diabetes duration 5-10 years group, C represents diabetes duration > 10 years group, and D represents DR(-)UACR (-)

group. SUPPLEMENTARY TABLE 1. CLINICAL CHARACTERISTICS OF 407 PEOPLE WITH T2DM AMONG DIFFERENT GROUPS SUPPLEMENTARY TABLE 2. CLINICAL CHARACTERISTICS AND URINARY BIOMARKERS OF 407 PEOPLE

WITH T2DM BY UACR GROUPS SUPPLEMENTARY TABLE 3. CLINICAL CHARACTERISTICS AND URINARY BIOMARKERS OF 189 PEOPLE WITH T2DM BY EGFR GROUPS SUPPLEMENTARY TABLE 4. CLINICAL CHARACTERISTICS AND

URINARY BIOMARKERS OF 203 PEOPLE WITH T2DM BUT WITHOUT HYPERTENSION SUPPLEMENTARY TABLE 5. CLINICAL CHARACTERISTICS AND URINARY BIOMARKERS OF 204 PEOPLE WITH T2DM AND HYPERTENSION RIGHTS AND

PERMISSIONS OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any

medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The

images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not

included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly

from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Zhang, C., Liu,

T., Wang, X. _et al._ Urine biomarkers in type 2 diabetes mellitus with or without microvascular complications. _Nutr. Diabetes_ 14, 51 (2024). https://doi.org/10.1038/s41387-024-00310-5

Download citation * Received: 22 November 2023 * Revised: 18 June 2024 * Accepted: 20 June 2024 * Published: 10 July 2024 * DOI: https://doi.org/10.1038/s41387-024-00310-5 SHARE THIS ARTICLE

Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative