Role of Increased miR-222-3p Expression in Peripheral Blood and Wound Marginal Tissues of Type 2 Diabetes Mellitus Patients with Diabetic Foot Ulcer

Abstract

Purpose

To study the correlations of miR-222-3p expression in the peripheral blood and wound marginal tissues of type 2 diabetes mellitus (T2DM) patients with the onset of diabetic foot ulcer (DFU), as well as explore the clinical value possessed by miR-222-3p in the diagnosis and treatment outcomes of DFU.

Methods

The study included 70 T2DM patients who did not suffer foot ulcers (T2DM group), 146 T2DM patients who suffered foot ulcers (DFU group), as well as 70 normal controls (NC group). Quantitative real-time PCR determined the MiR-222-3p relative expression. Clinical features and risk factors regarding DFU were assessed. Multiple stepwise logistic regression analysis assisted in confirming whether miR-222-3p expression could serve for independently predicting the risk factors for DFU. ROC curve analysis evaluated the diagnostic value exhibited by miR-222-3p level against DFU.

Results

T2DM group exhibited an obviously higher MiR-222-3p expression relative to NC group [1.98 (0.98, 3.62) vs 0.92 (0.61, 1.87)] (P < 0.01), but DFU group exhibited an obviously higher miR-222-3p expression relative to T2DM group [5.61 (1.98, 10.24) vs 1.98 (0.98, 3.62)] (P < 0.01). Besides, miR-222-3p expression presented a negative correlation with DFU healing rate (P < 0.05). According to Kaplan–Meier survival curve analysis, the group with high miR-222-3p expression showed higher unhealed DFU cumulative rate relative to the group with low expression (log-rank, P = 0.011, 0.001, respectively). Multivariate logistic regression analysis confirmed that high miR-222-3p expressions could independently predict DFU risk (OR=3.85, 95% CI 1.18~12.37, P = 0.008). According to the ROC curve analysis, the AUC of miR-222-3p specific to DFU diagnosis reached 0.803, with the best sensitivity of 95.93% and best specificity of 96.27%.

Conclusion

The increased expression of miR-222-3p in the peripheral blood of T2DM patients is closely related to the occurrence of DFU. MiR-222-3p is a biomarker with potential clinical value in diagnosing and evaluating the prognosis of DFU.

Keywords:

• miR-222-3p
• diabetic foot ulcer
• type 2 diabetes mellitus
• microRNA
• biomarker

Abbreviations

T2DM, type 2 diabetes mellitus; DFU, diabetic foot ulcer; FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin A1c; TCH, total cholesterol; TG, triacylglycerol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ALB, serum albumin; Hb, hemoglobin; WBC, white blood cell; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; P-IL-6, IL-6 level in peripheral blood; P-IL-10, IL-10 level in peripheral blood; TcPO2, transcutaneous oxygen pressure; ABI, ankle brachial index; qRT-PCR, Real-time quantitative PCR assays; T-VEGF, vascular endothelial growth factor mRNA expression in wound margin tissue; T-CD31, CD31 mRNA expression in wound margin tissue; T-IL-6, interleukin-6 mRNA expression in wound margin tissue; T-IL-10, interleukin-10 mRNA expression in wound margin tissue; MiR, MicroRNA; LPS, lipopolysaccharide; ROC, Receiver operating characteristic; AUC, area under the curves; IDSA, Infectious Disease Society of America; MPP, Mycoplasma pneumoniae pneumonia.

Data Sharing Statement

The datasets used and/or analyzed in the study can be obtained from the corresponding author on reasonable request. Inquiries for data access may be sent to: [email protected].

Ethical Approval

The study completed with the approval of the Medical Ethics Committee of the First Affiliated Hospital of Anhui Medical University (Ethics batch number P20210039), and received written informed consent from all participants. In studies involving human participants, all procedures were performed following the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Acknowledgments

We want to express our appreciation to all patients for their participation, and to all medical staff and researchers, including doctors, nurses, and researchers from the Department of Endocrinology and the Burns Department in the First Affiliated Hospital of Anhui Medical University.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This study was completed with the support from the Natural Science Foundation of Anhui Province in China (2108085MH269) and the Natural Science Research Project of Colleges and Universities in Anhui Province (KJ2021A0274). The funding body did not participate or impact the study design, data collection, analysis, and interpretation, or the manuscript writing.