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Predicting the risk of developing DPN is important for clinical decision-making and designing clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We retrospectively reviewed the data of 1278 patients with diabetes treated in two central hospitals from 2020 to 2022. The\u00a0data included medical history, physical examination, and biochemical index test results. After feature selection and data balancing, the cohort was divided into training and internal validation datasets at a 7:3 ratio. Training was made in logistic regression, k-nearest neighbor, decision tree, naive bayes, random forest, and extreme gradient boosting (XGBoost) based on machine learning. The k-fold cross-validation was used for model assessment, and the accuracy, precision, recall, F1-score, and the area under the receiver operating characteristic curve (AUC) were adopted to\u00a0validate the models\u2019 discrimination and clinical practicality. The SHapley Additive exPlanation (SHAP) was used to interpret the best-performing model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The XGBoost model outperformed other models, which had an accuracy of 0\u00b7746, precision of 0\u00b7765, recall of 0\u00b7711, F1-score of 0\u00b7736, and AUC of 0\u00b7813. The\u00a0SHAP results indicated that age, disease duration, glycated hemoglobin, insulin resistance index, 24-h urine protein quantification, and urine protein concentration were risk factors for DPN, while the ratio between 2-h postprandial C-peptide and fasting C-peptide(C2\/C0), total cholesterol, activated partial thromboplastin time, and creatinine were protective factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The machine learning approach helped established a DPN risk prediction model with good performance. 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