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Diabetic foot ulcer (DFU), the major complication associated with diabetes mellitus, has been shown to precede amputation in up to 90% of cases. Recent data reveal that procalcitonin (PCT) is a valid marker for the diagnosis of bacterial infections compared with traditional markers like white blood cell count, C-reactive protein levels, and erythrocyte sedimentation rate in DFU patients. Furthermore, cytokines are proposed to act as modulators and mediators for the expression and release of PCT into the circulation. Hence, this preliminary study was conducted to evaluate the diagnostic accuracy of PCT compared with other traditional markers and to predict the association of PCT plasma levels with inflammatory cytokines and clinical parameters of incident diabetes among South Indian DFU subjects.There were 185 subjects with type 2 diabetes mellitus (T2DM) selected in this cross-sectional study, subdivided into three groups: group I, control/T2DM subjects free from DFU (n = 75; male, 43; female, 32); group II, T2DM subjects with noninfected DFU (n = 34; male, 19; female, 15); and group III, T2DM subjects with infected DFU (IDFU; n = 76; male, 46; female, 30). Patients with IDFU were further divided into three subgroups as per the Infectious Diseases Society of America-International Working Group on the Diabetic Foot classification criteria: grade 2 (n = 27), grade 3 (n = 38), and grade 4 (n = 11). Subjects with type 1 diabetes, gestational diabetes, pneumonia, sepsis, inflammatory bowel disease, meningitis, or hematologic diseases and those who underwent surgery in the past 2 to 3 weeks were excluded from this study. For investigation of clinical parameters, blood samples were drawn from all the study subjects; plasma samples were used for estimating PCT by the enzyme-linked immunosorbent assay method. The profiling of plasma cytokines was carried out using a multiplex bead-based assay. Data are presented as mean ± standard deviation for clinical and biochemical variables and as geometric mean with 95% confidence interval (CI) for cytokines. All analysis was done using the Statistical Package for the Social Sciences (version 20.0; IBM Corp, Armonk, NY); P < .05 was considered to be statistically significant.We found PCT to be a valid diagnostic marker for IDFU with higher sensitivity and specificity than other traditional markers. For PCT, the area under the receiver operating characteristic curve was found to be high (0.99; 95% CI, 0.96–1.0), followed by C-reactive protein levels (0.78; 95% CI, 0.65–0.81), white blood cell count (0.76; 95% CI, 0.67–0.86), and erythrocyte sedimentation rate (0.74; 95% CI, 0.68–0.80) in IDFU subjects. We found the cutoff value of ≥0.5 ng/mL to have 54% sensitivity and 100% specificity for PCT with a positive predictive value of 100% and a negative predictive value of 12% for IDFU diagnosis. Moreover, PCT circulatory levels showed a positive correlation with helper T-cell subtype 1 cytokines, such as interferon γ (r = 0.21; P = .03) and interleukin 28A (r = 0.31; P = .003), and subtype 17 cytokines, such as interleukin 29/interferon λ1 (r = 0.20; P = .037).PCT could be a valuable marker for diagnosis of T2DM patients with IDFU.We aimed to assess the diagnostic accuracy of procalcitonin (PCT) compared with other traditional markers and its association with inflammatory cytokines. The findings showed a significant difference in the levels of PCT up to sevenfold in infected diabetic foot ulcer (DFU) compared with noninfected DFU, which was better than for other traditional markers, such as C-reactive protein levels, white blood cell count, and erythrocyte sedimentation rate. Moreover, PCT was found to have positively correlated with helper T-cell subtypes 1 and 17 inflammatory cytokines. Based on our findings, we could clinically use PCT as a marker to distinguish the mild line between infected and noninfected DFUs.