Systemic immune-inflammation index is associated with diabetic peripheral neuropathy: evidence from NHANES, an external clinical cohort, and exploratory human nerve gene-expression analysis.

BACKGROUND

The association between the systemic immune-inflammation index (SII) and diabetic peripheral neuropathy (DPN) remains inconsistent across studies. We investigated the association between SII and prevalent DPN across independent populations and explored complementary biological context using human sural nerve gene-expression data.

METHODS

We analyzed a discovery cohort of 555 adults with diabetes from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 and performed an exploratory targeted gene-expression analysis of human sural nerve samples from GSE95849. Findings were further evaluated in an independent hospital-based cohort of 400 patients with type 2 diabetes mellitus (T2DM), including 290 with DPN and 110 without DPN. Multivariable logistic regression, component analyses, sensitivity analyses, and restricted cubic spline models were used to evaluate the association between SII and prevalent DPN.

RESULTS

In NHANES, higher SII was inversely associated with prevalent DPN. Compared with participants in the lowest SII quartile, those in the highest quartile had lower odds of DPN (odds ratio [OR] = 0.239, 95% confidence interval [CI]: 0.102-0.560; P < 0.001). Exploratory targeted analysis of sural nerve tissue showed significantly lower BDNF expression in DPN samples than in samples from patients with diabetes without DPN (BH-adjusted P = 0.0004). JUN expression was also lower in DPN at the nominal level, but the difference did not remain statistically significant after multiple-comparison correction (BH-adjusted P = 0.0686), whereas PDGFRA expression did not differ between groups. In the external cohort, patients with DPN had lower platelet counts than those without DPN (81.6 vs. 135.9 × 109/L; P < 0.001). SII remained inversely associated with prevalent DPN after multivariable adjustment (OR = 0.396 per 100-unit increase, 95% CI: 0.304-0.516; P < 0.001). Restricted cubic spline analysis indicated a significant nonlinear association (P for nonlinearity < 0.001). Among the hematological components examined, platelet count showed the strongest and most consistent association with DPN, whereas the neutrophil-to-lymphocyte ratio (NLR) was no longer significant after mutual adjustment.

CONCLUSIONS

Lower SII was consistently associated with prevalent DPN across two independent populations, with a significant nonlinear relationship observed in the external cohort. Platelet count showed the strongest and most consistent association among the hematological components examined. Exploratory nerve-tissue gene-expression findings provide complementary biological context but do not establish a mechanistic or causal link between platelet-related hematological indices and DPN.