Serum Short-Chain Fatty Acid Profiles as Metabolic Signatures of Diabetic Cognitive Impairment: Multinomial Modelling...

Diabetic cognitive impairment (DCI) is a clinically important complication of type 2 diabetes mellitus (T2DM), and circulating gut microbiota-derived short-chain fatty acids (SCFAs) may reflect metabolic-neurocognitive vulnerability. We quantified serum acetate, propionate and butyrate across healthy controls (HC), T2DM and DCI, and compared their independent associations and internally validated multiclass and pairwise discrimination, with particular focus on DCI versus T2DM.

This case-control study enrolled 180 older adults (n = 60/group). Parallel SCFA-specific multinomial models were fitted (reference: T2DM; Model 0: SCFA only; Model 1: SCFA plus covariates), and discrimination was evaluated using multiclass and pairwise ROC analyses with bootstrap internal validation (2000 resamples) to derive optimism-corrected AUCs (AUCc) with 95% CIs.

In adjusted models, acetate was associated with higher odds of HC versus T2DM (OR = 1.153, 95% CI: 1.004-1.324, p = 0.044) and lower odds of DCI versus T2DM (OR = 0.797, 95% CI: 0.650-0.977, p = 0.029). Propionate and butyrate were positively associated with HC versus T2DM but were not independently associated with DCI versus T2DM. Discrimination was modest for SCFA-only models (Hand-Till AUCc 0.585-0.629) and improved after covariate adjustment (AUCc 0.733-0.740). DCI versus T2DM remained the most challenging contrast, with acetate yielding the highest AUCc in both Model 0 and Model 1.

SCFAs, particularly acetate, may serve as adjunct biomarkers within multivariable risk profiles to support earlier identification of DCI.