Higher plasma levels of certain short-chain fatty acids may be early biomarkers of type 2 diabetes risk, according to findings from a prospective study.
Investigators followed 2241 adults without diabetes at baseline in this nationwide, population-based study using cluster sampling from the Spanish population aged older than 18 years. Participants underwent physical examination, completed dietary assessments, and provided fasting blood samples for metabolic analysis. Plasma concentrations of four short-chain fatty acids (SCFAs)—acetate, propionate, butyrate, and isobutyrate—were measured using gas chromatography–mass spectrometry.
Over a median follow-up of 7 years, 149 participants (6.6%) developed type 2 diabetes (T2D). Baseline concentrations of butyrate (12.3 vs 11.4 μmol/L; P = .040) and isobutyrate (0.96 vs 0.90 μmol/L; P = .004) were significantly higher in participants who later developed diabetes compared with those who did not. These associations remained statistically significant after adjustment for age, sex, obesity, hypertension, dyslipidemia, family history of T2D, and prediabetes, with odds ratios of 1.03 (95% CI, 1.01-1.07; P = .037) for butyrate and 1.9 (95% CI, 1.2-3.1; P = .009) for isobutyrate.
The predictive performance of SCFAs was evaluated in comparison with conventional clinical risk models and the Finnish Diabetes Risk Score (FINDRISK). A reference model incorporating clinical risk factors yielded a C-statistic of 0.840 (95% CI, 0.807-0.873). Addition of butyrate increased the C-statistic to 0.847 (95% CI, 0.816-0.877); addition of isobutyrate increased it to 0.843 (95% CI, 0.812-0.875). Both models outperformed the FINDRISK (C-statistic, 0.785; 95% CI, 0.746-0.823), although improvements beyond the clinical model alone were modest and not statistically significant by net reclassification improvement or integrated discrimination improvement metrics.
Circulating SCFAs were positively associated with dietary intake of high-fiber foods, including fruits, vegetables, legumes, whole grains, and potatoes. However, neither high-fiber consumption nor adherence to a Mediterranean diet independently predicted incident T2D in the overall cohort.
In sensitivity analyses excluding 267 individuals with prediabetes at baseline, 69 of 1974 participants (3.5%) developed T2D. In this subgroup, high-fiber food intake was inversely associated with T2D risk, and associations between SCFA levels and incident diabetes became stronger. These findings suggest metabolic differences between normoglycemic and prediabetic individuals may influence SCFA effects.
Although SCFAs are generally considered metabolically beneficial, the authors noted that elevated circulating levels might reflect altered intestinal permeability, dysbiosis, or other maladaptive processes in individuals at increased risk for diabetes. Thus, butyrate and isobutyrate may serve as early markers of systemic metabolic dysfunction.
The study authors reported that SCFAs may serve as biomarkers for diabetes risk stratification. They suggested that future research should examine whether dietary or microbiota-targeted interventions influence SCFA profiles and diabetes incidence.
The authors reported no competing interests.
Source: BMC Medicine