Serum carbon and nitrogen stable isotopes as potential biomarkers of dietary intake and their relation with incident type 2 diabetes: the EPIC-Norfolk study(1)(2)(3)

Background: Stable-isotope ratios of carbon ((13)C/(12)C, expressed as δ(13)C) and nitrogen ((15)N/(14)N, or δ(15)N) have been proposed as potential nutritional biomarkers to distinguish between meat, fish, and plant-based foods. Objective: The objective was to investigate dietary correlates of δ(13)C and δ(15)N and examine the association of these biomarkers with incident type 2 diabetes in a prospective study. Design: Serum δ(13)C and δ(15)N (‰) were measured by using isotope ratio mass spectrometry in a case-cohort study (n = 476 diabetes cases; n = 718 subcohort) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)–Norfolk population-based cohort. We examined dietary (food-frequency questionnaire) correlates of δ(13)C and δ(15)N in the subcohort. HRs and 95% CIs were estimated by using Prentice-weighted Cox regression. Results: Mean (±SD) δ(13)C and δ(15)N were −22.8 ± 0.4‰ and 10.2 ± 0.4‰, respectively, and δ(13)C (r = 0.22) and δ(15)N (r = 0.20) were positively correlated (P < 0.001) with fish protein intake. Animal protein was not correlated with δ(13)C but was significantly correlated with δ(15)N (dairy protein: r = 0.11; meat protein: r = 0.09; terrestrial animal protein: r = 0.12, P ≤ 0.013). δ(13)C was inversely associated with diabetes in adjusted analyses (HR per tertile: 0.74; 95% CI: 0.65, 0.83; P-trend < 0.001], whereas δ(15)N was positively associated (HR: 1.23; 95% CI: 1.09, 1.38; P-trend = 0.001). Conclusions: The isotope ratios δ(13)C and δ(15)N may both serve as potential biomarkers of fish protein intake, whereas only δ(15)N may reflect broader animal-source protein intake in a European population. The inverse association of δ(13)C but a positive association of δ(15)N with incident diabetes should be interpreted in the light of knowledge of dietary intake and may assist in identifying dietary components that are associated with health risks and benefits.