Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts

Abstract

Aims/hypothesis: Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults.

Methods: NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up.

Results: Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31-1.33) and triacylglycerol within VLDL particles (OR 1.33-1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years).

Conclusions/interpretation: Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.

Keywords: Branched-chain amino acid; Isoleucine; Leucine; Metabolomics; Type 2 diabetes.

Fig. 1

Relationship between baseline circulating metabolite concentrations and risk of future type 2 diabetes. Values are ORs (95% CIs) per 1 SD log_e-transformed metabolite concentration. ORs were adjusted for sex, baseline age, BMI and fasting glucose. The results were meta-analysed for 11,896 young adults from four prospective cohorts. PG, phosphoglyceride; TG, triacylglycerol

Fig. 2

Relationship between baseline circulating lipoprotein measures and risk of future type 2 diabetes. Values are ORs (95% CIs) per 1 SD log_e-transformed metabolite concentration. ORs were adjusted for sex, baseline age, BMI and fasting glucose. The results were meta-analysed for 11,896 young adults from four prospective cohorts. ORs for the remaining 125 metabolic measures assayed are shown in ESM Fig. 2. ApoA1, apolipoprotein A1; ApoB, apolipoprotein B

Fig. 3

Relationship between baseline circulating metabolites and lipids to blood glucose measures at follow-up. The prospective associations were assessed for fasting glucose (n = 5017), 2 h glucose (n = 3028) and HOMA-IR (n = 5010). Values are β-coefficients (95% CIs) scaled to 1 SD in each of the measures of blood glucose per 1 SD log_e-transformed metabolite concentration. Associations were adjusted for sex, baseline age, BMI and fasting glucose. ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; PG, phosphoglyceride; TG, triacylglycerol