Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life

BackgroundType 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to detailed metabolic traits across early life.Methods and FindingsData were from up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children cohort. Linear models were used to examine effects of a genetic risk score (GRS, including 162 variants) for adult type 2 diabetes on 4 repeated measures of 229 traits from targeted nuclear magnetic resonance (NMR) metabolomics. These traits included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, inflammatory glycoprotein acetyls, and others, and were measured in childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y). For replication, two-sample Mendelian randomization (MR) was conducted using summary data from genome-wide association studies of metabolic traits from NMR in an independent sample of adults (N range 13,476 to 24,925; mean (SD) age range 23.9y (2.1y) to 61.3y (2.9y)). Among ALSPAC participants (49.7% male), the prevalence of type 2 diabetes was very low across time points (< 5 cases when first assessed at age 16y; 7 cases (0.4%) when assessed at age 25y). At age 8y, type 2 diabetes liability (per SD-higher GRS) was associated with lower lipids in high-density lipoprotein (HDL) particle subtypes – e.g. −0.03 SD (95% CI = −0.06, −0.003; P = 0.03) for total lipids in very-large HDL. At age 16y, associations remained strongest with lower lipids in HDL and became stronger with pre-glycemic traits including citrate (−0.06 SD, 95% CI = −0.09, −0.02; P = 1.41×10−03) and with glycoprotein acetyls (0.05 SD, 95% CI = 0.01, 0.08; P = 0.01). At age 18y, associations were stronger with branched chain amino acids including valine (0.06 SD; 95% CI = 0.02, 0.09; P = 1.24×10−03), while at age 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Results of two-sample MR in an independent sample of adults indicated persistent patterns of effect of type 2 diabetes liability, with higher type 2 diabetes liability positively associated with VLDL lipids and branched chain amino acid levels, and inversely associated with HDL lipids – again for large and very large HDL particularly (−0.004 SD (95% CI = −0.007, −0.002; P = 8.45×10−04) per 1 log odds of type 2 diabetes for total lipids in large HDL). Study limitations include modest sample sizes for ALSPAC analyses and limited coverage of protein and hormonal traits; insulin was absent as it is not quantified by NMR and not consistently available at each time point. Analyses were restricted to white-Europeans which reduced confounding by population structure but limited inference to other ethnic groups.ConclusionsOur results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability which precedes higher branched chain amino acid and inflammatory glycoprotein acetyl levels. This feature is apparent in childhood as early as age 8y, decades before the clinical onset of disease.Author summaryWhy was this study done?Type 2 diabetes develops for many years before diagnosis. Clinical disease is characterised by numerous metabolic perturbations that are detectable in circulation, but which of these reflect the developmental stages of type 2 diabetes – as opposed to independent causes of type 2 diabetes or markers of other disease processes – is unknown. Revealing traits specific to type 2 diabetes development could inform the targeting of key pathways to prevent the clinical onset of disease and its complications.Genetic liability to type 2 diabetes is less prone to confounding than measured type 2 diabetes or blood glucose and may help reveal early perturbations in the blood that arise in response to type 2 diabetes liability itself.What did the researchers do and find?We examined effects of genetic liability to adult type 2 diabetes, based on a genetic risk score including 162 variants, on detailed metabolic traits measured on the same individuals across four stages of early life – childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y).We found that higher type 2 diabetes liability was associated most consistently across ages with lower lipid content in certain subtypes of HDL particles. Effects were more gradual on higher lipid content in VLDL particles and on higher branched chain amino acid and inflammatory glycoprotein acetyl levels.What do these findings mean?Signs of type 2 diabetes liability are detectable in the blood in childhood, decades before the disease becomes noticeable. These signs, taken to reflect the early features of, or coincident with, disease, likely involve lower lipid content in HDL particles, followed by higher levels of branched chain amino acids and inflammation.Genetic risk scores for adult diseases can be integrated with metabolic measurements taken earlier in life to help to reveal the timing at which signs of disease liability become visible and the traits most central to its development.