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

Joshua A Bell, Caroline J Bull, Marc J Gunter, David Carslake, Anubha Mahajan, George Davey Smith, Nicholas J Timpson, Emma E Vincent

Research output: Contribution to journalArticle (Academic Journal)peer-review

18 Citations (Scopus)
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Objective: Type 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 metabolomic traits across early life.

Research Design and Methods: Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoproteinsubclass-specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, others) measured at age 8y, 16y, 18y, and 25y. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent
sample of 24,925 adults.

Results: At age 8y, associations were most evident for type 2 diabetes liability (per SDhigher) with lower lipids in high-density lipoprotein (HDL) subtypes, e.g. -0.03 SD (95% CI=-0.06, -0.003) for total lipids in very-large HDL. At 16y, associations were stronger with pre-glycemic traits including citrate and with glycoprotein acetyls (0.05 SD, 95% CI=0.01, 0.08), and at 18y, associations were stronger with branched chain amino acids. At 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability.

Conclusions: Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8y, decades before the clinical onset of disease.
Original languageEnglish
Article numberdc192348
JournalDiabetes Care
Early online date28 Apr 2020
Publication statusE-pub ahead of print - 28 Apr 2020

Structured keywords

  • ICEP


  • type 2 diabetes
  • metabolism
  • genetics
  • NMR
  • epidemiology
  • Mendelian randomization


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