Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose

Diabetologia. 2018 Jun;61(6):1315-1324. doi: 10.1007/s00125-018-4599-x. Epub 2018 Apr 6.

Abstract

Aims/hypothesis: Identifying the metabolite profile of individuals with normal fasting glucose (NFG [<5.55 mmol/l]) who progressed to type 2 diabetes may give novel insights into early type 2 diabetes disease interception and detection.

Methods: We conducted a population-based prospective study among 1150 Framingham Heart Study Offspring cohort participants, age 40-65 years, with NFG. Plasma metabolites were profiled by LC-MS/MS. Penalised regression models were used to select measured metabolites for type 2 diabetes incidence classification (training dataset) and to internally validate the discriminatory capability of selected metabolites beyond conventional type 2 diabetes risk factors (testing dataset).

Results: Over a follow-up period of 20 years, 95 individuals with NFG developed type 2 diabetes. Nineteen metabolites were selected repeatedly in the training dataset for type 2 diabetes incidence classification and were found to improve type 2 diabetes risk prediction beyond conventional type 2 diabetes risk factors (AUC was 0.81 for risk factors vs 0.90 for risk factors + metabolites, p = 1.1 × 10-4). Using pathway enrichment analysis, the nitrogen metabolism pathway, which includes three prioritised metabolites (glycine, taurine and phenylalanine), was significantly enriched for association with type 2 diabetes risk at the false discovery rate of 5% (p = 0.047). In adjusted Cox proportional hazard models, the type 2 diabetes risk per 1 SD increase in glycine, taurine and phenylalanine was 0.65 (95% CI 0.54, 0.78), 0.73 (95% CI 0.59, 0.9) and 1.35 (95% CI 1.11, 1.65), respectively. Mendelian randomisation demonstrated a similar relationship for type 2 diabetes risk per 1 SD genetically increased glycine (OR 0.89 [95% CI 0.8, 0.99]) and phenylalanine (OR 1.6 [95% CI 1.08, 2.4]).

Conclusions/interpretation: In individuals with NFG, information from a discrete set of 19 metabolites improved prediction of type 2 diabetes beyond conventional risk factors. In addition, the nitrogen metabolism pathway and its components emerged as a potential effector of earliest stages of type 2 diabetes pathophysiology.

Keywords: Metabolomics; Normoglycaemia; Type 2 diabetes pathophysiology; Type 2 diabetes prediction.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Area Under Curve
  • Blood Glucose / metabolism*
  • Computational Biology
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Glycated Hemoglobin A / metabolism*
  • Glycine / metabolism
  • Humans
  • Incidence
  • Male
  • Mendelian Randomization Analysis
  • Metabolomics*
  • Middle Aged
  • Phenylalanine / metabolism
  • Prospective Studies
  • ROC Curve
  • Risk Factors
  • Tandem Mass Spectrometry
  • Taurine / metabolism

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Taurine
  • Phenylalanine
  • Glycine