Metabolite Profiles of Diabetes Incidence and Intervention Response in the Diabetes Prevention Program

Diabetes. 2016 May;65(5):1424-33. doi: 10.2337/db15-1063. Epub 2016 Feb 9.


Identifying novel biomarkers of type 2 diabetes risk may improve prediction and prevention among individuals at high risk of the disease and elucidate new biological pathways relevant to diabetes development. We performed plasma metabolite profiling in the Diabetes Prevention Program (DPP), a completed trial that randomized high-risk individuals to lifestyle, metformin, or placebo interventions. Previously reported markers, branched-chain and aromatic amino acids and glutamine/glutamate, were associated with incident diabetes (P < 0.05 for all), but these associations were attenuated upon adjustment for clinical and biochemical measures. By contrast, baseline levels of betaine, also known as glycine betaine (hazard ratio 0.84 per SD log metabolite level, P = 0.02), and three other metabolites were associated with incident diabetes even after adjustment. Moreover, betaine was increased by the lifestyle intervention, which was the most effective approach to preventing diabetes, and increases in betaine at 2 years were also associated with lower diabetes incidence (P = 0.01). Our findings indicate betaine is a marker of diabetes risk among high-risk individuals both at baseline and during preventive interventions and they complement animal models demonstrating a direct role for betaine in modulating metabolic health.

Trial registration: NCT00004992.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Betaine / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Cohort Studies
  • Combined Modality Therapy
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Diet, Reducing*
  • Exercise*
  • Female
  • Follow-Up Studies
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Incidence
  • Male
  • Metformin / therapeutic use
  • Middle Aged
  • Obesity / diet therapy
  • Obesity / drug therapy
  • Obesity / physiopathology
  • Obesity / therapy*
  • Overweight / diet therapy
  • Overweight / drug therapy
  • Overweight / physiopathology
  • Overweight / therapy*
  • Risk
  • United States / epidemiology
  • Up-Regulation* / drug effects


  • Biomarkers
  • Hypoglycemic Agents
  • Betaine
  • Metformin

Associated data