Metabolite Profiles of Incident Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program

Abstract

Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET], or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions.

Figure 1

Baseline metabolites associated with decreased risk of incident diabetes in the DPP. The pooled HRs and 95% CIs are shown for baseline metabolite associations with decreased risk of incident diabetes for every 1-SD increase in metabolite concentration in the entire metabolite profiling subcohort over an average follow-up of 2.8 years. Metabolites are arranged in increasing-HR order and color coded according to FDR q value. All metabolites with FDR q < 0.05 were included. Glutamine, serine, and asparagine were previously associated with decreased risk of incident diabetes in a smaller matched case-control metabolite profiling study in the DPP. They were included in the analysis for validation but were not included in the FDR q adjustment. Association with FDR q < 0.05, lightest green; unadjusted, gray. Weighted Cox models used are adjusted for treatment group, age, sex, race/ethnicity, hypertension status, baseline FPG, and baseline BMI. Symbols represent metabolite subclasses. Phospholipid notation denotes: total number of carbon atoms:total number of double bonds.

Figure 2

Baseline metabolites associated with increased risk of incident diabetes in the DPP. The pooled HRs and 95% CIs are shown for baseline metabolite associations with increased risk of incident diabetes for every 1-SD increase in metabolite concentration in the entire metabolite profiling subcohort over an average follow-up of 2.8 years. Metabolites are arranged in increasing-HR order and color coded according to FDR q value. All metabolites with FDR q < 0.05 were included. Tyrosine, phenylalanine, glutamate, α-glycerophosphocholine, methionine sulfoxide, leucine, valine, and isoleucine were associated with increased risk of incident diabetes in a smaller matched case-control metabolite profiling study in the DPP. They were included in the analysis for validation but were not included in the FDR q adjustment. Association with FDR q < 10⁻⁵, darkest green; q < 10⁻³, medium green; q < 0.05, lightest green; unadjusted, gray. Weighted Cox models used are adjusted for treatment group, age, sex, race/ethnicity, hypertension status, baseline FPG, and baseline BMI. Symbols represent metabolite subclasses. Phospholipids notation denotes: total number of carbon atoms:total number of double bonds.

Figure 3

Treatment-specific hazard rates for incident diabetes across standardized baseline metabolite concentrations. Treatment-specific HRs for incident diabetes in ILS (●), MET (▲), and PLA (▪) are shown for an individual with metabolite value equal to the group mean. The associated curves represent the absolute risk gradient across standardized baseline metabolite concentrations. Phospholipid notation denotes total number of carbon atoms:total number of double bonds. pyrs, person-years.