Abstract Background The prevalence of type 2 diabetes mellitus (T2DM) varies significantly across ethnic groups. A better understanding of the mechanisms underlying the variation in different ethnic groups may help to elucidate the pathophysiology of T2DM. The present work aims to generate a hypothesis regarding “why do subjects with African background have excess burden of T2DM?”. Methods In the current study, we performed metabolite profiling of plasma samples derived from 773 subjects of three ethnic groups (Dutch with European, Ghanaian and African Surinamese background). We performed Bayesian lognormal regression analyses to assess associations between HbA1c and circulating metabolites. Results Here we show that subjects with African Surinamese and Ghanaian background had similar associations of HbA1c with circulating amino acids and triglyceride-rich lipoproteins as subjects with European background. In contrast, subjects with Ghanaian and African Surinamese background had different associations of HbA1c with acetoacetate, small LDL particle and small HDL particle concentrations, compared to the subjects with European background. Conclusions On the basis of the observations, we hypothesize that the excess burden of T2DM in subjects with African background may be due to impaired cholesterol efflux capacity or abnormal cholesterol uptake.