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Observational experimental designs are usually employed in metabolomics to elucidate pathological mechanisms underlying disease development and to discover candidate biomarkers for diagnosis. However, intervention trials can also be a suitable starting point before performing a validation study in lager epidemiological cohorts, with a great potential in personalized medicine to investigate how different patients respond to similar stimuli. In the present work, we provide a review of the literature on the application of metabolomics to investigate metabolic alterations associated with diabetes, the diabetes predisposing state of insulin resistance and the oral glucose tolerance test as a case study to demonstrate the complementarity of observational and interventional study designs.