Type 2 diabetes mellitus (T2DM) is not simply a disorder of blood sugar control, but a condition in which multiple biochemical pathways are impacted. An illustrative example of this is the elevated blood ketone body concentration typical of T2DM, which can progress to diabetic ketoacidosis if insulin action and/or availability deteriorates.The elevations of ketone bodies and the acetone accumulation (with associated “sweet breath odor”) of severe or poorly controlled diabetes are indicative of abnormal fatty acid homeostasis and specifically, high lipolysis and hepatic β-oxidation. These observations form the basis for the perspective that a primary event on the path to T2DM development is an aberration in lipid metabolism, that is, chronic exposure of peripheral tissues, liver and pancreatic β cells to high free fatty acids. According to this view, excess free fatty acids promote tissue insulin resistance, increase hepatic glucose output and act in pancreatic β cells to trigger hyperinsulinemia in response to insulin secretagogues [1,2]. While links between altered fatty acids and T2DM-relevant metabolic phenotypes have become well accepted, the mechanisms underlying the associations remain controversial, and a great deal is yet to be learned about other pathways and fuels that contribute to or are impacted by insulin resistance and diabetes. Broad-based metabolite profiling of blood and urine using targeted and untargeted analytical platforms can be a valuable approach in this regard.
By assessing how hundreds of individual metabolites are altered in human and animal models of T2DM, prediabetes, or insulin resistance, it has become evident that these conditions are often associated with alterations in fasting blood or tissue amino acids and their derivatives, systemic bile acids, blood phospholipids, and many as-yet non-annotated “unknown” metabolites. More research is needed to determine which of 275 these metabolite factors drive disease development and progression, and which are changed in response to deterioration of metabolic homeostasis. This is important not just from the standpoint of understanding basic pathophysiology and symptom etiologies in T2DM, but also to consider if select metabolites or combinations of metabolites have prognostic utility in terms of diabetes risk or disease staging. For instance, despite the clinical utility and cost-effectiveness of blood glucose measurement to diagnose T2DM (and more recently to define prediabetes), elevated blood glucose develops quite late in disease development and progression. Metabolomics tools can move the T2DM field beyond “glucocentric” medicine, to identify earlier biomarkers of disease risk, to foster therapeutic strategies targeting novel metabolic pathways, and ultimately to thwart diabetes or limit its progression and severity. For more comprehensive analysis of “omics” applications to insulin resistance and diabetes, the interested reader is referred to several recent reviews [3–5].