Advances in mass spectrometry and lipidomics techniques are providing new insights into the role of lipid metabolism in obesity and its metabolic sequelae. However, human lipidomic studies have produced inconsistent results, owing in part to the use of indirect proxy measures of obesity and insulin resistance and the relatively limited coverage of the lipidome. Here, we explored the relationship between the plasma lipidome and metabolic profiles using direct gold-standard measures of adiposity, insulin sensitivity, and insulin secretion, in addition to comprehensive lipidomic profiling (>450 species) and measurement of inflammatory cytokines and adipokines. We present new evidence showing a strong and independent positive correlation between the lysophosphatidylinositol (LPI) lipid class and insulin secretion in vivo in humans, supporting the insulinotropic effects of LPI demonstrated in mouse islets. Dihydroceramide, a sphingolipid precursor, was independently and negatively correlated with insulin sensitivity, indicating a possible upregulation in sphingolipid synthesis in obese individuals. We also show that phosphatidylethanolamine and its vinyl ether-linked (plasmalogen) derivatives correlate negatively with body fat, while dihexosylceramide correlates positively with interleukin-10. Together, these lipid classes may signify early pathogenesis toward type 2 diabetes and could serve as novel therapeutic targets or biomarkers for identification of high-risk individuals.