Ceramides Are Early Responders In Metabolic Syndrome Development In Rhesus Monkeys

Metabolic syndrome increases risk of complicating co-morbidities. Current clinical indicators reflect established metabolic impairment, preventing earlier intervention strategies. Here we show that circulating sphingolipids are altered in the very early stages of insulin resistance development. The study involved 16 overweight but healthy, euglycemic monkeys, one-half of which spontaneously developed metabolic syndrome over the course of 2 years while the other half remained healthy. As previously reported, adiposity and glycemic status were equivalent across the cohort and did not explain divergent health outcomes. Using mass spectrometry, we detected and quantified circulating ceramides and other sphingolipids in healthy and impaired animals at both time points. Several ceramides were significantly different between healthy and impaired at time of diagnosis. Correlation analysis revealed differences in the interactions among ceramides in impaired animals at diagnosis and even pre-diagnosis, when animals were clinically indistinguishable from healthy controls. Importantly, correlations between ceramides and diacylglycerols and non-esterified fatty acids were distinct for healthy and impaired states, indicative of coordinated changes in lipid handling. Impaired animals displayed extensive differences in correlations among sphingolipids even in advance of loss of insulin sensitivity. These data suggest that circulating ceramides are clinically relevant in identifying disease risk and in devising preventative strategies.