Strong Heart, Low Ceramides.

Abstract

Serum ceramides have emerged as potential biomarkers of insulin resistance, diabetes, and heart disease. In this issue of Diabetes , Lemaitre et al. (1) report the largest longitudinal study to date correlating sphingolipids with insulin resistance, profiling a cohort of 2,086 American Indians at high risk for diabetes. With the analytical power that derives from profiling such a large number of samples obtained at two visits, 5 years apart, the data from the Strong Heart Family Study (SHFS) revealed that several ceramide species correlated with hyperinsulinemia and the HOMA of insulin resistance (HOMA-IR) in this at-risk population. Here, we summarize these results in the context of other preclinical and clinical studies investigating roles for ceramides as drivers of cardiometabolic dysfunction. Ceramides are central intermediates in the biosynthetic pathway that produces the large family of sphingolipids, which includes more than 4,000 distinct molecular entities. Much of the complexity in the cellular sphingolipid pool derives from the large number of acyl chains that can be incorporated into the ceramide scaffold. Over the past 20 years, a large number of studies in preclinical models suggest that ceramides may be among the most pathogenic nutrient metabolites that accumulate in obesity, linking overnutrition to insulin resistance and its sequelae of comorbidities. In cultured cells or isolated tissues, ceramides inhibit insulin signaling and action and inhibit lipid oxidation (2). In rodents, numerous ceramide-lowering interventions have been shown to improve insulin sensitivity and ameliorate diabetes and cardiovascular pathologies (2). Because of these data, a handful of companies have started to develop ceramide-reducing interventions in hopes of producing insulin-sensitizing therapeutics. Despite the strongly consistent findings obtained in preclinical models, the role of ceramides in human cardiometabolic pathologies has been controversial. The debate stems largely from discordance in …