Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance

Abstract

OBJECTIVE-To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these plasma levels to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation of ceramides within tissues in obese and diabetic subjects has been well described.RESEARCH DESIGN AND METHODS-We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp technique and with plasma tumor necrosis factor-␣ (TNF-␣) levels, a marker of inflammation. Ceramide species (C18:1, 18:0, 20:0, 24:1, and 24:0) were quantified using electrospray ionization tandem mass spectrometry after separation with high-performance liquid chromatography. RESULTS-Insulin sensitivity (mg ⅐ kgϪ1 ⅐ min Ϫ1 ) was lower in type 2 diabetic patients (4.90 Ϯ 0.3) versus control subjects (9.6 Ϯ 0.4) (P Ͻ 0.0001). Type 2 diabetic subjects had higher (P Ͻ 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely correlated with C18:0, C20:0, C24:1, C24:0, and total ceramide (all P Ͻ 0.01). Plasma TNF-␣ concentration was increased (P Ͻ 0.05) in type 2 diabetic subjects and correlated with increased C18:1 and C18:0 ceramide subspecies.CONCLUSIONS-Plasma ceramide levels are elevated in type 2 diabetic subjects and may contribute to insulin resistance through activation of inflammatory mediators, such as TNF-␣.

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

“…For example, serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin were recently found to be positively correlated with the markers of muscle NF‐κB activation, suggesting that these specific species could activate the intracellular inflammation (Bergman et al ., 2015). Furthermore, in a previous study, the levels of C18:0, C20:0, C24:1, and total ceramides were found to be elevated in type 2 diabetic subjects compared to controls and were inversely correlated with insulin sensitivity, concluding that these species may contribute to insulin resistance through the activation of inflammatory mediators, such as TNF‐alpha (Haus et al, 2009). In addition, C16:0 and C18:0 ceramides have been mechanistically linked to systemic metabolic health in genetic models (Xia et al ., 2015) and with insulin resistance in the muscle in obesity (Coen et al ., 2010).…”

“…Our findings are substantially in keeping with a number of previous studies in animal models and humans showing that plasma levels of ceramides are increased in obesity (Samad et al ., 2006; Haus et al ., 2009; Huang et al ., 2011). In fact, obese persons frequently have lower aerobic capacity and mitochondrial dysfunction and the cause of such dysfunction is less than clear.…”

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

“…Increased caloric intake from saturated fat can activate hepatic ceramide synthesis in overweight subjects (Haus et al. 2009; Holland et al. 2011), and subsequently increase lipoprotein ceramide packaging and export (Boon et al.…”

“…These proposed mechanisms are consistent with data from several studies that have reported elevated circulating ceramide in obese adolescents, adults with type 2 diabetes, or rodents with NAFLD (Haus et al. 2009; Lopez et al. 2013; Kasumov et al.…”

“…Previous research has confirmed that C24:0 ceramide is the most abundant ceramide in circulation (Haus et al. 2009), a subspecies produced by hepatic ceramide synthase 2 (Laviad et al. 2008) and exported within liver‐derived lipoproteins (Lightle et al.…”