Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Abstract

Ceramides and sphingolipids are a family of lipid molecules that circulate in serum and accumulate in skeletal muscle, promoting insulin resistance. Plasma ceramide and dihydroceramide are related to insulin resistance, yet less is known regarding other ceramide and sphingolipid species. Despite its association with insulin sensitivity, chronic endurance exercise training does not change plasma ceramide and sphingolipid content, with little known regarding a single bout of exercise. We measured basal relationships and the effect of acute exercise (1.5 h at 50% V̇o2 max) and recovery on serum ceramide and sphingolipid content in sedentary obese individuals, endurance-trained athletes, and individuals with type 2 diabetes (T2D). Basal serum C18:0, C20:0, and C24:1 ceramide and C18:0 and total dihydroceramide were significantly higher in T2D and, along with C16:0 ceramide and C18:0 sphingomyelin, correlated positively with insulin resistance. Acute exercise significantly increased serum ceramide, glucosylceramide, and GM3 gangliosides, which largely decreased to basal values in recovery. Sphingosine 1-phosphate and sphingomyelin did not change during exercise but decreased below basal values in recovery. Serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin, but not the total concentrations of either of them, were positively correlated with markers of muscle NF-κB activation, suggesting that specific species activate intracellular inflammation. Interestingly, a subset of sphingomyelin species, notably C14:0, C22:3, and C24:4 species, was positively associated with insulin secretion and glucose tolerance. Together, these data show that unique ceramide and sphingolipid species associate with either protective or deleterious features for diabetes and could provide novel therapeutic targets for the future.

Keywords: athlete's paradox; insulin sensitivity; lipid composition; plasma biomarkers.

Fig. 1.

Concentration of serum sphingosine and sphingosine 1-phosphate (S-1-P) between groups at rest (A), total concentration during rest, exercise, and recovery (B), and change from rest to recovery by group (C). Values are means ± SE. T2D, type 2 diabetes; Ath, endurance-trained athletes. ¥Significantly different from rest; ‡significantly different from exercise.

Fig. 2.

Concentration of serum ceramide (CER) species between groups at rest (A), total concentration during rest, exercise, and recovery (B), change from rest to exercise by group (C), and change from rest to recovery by group (D). Values are means ± SE. ¥Significantly different from rest; #significantly different from athletes; §significantly different from obese.

Fig. 3.

Concentration of serum dihydroceramide (DHCER) species between groups at rest (A) and total concentration during rest, exercise, and recovery (B). Values are means ± SE. #Significantly different from athletes; §significantly different from obese.

Fig. 4.

Concentration of serum glucosylceramide (Gluccer) species between groups at rest (A), total concentration during rest, exercise, and recovery (B), and change from rest to exercise by group (C). Values are means ± SE. ¥Significantly different from rest.

Fig. 5.

Concentration of serum GM3 ganglioside species between groups at rest (A), total concentration during rest, exercise, and recovery (B), change from rest to exercise by group (C), and change from rest to recovery by group (D). Values are means ± SE. ¥Significantly different from rest; §significantly different from obese.

Fig. 6.

Concentration of serum sphingomyelin (SPM) species between groups at rest (A), total concentration during rest, exercise, and recovery (B), and change from rest to recovery by group (C). Values are means ± SE. #Significantly different from athletes; *significantly different from T2D; §significantly different from obese; ¥significantly different from rest; ‡significantly different from exercise.

Fig. 7.

Skeletal muscle protein expression for obese sedentary individuals, individuals with T2D, and Ath for IKKα Ser^176/180 phosphorylation (A) as well as the relationship of IKKα Ser^176/180 phosphorylation to serum C16:0 ceramide (B), C18:0 ceramide (C), and C18:0 sphingomyelin (D).