Relationship Between Insulin Sensitivity and Sphingomyelin Signaling Pathway in Human Skeletal Muscle

Abstract

In vitro studies revealed that insulin resistance might be associated with the intracellular formation of ceramide, the second messenger in the sphingomyelin signaling pathway. The aim of the present study was to examine the content and composition of fatty acids in ceramide and sphingomyelin in human muscle and to evaluate their relationships with insulin sensitivity. The study was conducted on 27 male subjects with normal glucose tolerance. Euglycemic-hyperinsulinemic clamps and biopsies of vastus lateralis muscle were performed. In 10 subjects, additional biopsies were taken after a 4-h clamp and after a clamp with concurrent Intralipid/ heparin infusion. We identified 13 ceramides and sphingomyelins according to fatty acid residues. Insulin sensitivity was related to total ceramide content (r ‫؍‬ ؊0.49, P ‫؍‬ 0.01) and to ceramide consisting of palmitic (r ‫؍‬ ؊0.48, P ‫؍‬ 0.011), palmitoleic (r ‫؍‬ ؊0.45, P ‫؍‬ 0.019), mirystic (r ‫؍‬ ؊0.42, P ‫؍‬ 0.028), and nervonic acid (r ‫؍‬ ؊0.39, P ‫؍‬ 0.047). Hyperinsulinemia did not affect estimated muscle parameters. Intralipid/heparin infusion resulted in a 24.73% decrease in insulin sensitivity (P ‫؍‬ 0.007) and a 47.81% increase in ceramide content (P ‫؍‬ 0.005). These changes were significantly related to each other (r ‫؍‬ ؊0.64, P ‫؍‬ 0.046). A relationship with the decrease in insulin sensitivity was also observed for ceramides consisting of palmitic (r ‫؍‬ ؊0.68, P ‫؍‬ 0.03) and linoleic (r ‫؍‬ ؊0.66, P ‫؍‬ 0.038) acid. Our data indicate that the sphingomyelin signaling pathway in muscle might be an important factor determining the development of insulin resistance in humans.

Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity

“…Effect of insulin on muscle ceramide content In the present study, muscle ceramide content was not influenced by stimulation with low or high insulin levels during the clamp, which is consistent with prior observations showing no effect of insulin on muscle ceramide content in human skeletal muscle [11,15,16]. Muscle ceramides are generated primarily through de novo synthesis from palmitate and serine, or through the breakdown of sphingomyelin in the membranes [22,28,29].…”

“…However, in contrast, we observed similar muscle ceramide content in endurancetrained compared with untrained normal young men [14]. Studies using lipid infusion to decrease insulin sensitivity under a euglycaemic-hyperinsulinaemic clamp have also produced conflicting results: one group observed no change in muscle ceramide levels after 6 h [15], whereas another group found that ceramide levels were increased after 4h [16]. Overall, it is not clear from the literature whether muscle ceramide content plays a major role in skeletal muscle insulin sensitivity.…”

“…In fact, a positive, albeit weak, correlation was observed between muscle ceramide concentration and insulin sensitivity, which is somewhat surprising given that two prior studies have suggested the presence of an inverse correlation between muscle ceramide content and insulin sensitivity [12,16]. Moreover, as neither low nor high insulin influenced muscle ceramide content, it seems that, in man, muscle ceramide does not play a key role in insulinmediated glucose uptake.…”

“…During insulin stimulation, plasma fatty acids are markedly decreased through insulin-induced inhibition of adipose tissue lipolysis, and de novo synthesis is therefore very limited as a result of reduced palmitate availability. When plasma NEFA levels were increased by lipid infusion during an euglycaemic-hyperinsulinaemic clamp, muscle ceramide content remained unchanged [15] or was increased [16] in healthy men. This inconsistency between studies may have been due to the somewhat higher plasma NEFA concentrations observed after lipid heparin infusion in the study by Straczkowski [16].…”

“…When plasma NEFA levels were increased by lipid infusion during an euglycaemic-hyperinsulinaemic clamp, muscle ceramide content remained unchanged [15] or was increased [16] in healthy men. This inconsistency between studies may have been due to the somewhat higher plasma NEFA concentrations observed after lipid heparin infusion in the study by Straczkowski [16]. It is not clear whether the generation of ceramide from sphingomyelin degradation in human skeletal muscle is influenced by insulin infusion and/or the ceramide degradation is influenced by insulin.…”