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

Abstract

Aims/hypothesis In skeletal muscle, ceramides may be involved in the pathogenesis of insulin resistance through an attenuation of insulin signalling. This study investigated total skeletal muscle ceramide fatty acid content in participants exhibiting a wide range of insulin sensitivities. Methods The middle-aged male participants (n = 33) were matched for lean body mass and divided into four groups: type 2 diabetes (T2D, n = 8), impaired glucose tolerance (IGT, n = 9), healthy controls (CON, n = 8) and endurancetrained (TR, n = 8). A two step (28 and 80 mU m −2 min −1 ) sequential euglycaemic-hyperinsulinaemic clamp was performed for 120 and 90 min for step 1 and step 2, respectively. Muscle biopsies were obtained from vastus lateralis at baseline, and after steps 1 and 2. Results Glucose infusion rates increased in response to insulin infusion, and significant differences were present between groups (T2D<IGT<CON<TR). At baseline, muscle ceramide content was 108 ± 7, 95 ± 6, 126 ± 12 and 156 ± 25 nmol total ceramide fatty acids/g wet weight of tissue in the T2D, IGT, CON and TR groups, respectively, and muscle ceramide content was higher (p<0.01) in the TR than the IGT group. Muscle ceramide content was not influenced by insulin infusion. Interestingly, a positive correlation (r = 0.42, p<0.05) was present between muscle ceramide content at baseline and insulin sensitivity. Conclusions/interpretation Total muscle ceramide content was similar between individuals showing marked differences in insulin sensitivity, and therefore does not seem to be a major factor in muscle insulin resistance. Furthermore, aerobic capacity does not appear to influence muscle ceramide content.

Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

“…Other lipid species such as ceramides and LCCoAs have also been implicated in causing insulin resistance in liver and skeletal muscle (29)(30)(31). However, we did not detect any correlation between hepatic ceramide or LCCoA content and insulin resistance, arguing against a major role for these lipid metabolites in the pathogenesis of hepatic insulin resistance in humans, consistent with previous animal studies (26,32). Given our findings showing important differences in the subcellular fractions of DAGs in liver and its relationship with insulin resistance, it will be of interest to apply these same subcellular fractionation methods to ceramides.…”

Fatty acid metabolism, energy expenditure and insulin resistance in muscle

“…In fact, a recent study has found that total DAG content is actually elevated in the muscle of highly insulin-sensitive endurance-trained athletes compared with the skeletal muscle of obese individuals (Amati et al 2011). Furthermore, a positive correlation between total muscle ceramide content and insulin sensitivity has been reported (Skovbro et al 2008). These data suggest a more complex role for DAG and ceramide in the regulation of insulin action (Amati et al 2011) and emphasise the importance of not only determining the total content of these lipids but also examining specific molecular species as well as their subcellular localisation, as these are likely to be critical factors that influence the relationship between lipids, insulin signalling and muscle insulin sensitivity (Bergman et al 2012).…”

Ceramide: a contributor to insulin resistance or an innocent bystander?

“…It is, of course possible that the results could have been skewed because of unidentified factors, such as prestudy differences in food intake or physical activity. However, total muscle ceramide content in obese patients with type 2 diabetes in the study by Skovbro et al [7] was approximately six times lower than that in obese patients with impaired glucose tolerance in the study by Straczkowski et al (~150 vs~900 nmol/g tissue) [8], which suggests that the different results may have been due, at least in part, to methodological problems. Moreover, ceramide, because of its highly hydrophobic nature, is confined to cell membranes, and there are ceramide rich regions within membranes (called rafts) that constitute important signalling microdomains [10].…”

“…The paper by Skovbro et al [7] in this issue of Diabetologia addresses this question. Ceramide content was measured in muscle biopsy samples taken from 33 men with a wide range of insulin sensitivities (determined by euglycaemichyperinsulinaemic clamp), ranging from very low (patients with type 2 diabetes) to very high (endurance-trained healthy men).…”