Aims/hypothesis Intramyocellular lipids, including ceramide, a second messenger in the sphingomyelin signalling pathway, might contribute to the development of insulin resistance. The aim of our study was to assess parameters of the skeletal muscle sphingomyelin signalling pathway in men at risk of developing type 2 diabetes. Methods We studied 12 lean (BMI<25 kg/m 2 ) men without a family history of diabetes (control group), 12 lean male offspring of type 2 diabetic patients, and 21 men with overweight or obesity comprising 12 with NGT (obese-NGT) and nine with IGT (obese-IGT). A euglycaemic-hyperinsulinaemic clamp and a biopsy of vastus lateralis muscle were performed. Ceramide, sphingomyelin, sphinganine and sphingosine levels and sphingomyelinase and ceramidase activities were measured in muscle. Muscle diacylglycerol and triacylglycerol levels were estimated in a subgroup of 27 men (comprising men from all the above groups). Results Compared with the control group, the lean offspring of diabetic patients and the men with overweight or obesity showed lower insulin sensitivity (all p<0.005) and a greater muscle ceramide level (all p<0.01). The obese-IGT group had lower insulin sensitivity (p=0.0018) and higher muscle ceramide (p=0.0022) than the obese-NGT group. There was lower muscle sphingosine level and alkaline ceramidase activity in offspring of diabetic patients (p=0.038 and p=0.031, respectively) and higher sphinganine level in the obese-NGT (p=0.049) and obese-IGT (p=0.002) groups than in the control group. Muscle sphingomyelin was lower (p=0.0028) and neutral sphingomyelinase activity was higher (p=0.00079) in the obese-IGT than in the obese-NGT group. Muscle ceramide was related to insulin sensitivity independently of other muscle lipid fractions. Conclusions/interpretations Ceramide accumulates in muscle of men at risk of developing type 2 diabetes.

Influence of fish oil on skeletal muscle mitochondrial energetics and lipid metabolites during high-fat diet.

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Background/Aims: Muscle bioactive lipids accumulation leads to several disorder states. The most common are insulin resistance (IR) and type 2 diabetes. There is an ongoing debate which of the lipid species plays the major role in induction of muscle IR. Our aim was to elucidate the role of particular lipid group in induction of muscle IR. Methods: The analyses were performed on muscle from the following groups of rats: 1. Control, fed standard diet, 2 HFD, fed high fat diet, 3. HFD/Myr, fed HFD and treated with myriocin (Myr), an inhibitor of ceramide de novo synthesis. We utilized [U¹³C] palmitate isotope tracer infusion and mass spectrometry to measure content and synthesis rate of muscle long-chain acyl-CoA (LCACoA), diacylglycerols (DAG) and ceramide (Cer). Results: HFD led to intramuscular accumulation of LCACoA, DAG and Cer and skeletal muscle IR. Myr-treatment caused decrease in Cer (most noticeable for stearoyl-Cer and oleoyl-Cer) and accumulation of DAG, possibly due to re-channeling of excess of intramuscular LCACoA towards DAG synthesis. An improvement in insulin sensitivity at both systemic and muscular level coincided with decrease in ceramide, despite elevated intramuscular DAG. Conclusion: The improved insulin sensitivity was associated with decreased muscle stearoyl- and oleoyl-ceramide content. The results indicate that accumulation of those ceramide species has the greatest impact on skeletal muscle insulin sensitivity in rats.

Consumption of high fat diet leads to muscle lipid accumulation which is an important factor involved in induction of insulin resistance. Ceramide is likely to partially inhibit insulin signaling cascade. The aim of this study was to examine the effect of different high fat diets on ceramide metabolism in rat skeletal muscles. The experiments were carried out on rats fed for 5 weeks: (1) a standard chow and (2) high fat diet rich in polyunsaturated fatty acids (PUFA) and (3) diet enriched with saturated fatty acids (SAT). Assays were performed on three types of muscles: slow-twitch oxidative (soleus), fast-twitch oxidative-glycolytic, and fast-twitch glycolytic (red and white section of the gastrocnemius, respectively). The activity of serine palmitoyltransferase (SPT), neutral and acid sphingomyelinase (n-and aSMase), and neutral and alkaline ceramidase (n-and alCDase) was examined. The content of ceramide, sphinganine, sphingosine, and sphingosine-1-phosphate was also measured. The ceramide content did not change in any muscle from PUFA diet group but increased in the SAT diet group by 46% and 52% in the soleus and red section of the gastrocnemius, respectively. Elevated ceramide content in the SAT diet group could be a result of increased SPT activity and simultaneously decreased activity of nCDase. Unchanged ceramide content in the PUFA diet group might be a result of increased activity of SPT and alCDase and simultaneously decreased activity of SMases. We conclude that regulation of muscle ceramide level depends on the diet and type of skeletal muscle.