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.

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.

Aims/hypothesis Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor γ, which improve wholebody insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity.Methods Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). Results DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, Diabetologia (2009) 52:941-951

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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