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.
Visfatin is associated with insulin resistance and markers of hyperandrogenism in lean PCOS patients.
Resistin is a cysteine-rich adipokine originally described as a molecular link between obesity and insulin resistance in rodents. In this study, we hypothesised that serum resistin concentrations are elevated in patients with gestational diabetes mellitus (GDM) when compared with pregnant women with normal glucose tolerance (NGT) and related to proinflammatory interleukin-6 (IL-6) and other factors conferring insulin resistance. Serum resistin and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA) in 81 women with GDM, 82 women with NGT between 24 and 31 weeks of gestation and 25 healthy non-pregnant women. Resistin concentrations were significantly higher in the GDM (21.9 [17.55-25.40] ng/ml) than in the NGT group (19.03 [15.92-23.91] ng/ml, p = 0.047), as well as in the non-pregnant women (14.8 [13.7-16.6] ng/ml, p < 0.0001). Serum IL-6 levels were elevated in the GDM (1.0 [0.7-1.5] pg/ml) as compared with the NGT group (0.8 [0.5-1.1] pg/ml, p = 0.006) and the non-pregnant controls (0.7 [0.5-1.1] pg/ml, p = 0.04). Multiple regression analysis revealed that in the pregnant women circulating resistin was related to serum IL-6 (beta = 0.33, p = 0.0004) but not to insulin or the index of insulin resistance. It is concluded that the finding of high resistin and IL-6 levels in women with gestational diabetes might confirm a role of low-grade inflammation in the pathogenesis of GDM.
In this study we measured serum concentrations of proinflammatory interleukin-6, interleukin-8, and interleukin-18 as well as anti-inflammatory interleukin-10 in 30 pregnant women with normal glucose tolerance, in 32 women with abnormal results of a 50-g glucose challenge test, and in 57 patients with gestational diabetes mellitus. Patients with gestational diabetes had significantly higher IL-6 (median 1.0 [0.7-1.5] vs. 0.7 [0.4-0.8] pg/ml, p=0.001), IL-8 (2.1 [1.1-4.2] pg/ml vs. 0.7 [0.4-0.9] pg/ml, p<0.0001), and IL-18 (249.3 [188.5-318.7] pg/ml vs. 186.7 [139.9-243.9] pg/ml, p=0.005) as well as lower IL-10 levels than healthy pregnant women (0.6 [0.5-1.5] pg/ml vs. 2.9 [1.8-3.2] pg/ml, p<0.0001). After adjusting for glucose, insulin, and BMI values, the differences in IL-8 and IL-18 became insignificant, whereas the differences in IL-6 and IL-10 levels remained highly significant (p<0.0001). The subjects with abnormal glucose challenge test results had higher IL-6 levels (0.9 [0.7-1.3] pg/ml, p=0.005) and similar levels of other cytokines as compared with the women with normal glucose tolerance. Our results suggest an impaired balance between circulating pro- and anti-inflammatory cytokines in patients with gestational diabetes; however, a significant contribution of maternal obesity to the increased levels of IL-8 and IL-18 should be underlined.
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