Gymnastik- och idrottshögskolan, GIH

Altered ceramide accumulation contributes to skeletal muscle insulin resistance, but mechanisms underlying fibre-type-specific susceptibility remain unclear. We hypothesized that fibre-type-specific ceramide metabolism governs vulnerability to lipid-induced insulin resistance. Lipidomics and quantification of ceramide-pathway enzymes were performed in mouse skeletal muscles with distinct fibre-type composition (oxidative, mixed and glycolytic) from control-diet (n = 12) and high-fat-diet (HFD; n = 12) mice. In humans, lipidomics and enzyme profiling were done in vastus lateralis biopsies from 36 adults stratified into oxidative or glycolytic phenotypes; insulin sensitivity was determined by glucose tolerance testing. siRNA-mediated silencing of SGMS1 and SGMS2 followed by lipidomics probed sphingomyelin-ceramide cycling in human myoblasts. In mouse muscle, ceramide composition rather than total content, differed by fibre type: oxidative muscle was enriched in very-long-chain ceramides, whereas glycolytic and mixed muscles contained higher C18-ceramides, paralleled by fibre-type-specific expression of enzymes involved in de novo synthesis and sphingomyelin-ceramide cycling. HFD induced ceramide remodelling, with C18-ceramides accumulating in oxidative and mixed muscles and very-long-chain species decreasing in glycolytic muscle; among all assessed enzymes, only SGMS2 was significantly downregulated in oxidative muscle. In humans, an oxidative phenotype associated with higher very-long-chain ceramides and insulin sensitivity, whereas a glycolytic phenotype displayed higher C16-18 ceramides, higher SGMS1 and SMPD2 expression, and lower insulin sensitivity. Elastic net regression identified C16-18 ceramides and galactosylceramides as negative predictors of insulin sensitivity. SGMS2 silencing caused broader ceramide accumulation than SGMS1 silencing, supporting a central role for SGMS2-mediated sphingomyelin-ceramide cycling in limiting ceramide burden.

CONTEXT: Insulin resistance (IR) is a major risk factor for the development of several diseases that have reached epidemic proportions worldwide, including hypertension, obesity and type 2 diabetes. In many diseased states, IR is associated with fasting hyperinsulinemia/excessive glucose-stimulated insulin secretion. However, it is not known whether hyperinsulinemia precedes/leads to the natural development of IR or vice versa.

OBJECTIVE: Here, we assess the relationship between hyperinsulinemia and insulin sensitivity in a cohort of healthy young lean men and women, where IR is observed in those who exhibit a low expression of type I skeletal muscle fibers and a high resting heart rate.

METHODS: Biopsies were obtained from the vastus lateralis muscle, followed by an intravenous glucose tolerance test. Insulin secretion and whole-body insulin sensitivity were calculated.

RESULTS: In this young population of normoglycemic, glucose-tolerant individuals, insulin sensitivity was significantly and negatively associated with fasting levels of plasma insulin, as well as insulin secretion in response to glucose infusion. Surprisingly, however, all the correlations became stronger when calculated in women, but became insignificant when calculated in men. In contrast, insulin sensitivity was significantly correlated with expression of type I skeletal muscle fibers and resting heart rate to similar extents in both sexes.

CONCLUSIONS: In the natural development of IR in men, it appears that hyperinsulinemia is a compensatory adaptation to peripheral IR rather than its cause.

OBJECTIVE: Here we use skeletal muscle fiber composition to investigate whether defects in amino acid metabolism are involved in the early development of IR in healthy young individuals before onset of clinical manifestations.

DESIGN: Two groups consisting of healthy young men and women, insulin-sensitive and insulin resistant, were studied using a cross-sectional design.

METHODS: Biopsies were obtained from the vastus lateralis muscle and an intravenous glucose tolerance test was performed. Plasma and muscle tissue were analyzed by metabolomics.

RESULTS: Subjects in group 1 (n=20; age 28±5 yrs; body mass index 22.3±2.7 kg/m2) had an expression of type I muscle fibers and whole-body insulin sensitivity, respectively, of 58.8±5.7% and 1.8±0.7 units. Subjects in group 2 (n=16; age 25±6 yrs; body mass index 22.6±3.0 kg/m2) had an expression of type I muscle fibers and whole-body insulin sensitivity, respectively, of 29.8±6.6% and 0.8±0.3 units (P<0.001 vs. group 1 for both). Anserine and β-alanine contents in muscle were significantly higher and taurine lower in group 2 vs. 1, consistent with the differences in muscle fiber composition between groups. Taurine correlated well with insulin sensitivity and expression of type I muscle fibers (r=0.63; P<0.001 for both). In contrast, there were no significant differences in plasma or tissue contents of glutamine, arginine, or branch-chain amino acids between groups.

CONCLUSIONS: These data demonstrate that the early development of IR is not a consequence of defects in amino acid metabolism. Rather, defects in amino acid metabolism in diseased states are more likely a consequence of IR.

Insulin resistance (IR) is a risk factor for the development of several major metabolic diseases. Muscle fiber composition is established early in life and is associated with insulin sensitivity. Hence, muscle fiber composition was used to identify early defects in the development of IR in healthy young individuals in the absence of clinical manifestations. Biopsies were obtained from the thigh muscle, followed by an intravenous glucose tolerance test. Indices of insulin action were calculated and cardiovascular measurements, analyses of blood and muscle were performed. Whole-body insulin sensitivity (SI_galvin) was positively related to expression of type I muscle fibers (r=0.49; P<0.001) and negatively related to resting heart rate (HR, r=-0.39; P<0.001), which was also negatively related to expression of type I muscle fibers (r=-0.41; P<0.001). Muscle protein expression of endothelial nitric oxide synthase (eNOS), whose activation results in vasodilation, was measured in two subsets of subjects expressing a high percentage of type I fibers (59±6%; HR = 57±9 beats/min; SI_galvin = 1.8±0.7 units) or low percentage of type I fibers (30±6%; HR = 71±11; SI_galvin = 0.8±0.3 units; P<0.001 for all variables vs. first group). eNOS expression was: 1. higher in subjects with high type I expression; 2. almost two-fold higher in pools of type I vs. II fibers; 3. only detected in capillaries surrounding muscle fibers; and 4. linearly associated with SI_galvin. These data demonstrate that an altered function of the autonomic nervous system and a compromised capacity for vasodilation in the microvasculature occur early in the development of IR.

AIM: The purpose of this study was to 1. investigate if glucose tolerance is affected after one acute bout of different types of exercise; 2. assess if potential differences between two exercise paradigms are related to changes in mitochondrial function; and 3. determine if endurance athletes differ from nonendurance-trained controls in their metabolic responses to the exercise paradigms.

METHODS: Nine endurance athletes (END) and eight healthy nonendurance-trained controls (CON) were studied. Oral glucose tolerance tests (OGTT) and mitochondrial function were assessed on three occasions: in the morning, 14 h after an overnight fast without prior exercise (RE), as well as after 3 h of prolonged continuous exercise at 65% of VO₂ max (PE) or 5 × 4 min at ~95% of VO₂ max (HIIT) on a cycle ergometer.

RESULTS: Glucose tolerance was markedly reduced in END after PE compared with RE. END also exhibited elevated fasting serum FFA and ketones levels, reduced insulin sensitivity and glucose oxidation, and increased fat oxidation during the OGTT. CON showed insignificant changes in glucose tolerance and the aforementioned measurements compared with RE. HIIT did not alter glucose tolerance in either group. Neither PE nor HIIT affected mitochondrial function in either group. END also exhibited increased activity of 3-hydroxyacyl-CoA dehydrogenase activity in muscle extracts vs. CON.

CONCLUSION: Prolonged exercise reduces glucose tolerance and increases insulin resistance in endurance athletes the following day. These findings are associated with an increased lipid load, a high capacity to oxidize lipids, and increased fat oxidation.