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.

The muscle contents of high-energy phosphates and their derivatives [ATP, ADP, AMP, creatine phosphate (CrP), and creatine], glycogen, some glycolytic intermediates, pyruvate, and lactate were compared in 11 dogs performing prolonged heavy exercise until exhaustion (at ambient temperature 20.0 +/- 1.0 degrees C) without and with trunk cooling using ice packs. Without cooling, dogs were able to run for 57 +/- 8 min, and their rectal (Tre) and muscle (Tm) temperatures increased to 41.8 +/- 0.2 and 43.0 +/- 0.2 degrees C, respectively. Compared with noncooling, duration of exercise with cooling was longer by approximately 45% while Tre and Tm at the time corresponding to the end of exercise without cooling were lower by 1.1 +/- 0.2 and 1.2 +/- 0.2 degrees C, respectively. The muscle contents of high-energy phosphates (ATP + CrP) decreased less, the rate of glycogen depletion was lower, and the increases in the contents of AMP, pyruvate, and lactate as well as in the muscle-to-blood lactate ratio were smaller. The muscle content of lactate was positively correlated with Tm. The data indicate that with higher body temperature equilibrium between high-energy phosphate breakdown and resynthesis was shifted to the lower values of ATP and CrP and glycolysis was accelerated. The results suggest that hyperthermia developing during prolonged muscular work exerts an adverse effect on muscle metabolism that may be relevant to limitation of endurance.

The effects of testosterone on insulin sensitivity were studied in oophorectomized female rats. Euglycemic, hyperinsulinemic clamp measurement showed a marked decrease of insulin sensitivity after 48 but not 24 h of testosterone exposure, which was overcome at high insulin concentrations. Insulin stimulation of 2-deoxyglucose uptake as well as glycogen synthesis was measured in the white and red parts of the gastrocnemius, the extensor digitorum longus, and soleus muscles as well as in the liver (only glycogen synthesis). After 24 h of treatment, inhibition of both 2-deoxyglucose uptake and glycogen synthesis was found in the most insulin-sensitive muscles. After 48 h of insulin stimulation, glycogen synthesis was inhibited in all examined individual muscles (white and red parts of gastrocnemius, extensor digitorum longus, and soleus) as was the activity of the insulin-sensitive part of glycogen synthase in muscle. Inhibition of insulin-stimulated 2-deoxyglucose uptake again affected the most insulin-sensitive muscles. There was a slight but significant change of muscle fiber composition toward less long-chain myosin and more short-chain myosin-containing fibers. Serum cortisol, plasma free fatty acids, and blood glycerol did not change. It is concluded that testosterone administration in moderate doses to oophorectomized female rats is followed by a rapid deterioration of insulin sensitivity in muscle, mediated mainly by perturbations of the insulin receptor-glycogen synthesis systems apparently coinciding with changes in muscle morphology.

Statistical studies repeatedly have shown an association between systemic insulin resistance and a preponderance of highly glycolytic, relatively insulin-insensitive muscle fibers as well as a low density of muscle capillaries. The nature of the relationship between these observations is, however, not clear. Female rats were made hyperinsulinemic for 7 days by implantation of osmotic minipumps. Elevated adrenergic activity and secretion of glucocorticoids were controlled by another minipump with propranolol and adrenalectomy was controlled with glucocorticoid substitution. This resulted in hyperinsulinemia and moderate hypoglycemia, the latter probably counteracted by overeating and increased glucagon secretion, as indicated by increased body weight and lower liver glycogen contents, respectively. Systemic insulin sensitivity was increased and measured with a hyperinsulinemic-euglycemic clamp technique. This was paralleled by an elevated glucose utilization estimated as uptake of 2-deoxyglucose in parametrial, retroperitoneal, and inguinal adipose tissues and the soleus and extensor digitorum longus muscles. Glycogen synthesis was also elevated in the soleus muscle. Muscle fiber composition changed with hyperinsulinemia and elevated 2-deoxyglucose uptake toward more fast-twitch, type II, particularly type IIb fibers, whereas the proportion of slow-twitch, type I fibers, diminished. Capillary density was elevated per unit muscle surface area as well as per muscle fiber. This was paralleled by increased insulin sensitivity systemically and in muscles. These results suggest that muscle fiber composition alterations may be a consequence rather than a cause of hyperinsulinemia and that capillarization rather than fiber composition is of importance for insulin sensitivity in muscle.

1. Plasma catecholamine, haemodynamic and metabolic responses to sustained isometric exercise were studied in eight healthy subjects, who maintained handgrip at the 30% level of maximal voluntary contraction (MVC) for as long as possible.2. The sustained handgrip was accompanied by a significant increase in plasma noradrenaline (NA) and adrenaline (A) concentrations.3. The increase in plasma NA during handgrip was greater than that associated with heavy dynamic work involving large muscle groups.4. The results suggest that the known haemodynamic responses to static effort are related to a powerful activation of the adrenergic system, which may result from a reflex mechanism initiated in the exercising muscles.Key words : static efforts, plasma catecholamines, activation of adrenergic system, haemodynamic responses to sustained handgrip.Sustained, static muscular efforts are known to produce significant haemodynamic responses. These responses occur even with exercise performed by small muscle groups provided that the isometric contraction is sufficiently strong. Sustained isometric handgrip exercise lasting 5-6 min causes significant increases in systolic, diastolic and mean arterial blood pressure, skin blood flow, heart rate and cardiac output with a small decrease in stroke volume (