Zofia Brzezinska

Effects of Hyperinsulinemia on Muscle Fiber Composition and Capillarization in Rats

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.

Mechanism of impaired capacity for prolonged muscular work following beta-adrenergic blockade in dogs

SummaryEffect of glucose infusion on running ability was studied in dogs after beta-adrenergic blockade. Dogs pretreated with Inderal performed treadmill exercise of moderate intensity until exhaustion. The amount of work performed until exhaustion was 47.7% smaller than in control experiments without blockade. During exercise a significant decrease was found in plasma FFA, blood glucose and muscle glycogen concentration. In order to explain whether the impairment of working capacity is related to hypoglycaemia and a subsequent reduction of glucose supply to the central nervous system, intracarotid glucose infusion at a rate of 70 mg/min was given at the point of exhaustion. This infusion did not restore the working ability. The intravenous glucose infusion at a rate 45 mg/kg per min enabled the previously exhausted dogs to continue the run within 5–7 min. Subsequently they were able to run with glucose infusion at a rate 20 mg/kg per min for a long period of time until they became again exhausted.It was concluded that the impairment of working capacity is directly related to a deficiency of energy substrates available for working muscles. Although the drop in blood glucose level could be a factor forcing the dogs to stop running, the increase of glucose supply to the brain only did not restore the running ability.

Testosterone affects hormone-sensitive lipase (HSL) activity and lipid metabolism in the left ventricle

Fatty acids, which are the major cardiac fuel, are derived from lipid droplets stored in cardiomyocytes, among other sources. The heart expresses hormone-sensitive lipase (HSL), which regulates triglycerides (TG) breakdown, and the enzyme is under hormonal control. Evidence obtained from adipose tissue suggests that testosterone regulates HSL activity. To test whether this is also true in the heart, we measured HSL activity in the left ventricle of sedentary male rats that had been treated with testosterone supplementation or orchidectomy with or without testosterone substitution. Left ventricle HSL activity against TG was significantly elevated in intact rats supplemented with testosterone. HSL activity against both TG and diacylglyceride was reduced by orchidectomy, whereas testosterone replacement fully reversed this effect. Moreover, testosterone increased left ventricle free fatty acid levels, caused an inhibitory effect on carbohydrate metabolism in the heart, and elevated left ventricular phosphocreatine and ATP levels as compared to control rats. These data indicate that testosterone is involved in cardiac HSL activity regulation which, in turn, may affect cardiac lipid and carbohydrate metabolism.

Mechanism of sympathetic activation during prolonged physical exercise in dogs

It seems likely that depletion of body carbohydrates may account for the rise in the sympathetic activity during prolonged exercise, since glucose given during or before exercise reduces the increase in plasma catecholamines. The aim of the present study was to find out whether the increase in plasma noradrenaline (NA) in response to exercise can be reduced by 1. increasing of the amount of carbohydrate available for metabolism without producing hyperinsulinemia and 2. by inhibition of afferent activity from hepatic glucoreceptors. The study was performed on dogs which exercised whilst receiving either the intravenous fructose infusion (2.2 mmol/min) or a slow glucose infusion (0.25 mmol/min) which was given either via the portal or a peripheral vein. Fructose infusion reduced the muscle glycogen depletion during exercise and reduced the increase in plasma NA and glycerol concentrations without altering the blood glucose or insulin levels. The exercise-induced increases in plasma NA and gycerol concentrations were significantly smaller with intraportal than with peripheral glucose infusion but there were no differences between these two cases in the concentration of glucose in the systemic circulation. These findings indicate that the reduction of the plasma NA response to physical effort under conditions of increased carbohydrate availability cannot be attributed to the inhibitory effect of insulin on sympathetic activity and provide evidence for the participation of hepatic glucoreceptors in the control of the sympathetic activity during exercise.

Lipid peroxides production after strenuous exercise and in relation to muscle morphology and capillarization.

The antioxidative capacity of slow twitch muscle fibers has been reported to be higher than that of fast twitch ones. The purpose of this study was to relate the production of lipid peroxides during exercise to the morphology and capillarization of human muscles. Twenty‐seven healthy volunteers performed a strenuous 90‐min exercise. The content of malonyldialdehyde (MDA) in the middle portion of vastus lateralis muscle was found positively correlated with percentage and the relative cross‐sectional area of the type I of muscle fibers (r = 0.46, P < 0.05, r = 0.43, P < 0.05, respectively) but negatively with type II muscle fibers (r = ‐0.46, P < 0.05, r = ‐0.43, P < 0.05, respectively), especially type IIB. The content of MDA in the vastus lateralis muscle correlated positively with the number of capillaries around type II muscle fibers (r = 0.71, P < 0.001). It is suggested that the production of lipid peroxides parallels the exercise‐induced increase of oxygen uptake in the muscle, being highest in more oxidative and better perfused, oxygen‐consuming muscle fibers.

Role of catecholamines in thyroxine-induced changes in metabolism and body temperature during exercise in dogs

Blockade of beta receptors inhibited thyroxine-induced increases in Tre, blood FFA and LA levels during exercise in dogs.

Thyroid hormone deficiency and muscle metabolism during light and heavy exercise in dogs

Muscle glycogen, glycolytic intermediate and high energy phosphate contents were compared in 5 intact-control /C/ and thyroidectomized /THY/ dogs after 30 min treadmill exercise of low /40W/ and high /70W/ intensities. Although after the exercise of relatively low intensity the rate of glycogenolysis and muscle lactate accumulation in THY dogs exceeded those in controls, the diminished oxidative capacity in the former was inadequately compensated, resulting in lowering of APT and CrP contents. At the higher work load the latter effects were more pronounced while the rate of glycogenolysis was similar or even lower than in controls. Inadequate fuel utilization may be considered as a factor limiting ability for heavy exercise in hypothyroidism.

Physiological responses to prolonged physical exercise in dogs

1. Duration of exercise until exhaustion is significantly correlated with body weight of dogs. 2. Rectal temperature (Tre) achieved at the end of the effort depends on the resting value of Tre, but the exercise-induced increases in Tre are unrelated to the initial Tre. 3. The magnitude of exercise-induced decrease in blood glucose (BG) level is positively correlated with the resting BG level and negatively correlated with the elevations of the plasma free fatty-acid (FFA) concentration. 4. A significant positive relationship is found between the exercise-induced increases in the plasma FFA levels and noradrenalinaemia.

EFFECT OF BETA-ADRENERGIC BLOCKADE ON EXERCISE METABOLISM IN DOGS

Studies on the rBle of catecholamines in the regulation of metabolism during exercise concerned mostly their effects on the metabolism of lipids. CARLSON (1967), TROYER et al. (1966), CRONIN (1967) and MUIR et al. (1964) showed that mobilization of free fatty acids (FFA) in exercise is almost completly inhibited by drugs blocking beta-adrenergic receptors. In the present study the effect of beta-adrenergic blockade on plasma level of lactic acid, pyruvic acid, glucose and FFA was studied in dogs under two experimental conditions : short period exercise of high intensity and prolonged exercise of moderate intensity performed until exhaustion. The purpose of the study was to elucidate the rB1e of catecholamines in the regulation of metabolism in exertion both during exercise associated with a high rate of anaerobic break-down of carbohydrates and in the case when the energy required is supplied mostly by lipids. It was also attempted to explain the r61e of sympathetic nervous system in determining the capacity for prolonged running in dogs.

Sympathetic Activity During Prolonged Physical Exercise in Dogs: Control of Energy Substrate Utilization

The activation of sympathetic nervous system during exercise has been well documented [3, 8, 10, 16, 17, 20]. There are few data however on the activity of adrenergic system during prolonged muscular work. Karki [14] described distinctly increased catecholamine excretion during long-term exercise in human subjects. The studies of Juchmes et al. [13] showed that during one-hour exercise in men plasma noradrenaline (NA) increased progressively whereas, adrenaline (A) did not display a uniform pattern of response. In rats after long-term exhaustive exercise a decrease in plasma NA [6] and the depletion of catecholamine stores in the adrenal medulla [11] were described.