Alterations in glucose and protein metabolism in animals subjected to simulated microgravity.

Reduction of physical activity due to disease or environmental restraints, such as total bed rest or exposure to spaceflight, leads to atrophy of skeletal muscle and is frequently accompanied by alterations in food intake and the concentration of metabolic regulatory hormones such as insulin. Hindlimb suspension of laboratory rats, as a model for microgravity, also shows marked atrophy of gravity dependent muscles along with a reduced gain in body weight. Suspended rats exhibit enhanced sensitivity to insulin-induced glucose uptake when compared with normal control rats and resistance to insulin action when compared with control rats matched similarly for reduced body weight gain. These changes are accompanied by decreased insulin binding and tyrosine kinase activity in soleus but not plantaris muscle, unchanged glucose uptake by perfused hindlimb and decreased sensitivity but not responsiveness to insulin-induced suppression of net proteolysis in hindlimb skeletal muscle. These findings suggest that loss of insulin sensitivity during muscle atrophy is associated with decreased insulin binding and tyrosine kinase activity in atrophied soleus muscle along with decreased sensitivity to the effects of insulin on suppressing net protein breakdown but not on enhancing glucose uptake by perfused hindlimb.

Effect of body weight gain on insulin sensitivity after retirement from exercise training.

The objectives of this study were to determine how long increased insulin sensitivity, elicited by exercise training, persists after the end of training and what the effect of weight gain is on this retention. Exercise-trained (ET) rats ran voluntarily in freely rotating wheel cages, and insulin sensitivity was assessed by oral glucose tolerance tests (OGTT) and insulin suppression tests (IST). After training, ET rats were retired for 1, 3, or 7 days (R1, R3, or R7). Initial OGTT and IST studies indicated that sensitivity to insulin-induced glucose uptake was increased in ET rats compared with sedentary control (C) rats and was progressively lost with retirement: ET greater than R1 and R3 greater than R7 and C rats, and this reaction was generally associated with a rapid gain in body weight. Subsequent IST tests were performed on C and R7 rats fed laboratory chow or a hypocaloric diet consisting of equal parts of cellulose and chow for 7 days before the test. The results of these tests showed that steady-state serum glucose (SSSG) levels averaged 165 +/- 12 mg/dl for chow-fed C rats and 172 +/- 11 mg/dl for chow-fed R7 rats that gained body weight at rates twice those of C rats. Chow-fed R7 rats, gaining weight at rates comparable to C rats, had SSSG levels of 104 +/- 6 mg/dl. C and R7 rats fed the hypocaloric diet had SSSG values of 102 +/- 6 and 59 +/- 4 mg/dl, respectively. Muscle glycogen levels were comparable in all groups, and liver glycogen was lower in C and R7 rats fed the hypocaloric diet.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of exercise training on insulin resistance in sedentary year old rats.

The purpose of this study was to determine if exercise training of 12-month-old Sprague-Dawley rats could reverse the resistance to insulin-induced glucose uptake that has been shown to occur in these animals. Twelve-month-old rats were trained to run 1 1/2 miles/day in motorized exercise wheel cages, and the ability of insulin to stimulate glucose uptake in these rats was compared with values observed in two groups of similar aged sedentary rats--one fed rat chow ad libitum and the other a calorie-restricted diet for 4 months. Body weight increased and insulin-stimulated glucose uptake decreased as rats fed chow ad libitum grew from 12 to 16 months of age. In contrast, 4 months of either exercise training or calorie restriction prevented weight gain and loss of insulin-stimulated glucose uptake. Thus, the intensity of exercise training attained in this study did not result in an improvement in insulin action in older rats above and beyond that related to the reduction in rate of body weight gain.

Spontaneous running activity in male rats: effect of age.

Alterations in the intensity and pattern of spontaneous running activity as rats increase in age from 7 wk to 1 yr was studied in male rats placed in exercise wheel cages. Daily running records were obtained on 27 rats for periods up to 12 mo, and 24-h activity recordings were made of selected runners to study the variation in activity during the day. The data indicate that for rats running over 2,940 revolutions (or 2 miles/day), the maximum intensity of running attained can be divided into a group of high achievers (approximately 8 miles/day) and moderate achievers (averaging 4.5 miles/day). For both groups, spontaneous running activity reached maximal rates after 4-5 wk. This maximal rate was sustained for 7-8 wk, then fell to levels approximately 60% of maximum for 4-5 mo, and then fell again to levels approximately 25% of maximum from 8 to 12 mo of age. The hourly pattern of running activity during the day was defined in rats of increasing age, who averaged 13,280, 6,662, 3,874, and 1,755 rev/day, corresponding to 9.0, 4.5, 2.6, and 1.2 miles/day, respectively. The overall patterns at each level indicated that the major running period occurred between 6:00 P.M. and 6:00 A.M., the greater activity of younger rats was paralleled by faster speeds and longer duration at each hour of the day, and the peak running activity for each group generally occurred between 7:00 and 9:00 P.M. In summary, there is a progressive loss in speed and duration of spontaneous running activity as male rats increase in age, with intensity of exercise falling below 2 miles/day after 7-8 mo of age.

Causes of the triglyceride-lowering effect of exercise training in rats.

Serum triglyceride (TG) levels are lower in exercise-trained (ET) compared with control rats throughout a 24-h period (P less than 0.01-0.001). To understand this phenomenon, the relationship between serum TG concentration and hepatic very low density lipoprotein (VLDL)-TG secretion rate was studied in intact rats. In addition, hepatic TG secretion was measured in isolated perfused liver and TG removal by isolated perfused hindlimbs at rest and during simulated exercise. In vivo, low TG levels are consistently associated with decreased serum insulin concentration and periodic decrease in free fatty acid (FFA) levels. At rest, with comparable FFA levels, VLDL-TG secretion was 50% lower in ET rats, proportionate to the reduction in serum TG levels. Hepatic TG secretion by perfused livers of ET and control rats was similar when studied at comparable FFA and insulin levels suggesting the fall in VLDL-TG secretion with exercise training was not the result of intrinsic change in the ability of the liver to esterify and secrete TG. Perfused muscle of ET and control rats remove TG at equal rates when perfused at rest. However, during simulated exercise, TG removal was increased only in hindlimbs from ET rats. Thus, low serum TG levels in ET rats seem to be due to a combined effect of decreased hepatic TG secretion, secondary to reduced substrate and insulin supply to the liver, and increased TG removal by muscle during exercise.

Insulin resistance in older rats.

Insulin-stimulated glucose utilization was estimated in vivo in 1.5-, 4-, and 12-mo-old rats with an insulin suppression test wherein the height of the steady-state plasma glucose ( SSPG ) concentration, at similar steady-state plasma insulin levels, provides a direct reflection of the efficiency of insulin-stimulated glucose disposal. In parallel studies, the effect of age on in vitro insulin-stimulated glucose uptake was assessed in perfused hindlimb preparations. In addition, changes in the activity of enzymes that regulate muscle glycolysis, glycogenesis, and glycogenolysis were determined in isolated soleus muscle. The results indicated that rats got heavier as they became older, and changes in weight were associated with parallel increases in mean (+/- SE) SSPG concentrations as rats grew from 1.5 (56 +/- 3 mg/dl) to 4 (172 +/- 6 mg/dl) to 12 mo of age (194 +/- 8 mg/dl). The age-related decline in in vivo insulin action was associated with a reduction in insulin action on muscle, and maximal insulin-stimulated glucose uptake by perfused hindlimbs of 12-mo-old rats was approximately 50% of the value seen with perfused hindlimbs from 1.5-mo-old rats. Soleus muscle enzyme activity also varied with age, with significant increases in glycogen synthase and decreases in glycogen phosphorylase documented. Furthermore, muscle glycogen phosphorylase activity, which fell during an insulin infusion in 1.5-mo-old rats, did not change when 12-mo-old rats were infused at comparable insulin levels. Finally, glycogen content was significantly increased (P less than 0.01) in soleus muscle from 12-mo-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of confinement in small space flight size cages on insulin sensitivity of exercise-trained rats.

Previous studies on men under conditions of total bed rest, and laboratory animals under limited physical activity, have shown resistance to insulin-induced glucose uptake and, conversely, increased sensitivity to insulin with exercise training. To determine whether the beneficial effects of exercise training on increasing insulin sensitivity are lost following end of exercise and confinement in small cages, oral glucose tolerance tests (OGTT) were given to control and exercise-trained rats before and after placement in small space flight size cages (11 X 4 X 4 1/2 in) for 7 d. The product of the area of the insulin and glucose curves of the OGTT (IG index) provides a measure of insulin resistance. Values obtained, before confinement, were one-half as high in exercise-trained rats as those in control rats (p less than 0.001), reflecting increased sensitivity to insulin with exercise training. After 7 d confinement, the IG index was not significantly different from initial values for both control and exercise-trained rats. These findings indicate that increased insulin sensitivity in exercise-trained rats persists 7 d after cessation of running activity. Furthermore, the data suggest that exercise training, before flight, may be beneficial in minimizing the loss of insulin sensitivity expected with decreased use of gravity dependent muscles during exposure to hypogravity in space flight.

Enhanced skeletal muscle insulin sensitivity in year-old rats adapted to hypergravity.

Rats adapted to hypergravity by continuous centrifugation at 4.15 g for 7 mo exhibit increased glucose uptake at lower plasma insulin levels than weight-matched control animals following oral glucose administration. To assess insulin sensitivity of specific tissues, glucose uptake by perfused skeletal muscle and liver from year-old hypergravic rats was compared with perfused tissue from weight-matched control rats (2.5-mo-old). The results show that metabolic clearance of glucose by skeletal muscle from hypergravic rats ws not significantly greater than control muscle when perfused in the absence of insulin (10.6 vs. 8.1 microliter.min-1.g muscle-1) but was twofold faster (23.0 vs. 9.5) at perfusate insulin levels of 35 microunits/ml. Conversely, glucose uptake by hypergravic livers was significantly decreased (P less than 0.001) compared with control livers (10.3 vs. 27.8) at perfusate insulin levels of 40 microunits/ml. These findings suggest that skeletal muscle rather than liver is the tissue primarily responsible for enhanced sensitivity to insulin observed in older rats adapted to hypergravity.

Site of enhanced insulin sensitivity in exercise-trained rats at rest.

Spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin and lower plasma insulin levels after oral glucose than sedentary control rats. To assess insulin sensitivity of specific organs, glucose uptake by perfused hindlimb muscle and liver from resting exercise-trained rats was compared with perfused organs from control rats. Glucose uptake, assessed by metabolic clearance formulas, was 17% faster in hindlimbs from exercise-trained rats when perfused without added insulin and 43% faster at perfusate insulin levels of 40 microU/ml. After an overnight fast, glucose clearance in exercise-trained hindlimbs increased over controls by 57% in the basal state and by 97% at low perfusate levels. In contrast, glucose clearance by livers from both fed and fasted exercise-trained rats was less than one-half that of livers from control rats. These results suggest that skeletal muscle, and not liver, is the organ primarily responsible for the increased sensitivity to insulin-induced glucose uptake with exercise training and that this response is enhanced after overnight fasting.

The site of insulin resistance in acute uremia.

In order to define the mechanism of glucose intolerance in acutely uremic rats, various studies were carried out 24 hours after bilateral nephrectomy. Glucose removal following intravenous glucose was significantly (p is less than 0.001) decreased in uremic rats compared with sham-operated rats (k = 2.1 +/- 0.03 per cent vs. 5.1 +/- 0.2 per cent). This deterioration in glucose tolerance was associated with higher insulin levels in uremic rats from one to 40 minutes after glucose administration, suggesting that insulin resistance accounted for the decrease in glucose removal by uremic rats. To identify the site of the insulin resistance, we compared the ability of insulin to enhance net glucose uptake by isolated perfused liver and muscle (hindlimb) preparations obtained from uremic and sham-operated rats. Insulin suppressed glucose outflow from perfused livers of uremic rats at least as well as it did from livers of sham-operated rats, and suppression occurred at both maximal ( greater than 600 micromicron./ml.) and threshold (75 micromicron./ml.) perfusate insulin levels. In contrast, there was a significant decrease in the ability of insulin (mean perfusate level = 225 micromicron./ml.) to enhance glucose uptake of perfused hindlimbs of uremic as compared with sham-operated rats. These results suggest that the insulin resistance of acute uremia may be due primarily to decreased insulin-mediated uptake of glucose by skeletal muscle without any decrease in sensitivity of the liver to insulin.

Insulin and glucose responses during bed rest with isotonic and isometric exercise.

The effects of daily intensive isotonic (68% maximum oxygen uptake (VO2 max)) and isometric (21% maximum extension force) leg exercise on plasma insulin and glucose responses to an oral glucose tolerance test (OGTT) during 14-day bed-rest (BR) periods were investigated in seven young healthy men. The OGTT was given during ambulatory control and on day 10 of the no-exercise, isotonic, and isometric exercise BR periods during the 15-wk study. The subjects were placed on a controlled diet (mean +/- SD = 344 +/- 34 g CHO/day and 3,073 +/- 155 (SD) kcal/day) starting 10 days before each BR period. During BR, basal plasma glucose concentration remained unchanged with no exercise, but increased (P less than 0.05) to 87-89 mg/100 ml with both exercise regimens on day 2, and then fell slightly below control levels on day 13. The fall of glucose content (-11 to -15%) during BR was independent of the exercise regimen and was an adjustment for the loss of plasma vol. The intensity of the response of insulin and glucose to the OGTT (integrated area under the curves) was inversely proportional to the total daily energy expenditure during BR; i.e., the largest response with no exercise, then isometric, isotonic, and ambulatory exercise. It was estimated that at least 1,020 kcal/day must be provided by supplemental exercise to restore the hyperinsulinemia to control levels.

Thermodynamics of aging in Drosophila melanogaster.

The data on mortality kinetics and decline in functions reported in the preceding article are used to calculate temperature coefficients for the aging process(es) in Drosophila. Different values are found, according to the model chosen to account for the mortality kinetics. The respective implications of three equally suitable models are discussed. Thus, organization parameters on two different levels can be identified: rates of changes assumed to occur at the elementary molecular level, and redundancy factors at a more integrated level. Their temperature coefficients are compared with those of protein denaturations and lipid peroxidation pigment accumulation. It is suggested that elementary molecular processes responsible for aging can indeed be protein denaturations, whereas the known lipid peroxidation pigment accumulation is more likely to be a secondary effect, resulting from a failure of the overall cellular organization at a more integrated, supramolecular, level.

Removal of insulin by perfused rat liver: effect of concentration.

The kinetics of insulin removal by isolated rat liver were investigated by measuring the rate of disappearance of insulin from the perfusate during recycling perfusion and by comparing the extraction of insulin over a wide range of constant arterial hormone levels during nonrecycling perfusion. In the recycling studies, insulin was removed from the perfusing medium at a uniform rate between 5 and 45 min. The reaction velocity constant, or hepatic clearance, during this period of uniform disappearance averaged 1.8 ml/min and represented 34% of the volume flow through the liver. In the nonrecycling flow-through studies at constant arterial insulin concentration, an initial period of accelerated hepatic uptake of insulin was seen. This period lasted for 3 to 7 min, was seen at every level of arterial insulin concentration, and was followed by a period of constant hepatic insulin removal. The hepatic removal rate during the period of constant uptake increased in a linear fashion until arterial insulin concentration reached 500 muU/ml and attained a maximal value at concentrations over 800 muU/ml. These findings indicate that the time course of hepatic insulin uptake by the perfused rat liver consists of two phases-an initial rapid phase, possibly associated with insulin binding, followed by a sustained rate of insulin removal, which probably represents insulin utilization and degradation. The rate of hepatic insulin removal was found to be proportional to arterial insulin concentration overa range of 20 to 500 muU/ML. Above this concentration, hepatic removal processes became saturated, reaching a maximal value of 183 muU of insulin per gram of liver per minute.

Insulin sensitivity of isolated perfused rat liver.

The responsiveness of the isolated perfused rat liver to different metabolic effects of insulin was investigated during recycling perfusion. Infusion of porcine insulin at rates of 6, 9, 16 and 33 mU/hr. resulted in stable perfusate insulin levels averaging 41, 72, 120 and 229 muU/ml., respectively. Since the portal vein insulin concentration in the intact rat averaged 48 muU/ml. after a twenty-six-hour fast and 125 muU/ml. two hours after removal of food, the studies were conducted at insulin levels within the physiological range. The effect of each insulin concentration on the net accumulation of K+, AMINO ACID NITROGEN, UREA NITROGEN AND GLUCOSE IN The perfusing medium was assessed against the net accumulation of perfusate constituents during perfusion of control livers and livers perfused with perfusate insulin levels greater than 500 muU/ml. The results indicate that essentially maximal suppression of amino acid nitrogen outflow and retention of K+ OCCURRED AT INSULIN CONCENTRAtions of 72 muU/ml., with lesser effects being noted at 41 muU/ml. Inhibition of ureogenesis was demonstrated at insulin levels above 120 muU/ml. However, significant effects of insulin on suppressing net glucose outflow was not observed until insulin levels had reached 500 muU/ml. due presumably to the absence of a sustained rate of glycogenolysis by control livers. The observation that perfused livers from normal rats are extremely sensitive to several metabolic effects of insulin at physiological concentrations suggests that this experimental approach can provide useful information as to the role of the liver in the pathogenesis of various insulin resistant states.

A mathematical analysis of the mortality kinetics of Drosophila melanogaster exposed to gamma radiation.

A mathematical model with nonlinear time-varying characteristics has been developed which describes the relationship between the kinetics of natural aging and radiation-induced delayed mortality. Based on this model, it appears that there is an immediate effect of radiation which is continuously, but nonlinearly, increasing in severity. Two phases appear in this variation, corresponding to the two phases (plateau and dying phase) of the mortality curves for control populations. Accordingly, S/E (survival time post-irradiation/further expectation of life) can best be interpreted as an increasing function during the plateau phase of normal mortality curves, which levels off during the ensuing dying phase.