Individuals with Type 1 Diabetes Mellitus (T1DM) can develop insulin resistance. Regular exercise may improve insulin resistance partially through increased expression of skeletal muscle GLUT4 content.

To examine if different exercise training modalities can alter glucose tolerance through changes in skeletal muscle GLUT4 content in T1DM rats.

Fifty rats were divided into 5 groups; control, diabetic control, diabetic resistance exercised, and diabetic high and low intensity treadmill exercised. Diabetes was induced using multiple low dose Streptozotocin (20 mg/kg/day) injections and blood glucose concentrations were maintained moderately hyperglycemic through subcutaneous insulin pellets. Resistance trained rats climbed a ladder with incremental loads, while treadmill trained rats ran on a treadmill at 27 or 15 m/min, respectively, all for 6 weeks.

At weeks 3 and 6, area under the curve measurements following an intravenous glucose tolerance test (AUC-IVGTT) in all diabetic groups were higher than control rats (p<0.05). At 6 weeks, all exercise groups had significantly lower AUC-IVGTT values than diabetic control animals (p<0.05). Treadmill trained rats had the lowest insulin dose requirement of the T1DM rats and the greatest reduction in insulin dosage was evident in high intensity treadmill exercise. Concomitant with improvements in glucose handling improvements, tissue-specific elevations in GLUT4 content were demonstrated in both red and white portions of vastus lateralis and gastrocnemius muscles, suggesting that glucose handling capacity was altered in the skeletal muscle of exercised T1DM rats.

These results suggest that, while all exercise modalities can improve glucose tolerance, each mode leads to differential improvements in insulin requirements and protein content alterations.

Nutrient intake is accompanied by increases in central sympathetic outflow, a response that has been mainly attributed to insulin. Insulin-mediated sympathoexcitation appears to be blunted in insulin-resistant conditions, suggesting that aside from peripheral insulin insensitivity, such conditions may also impair the central action of insulin in mediating sympathetic activation. What remains unclear is whether an insulin-sensitive state, such as that induced by chronic endurance training, alters the central sympathetic effects of insulin during postprandial conditions. To examine this question plasma insulin and glucose, muscle sympathetic nerve activity (MSNA), heart rate, and arterial blood pressure were measured in 11 high-fit [HF; peak oxygen uptake (V(O(2peak))) 65.9 +/- 1.4 ml x kg(-1) x min(-1)] and 9 average-fit (AF; V(O(2peak)) 43.6 +/- 1.3 ml x kg(-1) x min(-1)) male subjects before and for 120 min after ingestion of a mixed meal drink. As expected, the insulin response to meal ingestion was lower in HF than AF participants (insulin area under the curve(0-120): 2,314 +/- 171 vs. 4,028 +/- 460 microIU x ml(-1) x 120(-1), HF vs. AF, P < 0.05), with similar plasma glucose responses between groups. Importantly, following consumption of the meal, the HF subjects demonstrated a greater rise in MSNA compared with the AF subjects (e.g., 120 min: Delta21 +/- 1 vs. 8 +/- 3 bursts/100 heart beats, HF vs. AF, P < 0.05). Furthermore, when expressed relative to plasma insulin, HF subjects exhibited a greater change in MSNA for any given change in insulin. Arterial blood pressure responses following meal intake were similar between groups. Collectively, these data suggest that, in addition to improved peripheral insulin sensitivity, endurance training may enhance the central sympathetic effect of insulin to increase MSNA following consumption of a mixed meal.

The aim of the study was to explore the effect of lactate on insulin-stimulated glucose uptake in rats. Thirty Wistar rats, weighing 250 - 300 g. were arbitrarily divided into one of three groups (n =10): insulin (1 IU/kg) treated group, lactate (80 mg/kg), and insulin plus lactate treated groups. Blood glucose levels were measured in venous samples collected from the tail vein over 3 hour period after insulin or/and lactate administration in 30-minute intervals. To estimate the influence of lactate on insulin blood level, a total of 20 rats were divided into 4 groups (n = 5): saline, insulin, lactate, and insulin plus lactate treated group, respectively. Sixty minutes after the appropriate application of the same doses of insulin, lactate, and lactate plus insulin, as in the previous part of the experiment, plasma insulin and blood glucose levels were determined in blood samples drawn from the abdominal aorta. Lactate in combination with insulin, in comparison to insulin application alone, caused a dramatic increase in plasma insulin level (p<0,001) and more profound hypoglicaemia (p<0,001). The results of this investigation indicate that lactate application significantly increases the rate of glucose uptake from peripheral blood caused by exogenous insulin action. The possible involvement of lactate in the mechanism of enhanced glucose uptake due to insulin action after physical exercise is discussed.

For many years the reduction in the dietary fat has been recommended to the population, in order to prevent cardiovascular diseases, obesity, type 2 diabetes mellitus, among other chronic diseases. The consequence has been the replacement of carbohydrates by fat, resulting in the adoption of high carbohydrate diets. However, it has been still discussed if very rich carbohydrate diets should be recommended to the general population. Researches point out controversies about the association between these dietary habits and harmful effects on health and metabolic aspects, such as raise in de novo lipogenesis and triglyceride concentration, reduction in HDL concentration and effects on adiposity. This review evaluates the effects of diet modification, particularly the high-carbohydrate diet, in cardiovascular risk factors such as dyslipidemia and obesity. It also reviews its interaction with physical activity since it is still unknown with which extension it can minimize possible harmful effects of high carbohydrate diets in the long term.

Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APCMin) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise x sex interaction on polyp development and to begin to look at potential mechanisms.

Six-week-old APCMin mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m.min-1, 5% grade, 45 min.d-1, 5 d.wk-1 (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0-3), followed by treadmill running weeks 3-8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice.

EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 +/- 0.7, mean +/- SE) versus CON males (5.2 +/- 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 +/- 0.5 in EX; P = 0.01).

Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APCMin mice.

Insulin resistance of skeletal muscle glucose transport is a key defect in the development of impaired glucose tolerance and Type 2 diabetes. It is well established that both an acute bout of exercise and chronic endurance exercise training can have beneficial effects on insulin action in insulin-resistant states. This review summarizes the present state of knowledge regarding these effects in the obese Zucker rat, a widely used rodent model of obesity-associated insulin resistance, and in insulin-resistant humans with impaired glucose tolerance or Type 2 diabetes. A single bout of prolonged aerobic exercise (30-60 min at approximately 60-70% of maximal oxygen consumption) can significantly lower plasma glucose levels, owing to normal contraction-induced stimulation of GLUT-4 glucose transporter translocation and glucose transport activity in insulin-resistant skeletal muscle. However, little is currently known about the effects of acute exercise on muscle insulin signaling in the postexercise state in insulin-resistant individuals. A well-established adaptive response to exercise training in conditions of insulin resistance is improved glucose tolerance and enhanced skeletal muscle insulin sensitivity of glucose transport. This training-induced enhancement of insulin action is associated with upregulation of specific components of the glucose transport system in insulin-resistant muscle and includes increased protein expression of GLUT-4 and insulin receptor substrate-1. It is clear that further investigations are needed to further elucidate the specific molecular mechanisms underlying the beneficial effects of acute exercise and exercise training on the glucose transport system in insulin-resistant mammalian skeletal muscle.

To investigate whether regular endurance-type exercise can benefit rats submitted to a model of ovariectomy (OVX)-induced obesity with or without estrogen replacement.

OVX Sprague-Dawley rats were compared to an ovariectomized-estradiol-treated group (OVXE2) and a Sham-operated (Sham) group. Each of these groups were subdivided into a sedentary and a treadmill-trained (8 wk) group.

An experimental study in which various parameters, including fat depots, blood lipids and several organ weights were measured.

Plasma levels of 17beta-estradiol and uterus weights were significantly (P<0.05) lower in OVX compared to Sham and significantly (P<0.01) higher in OVXE2 (hyperestrogenic) compared to Sham rats. Body weights were significantly (P<0.01) different among groups, in the following decreasing order: OVX, Sham and OVXE2. The average daily food intake and food efficiency were significantly (P<0.01) increased in OVX compared to Sham, whereas estradiol treatment diminished this effect (P<0.01). Exercise training did not alter any of the above-mentioned variables in any of the three estrogen groups. Mesenteric and subcutaneous fat weights were significantly (P<0.01) increased by OVX. This increase was abolished by estrogen replacement or by exercise training. Exercise training also decreased fat weights in OVXE2 and Sham rats. OVX resulted in a decrease in the weights of several other tissues (femur, heart, lungs, liver and adrenal glands) while hyperestrogenic replacement resulted in an increase in weight of all measured tissues. Aside from fat depots, exercise training did not affect any of the tissue weights with the exception for an increase in the weight of the plantaris muscle and adrenal glands and a decrease in lung weight in all three estrogen groups.

In OVX animals, exercise training may bring about positive changes in body composition (ie reduction in fat weights) despite an ovariectomy-induced increase in body weight.

We have recently demonstrated (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ, J Appl Physiol 91: 145-153, 2001) that exercise training (ET) and the antioxidant R-(+)-alpha-lipoic acid (R-ALA) interact in an additive fashion to improve insulin action in insulin-resistant obese Zucker (fa/fa) rats. The purpose of the present study was to assess the interactions of ET and R-ALA on insulin action and oxidative stress in a model of normal insulin sensitivity, the lean Zucker (fa/-) rat. For 6 wk, animals either remained sedentary, received R-ALA (30 mg. kg body wt(-1). day(-1)), performed ET (treadmill running), or underwent both R-ALA treatment and ET. ET alone or in combination with R-ALA significantly increased (P < 0.05) peak oxygen consumption (28-31%) and maximum run time (52-63%). During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose response (17-36%) at 15 min relative to R-ALA alone and of the insulin response (19-36%) at 15 min compared with sedentary controls. Insulin-mediated glucose transport activity was increased by ET alone in isolated epitrochlearis (30%) and soleus (50%) muscles, and this was associated with increased GLUT-4 protein levels. Insulin action was not improved by R-ALA alone, and ET-associated improvements in these variables were not further enhanced with combined ET and R-ALA. Although ET and R-ALA caused reductions in soleus protein carbonyls (an index of oxidative stress), these alterations were not significantly correlated with insulin-mediated soleus glucose transport. These results indicate that the beneficial interactive effects of ET and R-ALA on skeletal muscle insulin action observed previously in insulin-resistant obese Zucker rats are not apparent in insulin-sensitive lean Zucker rats.

This study was undertaken to evaluate the effects of regular endurance-type exercise on glucose tolerance and glucose-stimulated insulin response (GSIR) in ovariectomized (OVX) rats with and without estrogen replacement. To do that, OVX Sprague-Dawley rats were compared with an OVX estradiol-treated group (OVXE2) and a sham-operated (Sham) group. Each of these groups was subdivided into a sedentary and a treadmill-trained (8 wk) group. Intravenous glucose tolerance tests (0.5 g/kg) were conducted in all rats 48 h after the last training session. Plasma levels of 17beta-estradiol and the uterus weight were significantly (P < 0.05) lower in OVX compared with results in Sham and significantly (P < 0.01) higher in OVXE2 (hyperestrogenic) compared with results in Sham. Body weights were significantly (P < 0.01) different among groups, in the following decreasing order: OVX, Sham, and OVXE2. The average daily food intake was significantly (P < 0.01) increased in OVX rats compared with Sham, whereas estradiol treatment diminished this effect (P < 0.01). Exercise training was found to alter none of the above-mentioned variables in all three experimental conditions. Although the mean integrated area under the glucose and insulin curves was not affected by OVX, training induced a significant (P < 0.01) reduction in the mean integrated area under the insulin curve in all three experimental conditions. It is concluded that the positive effects of physical training on improving GSIR in OVX and hyperestrogenic animals are similar to what has been found in Sham.

The purpose of the present investigation was to evaluate the effects of an acute hepatic vagotomy on hormonal responses to hyperglycemic and hypoglycemic challenges in rats previously submitted to an exercise protocol. Two experiments were conducted. In a first experiment, 8-week trained (TR) and untrained (UNTR) rats, subdivided into acutely hepatic vagotomized (HV) and sham-operated (SHM) groups, were submitted to an intraperitoneal glucose tolerance test (0.5 g/kg) under anesthesia. Training was associated with a tendency (P = 0.07) for blood glucose levels to be less elevated (at time point 10 min), and with a significant (P < 0.01) lower glucose/insulin ratio following the glucose injection. The HV did not have any effects on these responses. In a second experiment, non-exercised rats and a group of rats submitted to an acute bout of exercise (treadmill, 60 min, 26 m/min, 5% slope) 24 h before the experiment, each one of these two groups being subdivided into acutely HV and SHM groups, were submitted to an insulin-induced hypoglycemia protocol, under anesthesia. Blood glucose concentrations were decreased significantly (P < 0.01) to approximately 40 mg/dl in all groups 60 and 80 min after the insulin injection. Plasma adrenaline and noradrenaline levels were increased significantly (P < 0.01) in all groups. The catecholamine increase was not influenced by the HV or the acute exercise bout. The present results do not indicate an implication of the hepatic vagus nerve on hormonal responses to hyper and hypoglycemia following exercise.

The effects of exercise on alterations in the amount of B-cell mass, insulin content and fibrous tissue present in the pancreas were examined for a diabetic state induced by a 70% pancreatectomy and a prediabetic state in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model for the spontaneous development of non-insulin-dependent diabetes mellitus (NIDDM). The rats (5-weeks old) were trained either by a 6-week running program or sedentary controls, and at 6-weeks of age, received either a 70% pancreatectomy or a sham-pancreatectomy (sham). As in our previous report, persistent hyperglycemia was detected after surgery for both trained pancreatectomized (Px) and sedentary Px groups. In the nondiabetic sham rats, exercise training resulted in a significantly smaller increase in body weight and beneficial effects on the pancreas as reflected by an increase in pancreatic volume, accompanied by increases in B-cell mass and insulin content as well as less connective tissue in the pancreas compared with the sedentary nondiabetic sham rats. The effect was not sufficient to improve sustained hyperglycemia in the trained diabetic Px rats. This is probably due to a decreased capacity for B-cell proliferation in response to an increased demand for insulin. Although exercise failed to improve this inherent defect in B-cell proliferation, it ameliorated the further deterioration of the pancreas which occurred with hyperglycemia, and resulted in a higher quantity of insulin stored per milligram of B-cell mass (as function of B-cell mass) and less fibrosis in the pancreas, compared with the sedentary diabetic Px rats. The findings of the present study suggest that exercise training has a beneficial effect on the pancreas in the nondiabetic state, and also exerts some positive effects in the diabetic state in this model rat.

Antioxidant status was measured in heart, liver, kidney, lung, and erythrocytes of 2-week streptozotocin-diabetic male Wistar rats exposed to chronic intermittent psychological stress consisting of 1 h of restraint twice daily for 14 days. Diabetes reduced erythrocyte and heart and liver susceptibility to hydrogen peroxide-induced glutathione depletion. Susceptibility to peroxide-induced thiobarbituric acid reactive substance (TBARS) formation increased in erythrocytes, liver, kidney, and lung but decreased in heart. Significant changes also occurred in glutathione levels (increased in heart and decreased in liver) and in the activities of catalase (reduced in liver and kidney), glutathione reductase (elevated in heart and liver), and glutathione peroxidase (decreased in liver and lung), but not Cu,Zn-superoxide dismutase. Stress potentiated diabetes-associated hyperglycemia and attenuated diabetes-induced hyperlipidemia. In addition, the reduction in peroxide-induced glutathione depletion in heart and liver and the increased TBARS formation in kidney and lung were reversed. Similarly, the diabetes-induced induced increase in liver glutathione reductase and decreases in liver and lung glutathione peroxidase activities were abolished by stress. Thus, the relative resistance of antioxidant systems to stress can be modified under pathologic conditions in which antioxidant alterations are present.

Exercise training increases the concentration of GLUT-4 protein in skeletal muscle that is associated with an increase in maximal insulin-stimulated glucose transport. The purpose of this study was to determine whether exercise training results in a long-lasting increase in insulin-stimulated glucose transport in rat skeletal muscle. Glucose uptake and skeletal muscle 3-O-methyl-D-glucose (3-MG) transport were determined during hindlimb perfusion in the presence of a maximally stimulating concentration of insulin (10 mU/ml). Hindlimb glucose uptake was approximately 29% above sedentary (Sed) levels in rats examined within 24 h (24H) of their last exercise session. However, when rats were examined 48 h (48H) after their last exercise session, hindlimb glucose uptake was not different from Sed levels. Maximal 3-MG transport was enhanced, above Sed levels, in red (RG; 72% increase) and white (WG; 44% increase) gastrocnemius and plantaris (Plan; 67% increase) muscles, but not soleus (Sol), of 24H rats. GLUT-4 protein content was significantly elevated in those muscles that exhibited enhanced 3-MG transport in 24H rats. GLUT-4 protein content was also elevated in RG, WG, and Plan of 48H rats and was not different from 24H rats. Despite the elevated GLUT-4 protein content, 3-MG transport in 48H rats was only slightly, although statistically not significantly, higher than in Sed rats. These results provide evidence that exercise training does not result in a persistent increase in skeletal muscle glucose uptake or transport, despite an increase in GLUT-4 protein content.

We examined the effects of voluntary exercise on glucose transporter concentration in skeletal muscle from young adult and old female Long-Evans rats. Rats had free access to voluntary running wheels beginning at 4 months of age or remained sedentary. Exercising rats ran approximately 7.5, 6.2, 5.6 and 5.3 km/day during their 6th, 8th, 9th and 10th month of age, respectively. During the 23rd, 24th and 25th month of age running distance averaged 3.0, 2.8 and 2.4 km/day, respectively. At 10 and 25 months of age, glucose transporter protein concentration was assessed in epitrochlearis and flexor digitorum brevis muscles with a polyclonal antibody directed against the GLUT4 transporter isoform. GLUT4 protein concentration was not altered by the aging process (i.e., comparing 10- and 25-month-old rats) in either muscle type. Wheel running increased GLUT4 protein concentration by 45% in epitrochlearis muscles of 10-month-old rats relative to age-matched sedentary controls. The training-induced adaptation in GLUT4 protein was no longer present at age 25 months, probably because the running distance had declined by 50%. In the flexor digitorum brevis, exercise did not alter GLUT4 concentration at either 10 or 25 months, presumably due to insufficient recruitment of this muscle during wheel running as assessed by measurement of citrate synthase and hexokinase enzyme activities. Wheel running induced cardiac and soleus muscle hypertrophy in 10- and 25-month-old rats. In summary, voluntary wheel running can induce an increase in skeletal muscle GLUT4 protein concentration in adult rats. Older rats that run less exhibit cardiac and soleus muscle hypertrophy, but do not maintain an elevated GLUT4 protein concentration in the epitrochlearis muscle. Aging does not alter GLUT4 protein concentration in the epitrochlearis or FDB muscles.

In this study, the relationship between the concentration of extracellular insulin, insulin binding and insulin action was evaluated in skeletal muscle. Initially we investigated the dose-response relationship of insulin action using three different experimental models that are responsive to insulin, i.e. the isolated perfused rat hindquarter, incubated strips of soleus muscle, and insulin receptors partially affinity-purified from skeletal muscle. We selected as insulin-sensitive parameters glucose uptake in the perfused hindquarter, lactate production in the incubated muscle preparation, and tyrosine receptor kinase activity in the purified receptor preparation. Our results showed that the dose-response curves obtained in the perfused hindquarter and in the incubated muscle were superimposable. In contrast, the dose-response curve for insulin-stimulated receptor tyrosine kinase activity in partially purified receptors was displaced to the left compared with the curves obtained in the perfused hindquarter and in the incubated muscle. The differences between the dose-response curve for receptor tyrosine kinase and those for glucose uptake and lactate production were not explained by a substantial insulin concentration gradient between medium and interstitial space. Thus the medium/interstitial insulin concentration ratio, when assayed in the incubated intact muscle at 5 degrees C, was close to 1. We also compared the dose-response curve of insulin-stimulated receptor tyrosine kinase with the pattern of insulin-binding-site occupancy. The curve of insulin-stimulated receptor kinase activity fitted closely with the occupancy of high-affinity binding sites. In summary, assuming that the estimation of the medium/interstitial insulin concentration ratio obtained at 5 degrees C reflects the actual ratio under more physiological conditions, our results suggest that maximal insulin action is obtained in skeletal muscle at insulin concentrations which do allow full occupancy of high-affinity binding sites. Therefore our data provide evidence for a lack of spare high-affinity insulin receptors in skeletal muscle.

The purpose of this study was to examine the effect of physical training on the concentrations of glucose and lactate in the blood of rats during rest and after an acute bout of exercise. We used the following types and periods of training; (i) swimming for 4 weeks, (ii) running for 4 weeks, and (iii) running for 10 weeks. The results clearly show that the resting levels of blood glucose was significantly lower in groups trained by either swimming or running than untrained groups. In addition, after the acute exercise of swimming, animals trained by either running or swimming showed a lower increase in the blood lactate than untrained animals. Furthermore, the increases in the blood glucose after swimming were significantly lower in the group trained by swimming for 4 weeks and by running for 10 weeks than in untrained groups. These results suggest that after physical training by running, animals show an adaptation in the changes in the blood glucose and the blood lactate that are induced by a different type of physical stress, swimming.

It was previously found that voluntary wheel running induces an increase in the insulin-sensitive glucose transporter, i.e., the GLUT4 isoform, in rat plantaris muscle (K. J. Rodnick, J. O. Holloszy, C. E. Mondon, and D. E. James. Diabetes 39: 1425-1429, 1990). The present study was undertaken to determine whether 1) the increase in muscle GLUT4 protein is associated with an increase in maximally stimulated glucose transport activity, 2) a conversion of type IIb to type IIa or type I muscle fibers plays a role in the increase in GLUT4 protein, and 3) an increase in the GLUT1 isoform is a component of the adaptation of muscle to endurance exercise. Five weeks of voluntary wheel running that resulted in a 33% increase in citrate synthase activity induced a 50% increase in GLUT4 protein in epitrochlearis muscles of female Sprague-Dawley rats. The rate of 2-deoxy-glucose transport maximally stimulated with insulin or insulin plus contractions was increased approximately 40% (P less than 0.05). There was no change in muscle fiber type composition, evaluated by myosin ATPase staining, in the epitrochlearis. There was also no change in GLUT1 protein concentration. We conclude that an increase in GLUT4, but not of GLUT1 protein, is a component of the adaptive response of muscle to endurance exercise and that the increase in GLUT4 protein is associated with an increased capacity for glucose transport.

It has been reported that exercise training increases muscle glycogen storage in rats fed a high carbohydrate (CHO) diet in resting conditions. The purpose of this study was to examine whether a 3-week swimming training programme would increase muscle glycogen stores in rats fed a high-fat (FAT) diet in resting conditions. Rats were fed either the FAT or CHO diet for 7 days ad libitum, and then were fed regularly twice a day (between 0800 and 0830 hours and 1800 and 1830 hours) for 32 days. During this period of regular feeding, half of the rats in both dietary groups had swimming training for 3 weeks and the other half were sedentary. The rats were not exercised for 48 h before sacrifice. All rats were killed 2 h after their final meal (2030 hours). The glycogen contents in red gastrocnemius muscle, heart and liver were significantly higher in sedentary rats fed the CHO diet than in those fed the FAT diet. Exercise training clearly increased glycogen content in soleus, red gastrocnemius and heart muscle in rats fed the CHO diet. In rats fed the FAT diet, however, training did not increase glycogen content in these muscles or the heart. Exercise training resulted in an 87% increase of total glycogen synthase activity in the gastrocnemius muscle of rats fed the CHO diet. However, this was not observed in rats fed the FAT diet. The total glycogen phosphorylase activity in the gastrocnemius muscle of the rats of both dietary groups was increased approximately twofold by training.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to characterize an animal model of impaired glucose tolerance produced by streptozocin treatment of rats (45 mg/kg, intravenously [i.v.]) and selection of animals with plasma glucose concentrations less than 150 mg/dL. In addition, we determined the effects of physical training on glucose tolerance and metabolism in these animals. During 10 weeks of monitoring, it was determined that these animals have nearly normal plasma glucose concentrations; however, they have an impaired glucose tolerance when challenged with an oral glucose load. They also have normal fasting insulin, free fatty acid, and triglyceride concentrations, normal body weight and food consumption patterns, and normal rates of skeletal muscle glucose uptake, but impaired basal and insulin-stimulated glucose metabolism in isolated adipose cells. Ten weeks of exercise training normalized both the impaired glucose tolerance and adipose cell function present in the untrained streptozocin-treated rats. Low-dose streptozocin treatment of rats with appropriate selection of animals based on plasma glucose concentrations appears to be an excellent model of impaired glucose tolerance for studies of factors affecting insulin resistance and altered glucose metabolism.

The goal of this study was to assess the effects of voluntary running activity in rats on various aspects of carbohydrate and protein metabolism. After 6 wk of exercise training, rats (ET) were rested for 24 h and their hindquarters, along with those from sedentary control (SC) and dietary control (DC) rats, were perfused with 0, 60, 250, or 6,000 microU/ml insulin. At 0 insulin, glucose clearance was similar for all groups, and it was increased with added insulin. However, the insulin effect was 20-40% greater for ET rats at all insulin concentrations (P less than 0.05). Muscle glycogen deposition also increased with added insulin but showed muscle-specific differences. Specifically, glycogen content of the plantaris muscle was significantly higher in ET compared with SC or DC rats, whereas this pattern was reversed in soleus muscle. In plantaris muscle, insulin stimulated glucose 6-phosphate (G-6-P)-independent (-G-6-P) glycogen synthase activity only in SC and DC rats and increased its affinity for G-6-P at 250 microU/ml in all groups. In contrast, the -G-6-P synthase activity was not increased in soleus muscle and was actually decreased in all groups at 6,000 microU/ml. Tyrosine release was suppressed by insulin in all groups, but this effect was significantly greater at insulin levels of 60 microU/ml (P less than 0.02) in hindquarters from ET rats compared with SC and DC rats. Neither insulin nor exercise training decreased 3-methylhistidine release from perfused hindquarters.(ABSTRACT TRUNCATED AT 250 WORDS)

Male and female Wistar rats were exercise-trained for 6 or 11 weeks respectively, to examine the effects of acute exercise or exercise training per se on insulin-stimulated glucose utilization in soleus muscles isolated and incubated in vitro. The maximal activities of hexokinase and 2-oxoglutarate dehydrogenase were significantly elevated (by greater than 50%) in gastrocnemius muscle of exercise-trained male and female rats, indicating an adaptation to the training regime. No significant differences in any of the variables studied were observed between appropriately matched male and female rats. There were no significant differences in the sensitivity or responsiveness of the rates of lactate formation or glycogen synthesis in soleus muscles isolated from exercise-trained and sedentary animals at rest (exercise-trained animals were studied 40 h after the last exercise bout). On the other hand, acute exercise caused significant changes in soleus muscle glucose metabolism. Basal and insulin-stimulated rates of glycogen synthesis were significantly elevated in soleus muscles incubated from both sedentary and exercise-trained rats immediately after an exercise bout. In addition, the responsiveness of glucose utilization to insulin in soleus muscles from exercise-trained rats was significantly increased after acute exercise. The results indicate that significant changes in the control of glucose metabolism by insulin in soleus muscle occur as a result of an acute exercise bout, while no adaptive changes in insulin sensitivity occur in soleus muscle after exercise training.

We examined whether chronic exercise prevents insulin resistance developing in the high-fat-fed (HFF) rat, a model that otherwise develops profound peripheral insulin resistance. Insulin action (euglycemic clamp plus 2-[3H]deoxy-D-glucose-[14C]glucose tracer technique) was examined after 3 wk in sedentary control and sedentary or wheel cage exercise-trained HFF rats. At the whole body level, a reduction in peripheral insulin potency in HFF rats was prevented by concomitant chronic exercise; the 30-40% reduction in insulin-stimulated whole body net glucose utilization in sedentary HFF rats was abolished. Responses in individual muscles, however, suggested that the chronic exercise effect may be a compensation for, rather than a correction of insulin resistance induced by a high-fat diet; in six of eight muscles examined it produced an upward additive shift rather than a left shift in insulin dose response. Chronic exercise increased both muscle glycolytic flux and glycogen storage rates in the HFF rats, suggesting that glucose transport may be involved. We conclude that increased physical activity is beneficial in counteracting high-fat diet-induced insulin resistance. Different processes appear to be involved in the development of diet-induced insulin resistance in muscle and its amelioration by regular exercise.

The effect of treadmill exercise prior to and during pregnancy on maternal and fetal outcome was studied in nondiabetic and streptozotocin-induced diabetic rats. Animals were exercised daily on a motorized treadmill (16.1 m/min, 45 min/d) for three weeks prior to mating and throughout gestation. The catabolic state of diabetes was evidenced by changes in maternal body composition. Overall, fetuses of diabetic dams were smaller, lighter, had less calcified skeletons and had more malformations compared to control fetuses. Exercise in the nondiabetic dams resulted in a retardation of skeletal ossification compared to fetuses from sedentary controls. However, exercise improved fetal outcome in diabetic rats, resulting in increased fetal weight and a lower frequency of malformations compared to fetuses from sedentary diabetic dams.

We hypothesized that endurance training would alter blood glucose kinetics in rats given an exogenous glucose challenge. Primed-continuous infusion of H14CO3- and [3-3H]glucose were given to fasted rats during an intravenous glucose load of approximately 150% of the normal endogenous appearance rate for 3 h. In all rats blood glucose concentrations increased with loading, but in trained animals glucose stabilized at significantly lower levels. Trained animals had lower blood glucose turnover rates than the controls (75 +/- 2.3 vs. 120 +/- 6.3 mumoles/kg x min, respectively). Glucose metabolic clearance rates in trained rats (11.5 +/- 1.7) were not different from those in controls (11.6 +/- 1.2 ml/kg x min). Gluconeogenic rates estimated from incorporation of 14C into blood glucose did not differ between trained and untrained groups. However, the rate of hepatic glucose release estimated from the difference between tracer measured and exogenous appearance rate was lower in the trained group. These findings support the concept that when resting trained animals are challenged with an exogenous load, more glucose is diverted to anabolic processes as opposed to increased turnover.

Effects of endurance swimming training on myocardial contractility and left ventricular myosin isoenzymes were examined in diabetic rats. A diabetic condition was induced in 15-week-old male Wistar rats, by intravenous injection of streptozotocin (50 mg/kg). Swimming training was carried out for five to six weeks (90 min/day, 6 days/week). In order to estimate myocardial contractility, the isometric developed tension of the isolated left ventricular papillary muscle was measured. Myosin isoenzymes were obtained by pyrophosphate gel electrophoresis. Fasting blood glucose of the trained group was significantly lower than that of the sedentary group (sedentary vs. trained = 409.6 +/- 25.9 vs. 266.3 +/- 20.5 mg/dl, p less than 0.001). There was no significant difference in isometric developed tension (T) between the two groups, and the dT/dtmax of the trained group showed a tendency to increase (sedentary vs. trained, T: 2.8 +/- 0.8 vs. 2.9 +/- 0.8 g/mm2, dT/dtmax: 23.1 +/- 3.6 vs. 26.2 +/- 3.5 g/mm2.s, p less than 0.1). Myocardial mechanical responses to isoproterenol and dibutyryl cAMP were increased in the trained group. Left ventricular myosin isoenzyme pattern was shifted towards VM-1 by endurance swimming (sedentary vs. trained, VM-1: 5.6 +/- 4.5 vs. 19.6 +/- 8.8%, p less than 0.001, VM-3: 75.1 +/- 10.0 vs. 54.9 +/- 14.7%, p less than 0.001). These results indicate that endurance swimming can improve disordered glucose metabolism and also influence myocardial contractility, myocardial catecholamine responsiveness, and energetics in myocardial contraction.

The present studies were initiated to assess the effect of insulin on muscle, liver, and adipose tissue in eight control and eight physically trained individuals matched for age and body mass index. Results indicated that percent body fat was 53% lower and maximal oxygen consumption 50% higher in physically trained subjects. Although the plasma glucose response to a standard oral glucose challenge was similar in the two groups, the insulin response was significantly lower in the trained individuals (P less than 0.001). Mean (+/- SE) insulin-stimulated glucose uptake, quantified in vivo by the euglycemic hyperinsulinemic clamp technique, was significantly greater in physically trained individuals at steady-state plasma insulin concentrations of approximately 10 microU/ml (3.41 +/- 0.14 vs. 2.73 +/- 0.22 mg.kg fat free mass-1.min-1, P less than 0.05) and 50 microU/ml (13.58 +/- 0.75 vs. 9.82 +/- 0.53 mg.kg fat free mass-1.min-1, P less than 0.001). In addition, mean (+/- SE) hepatic glucose production rate was lower in physically trained subjects at insulin levels of 10 microU/ml (0.63 +/- 0.19 vs. 1.19 +/- 0.22 mg.kg body wt-1.min-1, P less than 0.05) and 50 microU/min (0.18 +/- 0.14 vs. 0.60 +/- 0.17 mg.kg body wt-1.min-1, P less than 0.05). Finally, the ability of insulin to stimulate mean (+/- SE) glucose uptake above basal levels was greater in adipocytes isolated from trained individuals (94 +/- 10 vs. 56 +/- 14 fl.cell-1.s-1, P less than 0.01). On the other hand, no difference in specific binding of insulin to its receptor on monocytes was noted between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Energy balance and brown adipose tissue growth were examined in four groups of male Wistar rats: (i) sedentary, living at 24 degrees C (warm), (ii) exercise-trained, 2 h daily, living at 24 degrees C, (iii) living at 24 degrees C but exposed to -5 degrees C, 2 h daily and (iv) living at 24 degrees C but exercise-trained while being exposed to -5 degrees C, 2 h daily. 2. Cold exposure during exercise training appeared to have little additional influence on body composition following 28 days of treatment; body mass gain, in addition to protein and fat gains, of exercised cold-exposed rats were similar to the gains observed in exercised warm-exposed control animals. However, in sedentary cold-exposed rats protein, fat and body mass gains were significantly lower than the gains measured in sedentary rats not exposed to cold. 3. Metabolizable energy intake, expressed mass-independently, was similar in sedentary warm-exposed rats and both groups of animals that were exercise-trained. Metabolizable energy intake was increased almost 15% in sedentary cold-exposed rats. 4. Energy expenditure (mass independent), excluding the net cost of exercise training, was not different in sedentary warm-exposed and exercised rats; energy expenditure was almost 20% higher in sedentary cold-exposed rats. 5. Total protein and deoxyribonucleic acid (DNA) contents of brown adipose tissue were more than doubled in sedentary rats exposed to cold; protein and DNA levels were similar among the other three groups of rats. 6. Treadmill running during daily, 2 h exposure at -5 degrees C appears to prevent the cold acclimation responses that occur in sedentary rats receiving similar cold exposure.

Thirteen-week-old male, Osborne-Mendel rats were exercised for 6 weeks on a motorized treadmill. Exercise depressed weight gain and cumulative light cycle food intake while cumulative dark cycle and 24-hour total food intake were unaffected. Rats in sedentary and exercise groups were killed 24 hours after the last bout of exercise to assess the effects of chronic exercise and at 48, 60, 72, and 84 hours to determine the effects of exercise termination. Compared to sedentary controls, exercise decreased plasma insulin, epididymal and retroperitoneal depot weight and cell size, and retroperitoneal lipoprotein lipase (LPL) activity. Forty-eight hours after exercise, plasma insulin concentration increased to sedentary levels. By 60 hours, dark cycle food intake was increased above and adipose LPL activity was comparable to sedentary levels. At 84 hours postexercise termination, dark cycle food intake, plasma triglyceride, and epididymal LPL activity per depot and per cell were significantly greater than sedentary values. Exercise termination resulted in a preparatory response for rapid lipid deposition probably arising from increased food intake, plasma insulin, and enhanced LPL activity within 84 hours following termination of exercise.

The effects of cold exposure (48 h at 4 degrees C) and insulin injection (0.5 U/kg iv) on the rates of net 2-[3H]deoxyglucose uptake (Ki) in peripheral tissues were investigated in warm-acclimated rats (25 degrees C). Cold exposure and insulin treatment independently increased Ki values in skeletal muscles (soleus, extensor digitorum longus, and vastus lateralis), heart, white adipose tissue (subcutaneous, gonadal, and retroperitoneal), and brown adipose tissue (P less than 0.01). The effects of cold exposure were particularly evident in brown adipose tissue where the Ki increased greater than 100 times. When the two treatments were combined (insulin injection in cold-exposed rats), it was found that cold exposure synergistically enhanced the maximal insulin responses for glucose uptake in brown adipose tissue, all white adipose tissue depots, and skeletal muscles investigated. The results indicate that cold exposure induces an "insulin-like" effect on Ki that does not appear to be specifically associated with shivering thermogenesis in skeletal muscles, because that effect was observed in all insulin-sensitive tissues. The data also demonstrate that cold exposure significantly potentiates the maximal insulin responses for glucose uptake in the same tissues. This potentialization may result from an enhanced responsiveness of peripheral tissues to insulin, possibly occurring at metabolic steps lying beyond the insulin receptor and an increased tissue blood flow augmenting glucose and insulin availability and thereby amplifying glucose uptake.

Two treatments that increase skeletal muscle insulin action are exercise training and high-carbohydrate diet. The purpose of the present study was to determine whether exercise training and a diet high in carbohydrates could function synergistically to reduce the muscle insulin resistance in the obese Zucker rat. Obese rats 4 wk of age were randomly assigned to an exercise or sedentary group. Each group was subdivided by diet with one-half of the rats fed a high-carbohydrate diet and one-half fed a high-fat diet. Lean Zucker rats fed the high-fat diet were used as controls. Muscle insulin resistance was assessed during hindlimb perfusion with a submaximally stimulating concentration of insulin. Exercise training and the high-carbohydrate diet increased the rate of muscle glucose uptake in the obese rat by 46 and 53%, respectively. More importantly, the combined effect of exercise training and high-carbohydrate diet was greater than the sum of their individual effects. Glycogen synthesis paralleled glucose uptake and was the major pathway for intracellular glucose disposal. Muscle glucose uptake for exercise-trained, high-carbohydrate fed obese rats was comparable with that of lean controls. It is concluded that exercise training and the high-carbohydrate diet functioned synergistically to reduce the muscle insulin resistance in the obese rat.

The interactive effects of exercise training (5-7 wk) and sucrose consumption (ad libitum feeding of a 32% sucrose solution and Purina chow) on intravenous glucose tolerance and plasma insulin levels were investigated using a 2 X 2 experimental design. Rats were divided in Purina-sedentary, Purina-trained, sucrose-sedentary, and sucrose-trained groups. Sucrose feeding of sedentary animals significantly increased basal and glucose-stimulated insulin levels and improved basal glycemia and glucose tolerance. On the other hand, exercise training of Purina-fed animals significantly reduced basal as well as glucose-stimulated insulinemia without altering basal glycemia or glucose tolerance. Such a sparing effect of exercise training on insulin requirements was not as evident in rats consuming sucrose. These animals displayed a reduced basal glycemia (P less than 0.01) with normal basal insulin levels. Their glucose tolerance was markedly improved (P less than 0.01) but their insulin response during intravenous glucose tolerance test remained as high as in sucrose-sedentary animals. Results from these studies indicate that sucrose feeding of sedentary animals leads to hyperinsulinemia without compensatory insulin resistance, resulting in an improvement of glucose tolerance, exercise training increases the sensitivity of peripheral tissues to insulin, and the marked improvement of glucose tolerance observed in sucrose-trained animals results from a synergistic combination of the above two factors, i.e., increased insulinemia (induced by diet) and enhanced insulin sensitivity (induced by training).

We examined the hypothesis that the exercise training-induced increase in skeletal muscle insulin sensitivity is mediated by adaptations in insulin binding to sarcolemmal (SL) insulin receptors. Insulin binding studies were performed on rat skeletal muscle SL isolated from control and trained rats. No significant differences were noted between groups in body weight or fat. An intravenous glucose tolerance test showed an increase in whole-body insulin sensitivity with training, and specific D-glucose transport studies on isolated SL vesicles indicated that this was due in part to adaptations in skeletal muscle. Enzyme marker analyses revealed no differences in yield, purity, or contamination of SL membranes between the two groups. Scatchard analyses indicated no significant differences in the number of insulin binding sites per milligram SL protein on the high-affinity (15.0 +/- 4.1 vs. 18.1 +/- 6.4 X 10(9)) or on the low-affinity portions (925 +/- 80 vs. 884 +/- 106 X 10(9)) of the curves. The association constants of the high-affinity (0.764 +/- 0.154 vs. 0.685 +/- 0.264 X 10(9) M-1) and of the low affinity sites (0.0096 +/- 0.0012 vs. 0.0102 +/- 0.0012 X 10(9) M-1) also were similar. These results do not support the hypothesis that the increased sensitivity to insulin after exercise training is due to changes in SL insulin receptor binding.

Effects of insulin on glycogen synthesis (GS), glycolytic utilization (GU), and glucose uptake (GT) were studied in isolated epitrochlearis muscles from exercise-trained or sedentary rats during recovery from acute exercise or at rest. During the 1st h after acute exercise, the enhanced basal and insulin-stimulated GT was directed mainly toward replenishment of glycogen but basal GU was also increased. During the second through third hours after exercise, basal GS decreased but remained greater than rest and basal GU and GT returned to normal. Insulin sensitivity of these parameters was enhanced. Training alone reduced basal GS but enhanced insulin sensitivity of GT and GU. Training reduced the acute exercise-stimulated increase in basal and insulin sensitivity of GS during recovery from acute exercise, probably due to elevated glycogen stores. Thus recovery from acute exercise or training, either alone or in combination, enhances insulin stimulated GT in muscle; however, the increased glucose is primarily channeled toward GS after acute exercise, which is reduced by prior training and is directed to GU in trained animals either at rest or after acute exercise.

In conclusion, a large body of available evidence indicates that the degree of physical conditioning is an important determinant of insulin sensitivity and overall glucose tolerance. Both acute exercise and chronic physical training are associated with enhanced disposal of a glucose load. Conversely, physical inactivity leads to a deterioration in glucose tolerance. The primary tissue responsible for accelerated glucose disposal following exercise is muscle. After an acute bout of exercise, enhanced glucose transport and augmented glycogen synthesis are largely responsible for the improvement in glucose tolerance. The beneficial effects of chronic physical training on glucose metabolism appear to be explained by multiple factors, including increased muscle mass, augmented muscle blood flow and capillary area, enhanced mitochondrial oxidative enzyme capacity, and activation of the glucose transport system. Despite these well-documented effects of training on glucose metabolism, the precise role of exercise in the treatment of diabetic patients remains to be established. In insulin-dependent (type I) diabetic individuals, acute exercise has been shown to be a helpful adjunct in establishing good glycemic control. However, the role of acute exercise in helping to smooth out glycemic control in non-insulin-dependent (type II) diabetic patients has received little attention. The role of chronic physical training in the treatment of both insulin-dependent (type I) and non-insulin-dependent (type II) diabetic individuals remains to be established.

Muscle homogenates representing slow-twitch oxidative, fast-twitch oxidative-glycolytic, fast-twitch glycolytic, and mixed fiber types were prepared from normal, diabetic, and insulin-treated diabetic rats. Diabetes was induced by injection of 80 mg . kg-1 of streptozotocin. The activities of citrate synthase, succinate dehydrogenase, and 3-hydroxyacyl-CoA dehydrogenase were employed as markers of oxidative potential, whereas phosphorylase, hexokinase, and phosphofructokinase activities were used as an indication of glycolytic capacity. Diabetes was associated with a general decrement in the activity of oxidative marker enzymes for all fiber types except the fast-twitch glycolytic fiber. In contrast, the fast-twitch glycolytic fibers demonstrated the greatest decline in glycolytic enzymatic activity. Insulin-treated animals, either trained or untrained, exhibited enzyme activities similar to their normal counterparts. Exercise training of diabetic rats mimicked the effect of insulin treatment and caused a near normalization of the activity of the marker enzymes. These findings suggest that the enzymatic potential of all skeletal muscle fiber types of diabetic rats may be normalized by exercise training even in the absence of significant amounts of insulin.

It has previously been suggested that exercise training leads to increased whole body insulin sensitivity. However, the specific tissues and metabolic pathways involved have not been examined in vivo. By combining the euglycemic clamp with administration of glucose tracers, [3H]2-deoxyglucose (2DG), [14C]glucose, and [3H]glucose, in vivo insulin action at the whole body level and within individual tissues has been assessed in exercise-trained (ET, running 1 h/d for 7 wk) and sedentary control rats at four insulin doses. Whole body insulin sensitivity was significantly increased in ET. In addition, the skeletal muscles, soleus, red and white gastrocnemius, extensor digitorum longus (EDL), and diaphragm all showed increased sensitivity of insulin-stimulated 2DG uptake with training. With the exception of EDL, no significant difference in insulin-mediated glycogen synthesis between control and ET could be found. Therefore, the increased insulin-induced 2DG uptake observed in muscle following training is apparently directed towards glucose oxidation. In ET animals, adipose tissue exhibited a significant increase in insulin-mediated 2DG uptake and [14C]glucose incorporation into free fatty acids but there was no difference from control in any parameters measured in lung or liver. EDL and white gastrocnemius, which are not primarily involved during exercise of this type, also demonstrated increased insulin sensitivity following training. In conclusion, exercise training results in a marked increase in whole body insulin sensitivity related mainly to increased glucose oxidation in skeletal muscle. This effect may be mediated by systemic as well as local factors and is likely to be of therapeutic value in pathological conditions exhibiting insulin resistance.

The effect of work-induced hypertrophy (without any concomitant change in circulating parameters) on skeletal muscle metabolism was studied in lean mice and in gold-thioglucose-obese mice. Soleus muscle was functionally overloaded in one leg by tenotomy of gastrocnemius muscle 4 days before muscle isolation, muscle in the other leg being used as control. Basal deoxyglucose uptake and glycolysis were markedly increased in overloaded muscles compared with control muscles, together with a ten-fold increase in fructose 2-6 bisphosphate content. In the presence of maximally effective insulin concentrations, deoxyglucose uptake and glycolysis were identical in overloaded and control muscles of lean mice, while the effects of overload and insulin were partly additive in muscles of gold-thioglucose-obese mice. The sensitivity to insulin and insulin binding to muscles were not modified in overloaded muscles. Insulin-stimulated glycogenogenesis was decreased by about 50% probably due to a lower amount of glycogen synthase in overloaded than in control muscles. Thus, in muscles of gold-thioglucose-obese mice work-induced hypertrophy increased the response to maximal insulin concentrations without modifying the altered insulin sensitivity and decreased insulin binding.

The maximal activities of 5'-nucleotidase, adenosine deaminase and adenosine kinase were measured in quadriceps or soleus muscle from animals in which the sensitivity to insulin was changed. Most conditions caused no effect on the activities but exercise-training increased the activity of adenosine deaminase and cold exposure increased the activity of 5'-nucleotidase in soleus muscle: in addition, ageing decreased markedly the activities of all three enzymes in both muscles. When the activities are based on mg protein they are much higher in both white and brown adipose tissue than in muscle, suggesting that changes in adenosine concentration may be important in changing insulin sensitivity in adipose tissue whereas changes in adenosine receptor number may be more important in muscle.

The effect of exercise on in vivo insulin sensitivity was examined in lean and obese Zucker rats. Rats (6 to 7 weeks of age) were swum two hours per day or kept sedentary for 8 weeks. Exercise decreased body weight gain as well as percent of fat in both genotypes. Sedentary obese rats had 62% higher gastrocnemius citrate synthase activity per gram of muscle than did lean rats. Exercise increased activity of this oxidative enzyme similarly in both genotypes. Compared to lean rats, obese rats had higher plasma-insulin levels and were less sensitive to insulin during an insulin tolerance test. Although training had no effect on plasma-insulin levels, exercise trained obese rats showed a greater drop in plasma glucose relative to sedentary controls following intravenous injection of three concentrations of insulin. It was concluded that moderate exercise training improved the insulin sensitivity of the obese Zucker rat.

Environmental factors, such as excessive caloric intake leading to obesity, altered dietary composition, physical inactivity, various forms of stress, hormonal imbalance, drugs, toxins, and the process of aging, may contribute to the development of noninsulin-dependent diabetes mellitus in the genetically predisposed subject but do not by themselves cause the disease. Both abnormal pancreatic beta-cell function and decreased sensitivity to insulin are present in most patients with noninsulin-dependent diabetes mellitus, and the degree of carbohydrate intolerance is dependent on the interaction between these two factors. Efforts to prevent or treat noninsulin-dependent diabetes mellitus should be aimed primarily towards eliminating factors associated with the development of insulin resistance and promoting those that increase insulin sensitivity. Obesity, the composition of the diet, and level of physical training are all important in this regard and are the major environmental factors discussed herein.

The half-maximal stimulation of the rates of glycolysis and glycogen synthesis in soleus-muscle strips from sedentary animals occurred at a concentration of insulin of about 100 microunits/ml. In soleus-muscle strips from exercise-trained rats (5 weeks of treadmill training), half-maximal stimulation of the rate of glycolysis occurred at about 10 microunits of insulin/ml, whereas that for glycogen synthesis occurred between 10 and 100 microunits of insulin/ml. The sensitivity of glycolysis to insulin after exercise training is similar to that of adipose tissue from sedentary animals. This finding suggests that, in sedentary animals, the effects of normal changes in insulin concentration may affect muscle primarily indirectly via the anti-lipolytic effect on adipose tissue, whereas after training insulin may effect the rate of glycolysis in muscle directly. A single period of exercise did not change the sensitivity of glycolysis in soleus muscle to insulin, nor probably that of glycogen synthesis. It is suggested that the improvement in insulin sensitivity of glycolysis in muscle caused by exercise-training could account, in part, for the well-established improvement in glucose tolerance and insulin sensitivity observed in man and rats after exercise-training.