Sympathetic control of metabolic and hormonal responses to exercise in rats

The importance of the sympatho-adrenal system for the pancreatic hormonal response to exercise and, furthermore, the role of glucagon and catecholamines for the hepatic glycogen depletion during exercise were studied. Rats were either surgically adrenomedullectomized and chemically sympathectomized with 6-hydroxydopamine or shamtreated. Two weeks later the rats had either rabbit-antiglucagon serum or normal rabbit serum injected. Subsequently the rats either rested or swam with a tail weight for 75 min. Immediately afterwards cardiac blood was drawn and liver and muscle tissue collected. In control rats in spite of an increase in blood glucose concentrati4ns during exercise plasma insulin concentrations were unchanged, while glucagon concentrations increased. In sympathectomized rats, compared to control rats, glucagon concentrations increased less, and insulin concentrations were higher, although glucose concentrations were lower during exercise. Sympathectomy completely abolished the exercise-induced decrease in liver and muscle glycogen concentrations, whereas neither glycogen depletion nor plasma catecholamine concentrations were influenced by the administration of glucagon antibodies. These findings indicate that the sympatho-adrenal system enhances glucagon secretion as well as muscular and hepatic glycogen depletion but inhibits insulin secretion in exercising rats. The increase in glucagon concentrations, however, does not enhance hepatic glycogen depletion at the work load used.     

Skeletal muscle and hormonal adaptation to physical training in the rat: role of the sympatho-adrenal system

The main purpose of the present study was to test the hypothesis that adrenergic stimulation of muscle fibres during exercise is a major stimulus for the training-induced enhancement of skeletal muscle respiratory capacity. Therefore, Sprague-Dawley rats either underwent bilateral surgical ablation of the adrenal medulla or were sham-operated. Furthermore, unilateral surgical extirpation of the lumbar sympathetic chain was performed. Half of the rats were then trained for 12 weeks by swimming (up to 5.5 h X day-1, 4 days X week-1) and the remaining rats were sedentary controls. In the gastrocnemius muscle, training significantly increased the mitochondrial enzymes citrate synthase, succinate dehydrogenase, cytochrome c oxidase, and 3-hydroxyacyl-CoA dehydrogenase. In sham-operated rats, the increases were 40%, 43%, 66%, and 25%, respectively, in legs with intact sympathetic innervation. The training-induced enzyme adaptation after adrenodemedullation and/or sympathectomy was not significantly lower than these control values. In sham-operated rats, training decreased resting plasma insulin and glucagon levels and increased liver glycogen content. Similar changes were induced by adrenodemedullation, but training did not augment these changes in adrenodemedullated rats. In conclusion, the data suggest that neither adrenomedullary hormones nor local sympathetic nerves are prerequisites for the training-induced increase in muscle mitochondrial enzymes. The training-induced decline in resting plasma insulin and glucagon levels in intact rats may be mediated by adrenomedullary hormones.     

The effect of lesions of the sympathoadrenal system on training induced adaptations in adipocytes and pancreatic islets in rats

Physical training increases insulin stimulated glucose uptake in adipocytes and decreases insulin secretion from pancreatic islets. The mechanism behind these adaptations is not known. Because in acute exercise adrenergic activity influences both adipocytes and pancreatic islets, the sympathetic nervous system was examined as the possible mediator. Rats were either adrenodemedullated or sham adrenodemedullated and underwent either unilateral abdominal sympathectomy or were sham sympathectomized. Resting plasma adrenaline concentration in adrenodemedullated rats was 32% of the concentration in sham adrenodemedullated rats (P<0.0001) and muscle noradrenaline content in sympathectomized leg was 9% of content in sham sympathectomized leg (P<0.0001). After operations rats were either swim trained for 10 weeks or remained sedentary. Insulin stimulated 3-O-[¹⁴C]methylglucose transport was measured in adipocytes from epididymal fat pads, and insulin secretion and glucose metabolism were measured in glucose stimulated pancreatic islets. Training increased insulin stimulated glucose transport in adipocytes (P<0.0001) and decreased their size (P<0.0001), but neither adrenodemedullation nor sympathetic denervation affected these parameters significantly. Training decreased insulin secretion (P<0.01) and increased glucose oxidation (P=0.02) and utilization (P=0.08) in pancreatic islets, but none of these parameters was affected significantly by adrenodemedullation. It is concluded that adrenergic activity is not important for the training induced decrease in size and increase in insulin stimulated glucose transport of adipocytes. Neither is an intact adrenal medulla necessary for training-induced adaptations in pancreatic beta cell function. Finally, in response to training, β cell insulin secretion and glucose metabolism changed in opposite directions.     

Catecholamines and exercise-induced glucagon and fatty acid mobilization in the rat.

Physical exercise in rats provokes an increase in plasma glucagon and free fatty acid concentrations. The persistence of exercise-induced glucagon stimulation in adrenodemedullated animals and conversely, its inhibition by immunosympathectomy, (-)-ropranolol, and pindolol substantiate the conclusion that stimulation of the alpha2 cells in exercise involves sympathetic stimulation of the beta-adrenergic receptors. The reduction of free fatty acid mobilization by immunosympathectomy and (-)-propranolol and its persistence after adrenodemedullation suggest that it is similarly mediated, at least in part, by adipose cell beta-sympathetic receptors.     

Contribution of liver nerves,glucagon, and adrenaline to the glycaemic response to exercise in rats

The contribution of hepatic sympathetic innervation, glucagon and adrenaline to the glycaemic response to exercise was investigated in rats. Hepatically denervated (LDX) or sham operated (SHAM) rats with permanent catheters were therefore submitted to swimming with or without infusion of somatostatin in combination with adrenodemedul–lation. Blood samples were taken for measurements of blood glucose, plasma free fatty acids (FFA), adrenaline (A), noradrenaline (NA), insulin and glucagon. Liver denervation by itself did not influence glucose levels during exercise. Infusion of somatostatin in SHAM animals, which inhibited the exercise–induced glucagon response, led to enhanced sympathoadrenal outflow (measured as plasma A and NA) and a reduced blood glucose during exercise, suggesting that glucagon serves as a powerful mediator of the glycaemic response during swimming. Infusion of somatostatin in LDX animals failed to enhance plasma NA levels and led to a more pronounced reduction in blood glucose levels. This indicates that liver nerves do contribute to the glycaemic response to exercise when glucagon secretion is suppressed. Reduced blood glucose levels after adrenodemedullation revealed that adrenal A is another important mediator of the glucose response to exercise. Infusion of somatostatin in adreno–demedullated SHAM or LDX animals was not accompanied with increased NA outflow, suggesting that adrenal A is necessary to allow the compensatory increased outflow of NA from sympathetic nerves. In conclusion, the study shows that pancreatic glucagon and adrenal A are the predominant factors influencing the glycaemic response to exercise, whereas a role of the sympathetic liver nerves becomes evident when glucagon secretion is suppressed.     

The effect of different diets and of insulin on the hormonal response to prolonged exercise

The importance of carbohydrate availability during exercise for metabolism and plasma hormone levels was studied. Seven healthy men ran on a treadmill at 70% of individual maximal oxygen uptake having eaten a diet low (F) or high (CH) in carbohydrate through 4 days. At exhaustion the subjects were encouraged to continue to run while glucose infusion increased plasma glucose to preexercise levels. Forearm venous blood, biopsies from vastus muscle and expiratory gas were analyzed. Time to exhaustion was longer in CH- (106 +/- 5 min (S.E.)) than in F-expts. (64 +/- 6). During exercise, overall carbohydrate combustion rate, muscular glycogen depletion and glucose and lactate concentrations, carbohydrate metabolites in plasma, and estimated rate of hepatic glucose production were higher, fat metabolites lower, and the decrease in plasma glucose slower in CH- than in F-expts. Plasma norepinephrine increased and insulin decreased similarly in CH- and F-expts., whereas the increase in glucagon, epinephrine, growth hormone and cortisol was enhanced in F-expts. Glucose infusion eliminated hypoglycemic symptoms but did not substantially increase performance time. During the infusion epinephrine decreased markedly and glucagon even to preexercise levels. Infusion of insulin (to 436% of preexercise concentration) in addition to glucose in F-expts. did not change the plasma levels of the other hormones more than infusion of glucose only but reduced fat metabolites in plasma. At exhaustion muscular glycogen depletion was slow, and the glucose gradient between plasma and sarcoplasma as well as the muscular glucose 6-phosphate concentration had decreased. Conclusions: The preceding diet modifies the energy depots, the state of which (as regards size, receptors and enzymes) is of prime importance for metabolism during prolonged exercise. Plentiful carbohydrate stores favor both glucose oxidation and lactate production. During exercise norepinephrine increases and insulin decreases independent of plasma glucose changes whereas receptors sensitive to glucose privation but not to acute changes in insulin levels enhance the exercise-induced secretion of glucagon, epinephrine, growth hormone and cortisol. Abolition of cerebral hypoglycemia does not inevitably increase performance time, because elimination of the hypoglycemia may not abolish muscular energy lack.     

Muscle and liver glycogen,protein, and triglyceride in the rat

Summary We have previously found that during exercise net muscle glycogen breakdown is impaired in adrenodemedullated rats, as compared with controls. The present study was carried out to elucidate whether, in rats with deficiencies of the sympatho-adrenal system, diminished exercise-induced glycogenolysis in skeletal muscle was accompanied by increased breakdown of triglyceride and/or protein. Thus, the effect of exhausting swimming and of running on concentrations of glycogen, protein, and triglyceride in skeletal muscle and liver were studied in rats with and without deficiencies of the sympatho-adrenal system. In control rats, both swimming and running decreased the concentration of glycogen in fast-twitch red and slow-twitch red muscle whereas concentrations of protein and triglyceride did not decrease. In the liver, swimming depleted glycogen stores but protein and triglyceride concentrations did not decrease. In exercising rats, muscle glycogen breakdown was impaired by adrenodemedullation and restored by infusion of epinephrine. However, impaired glycogen breakdown during exercise was not accompanied by a significant net breakdown of protein or triglyceride. Surgical sympathectomy of the muscles did not influence muscle substrate concentrations. The results indicate that when glycogenolysis in exercising muscle is impeded by adrenodemedullation no compensatory increase in breakdown of triglyceride and protein in muscle or liver takes place. Thus, indirect evidence suggests that, in exercising adrenodemedullated rats, fatty acids from adipose tissue were burnt instead of muscle glycogen.     

Enhancement of insulin and glucagon secretion by arginine after hepatic vagotomy

The hepatic vagus nerve consists of mostly afferent fibers in the rat, and is a major afferent pathway between the liver and the medulla. The present study was carried out to examine the role of the hepatic branch of the vagus nerve in secretion of insulin and glucagon after intraperitoneal injection of arginine (1 g/kg body wt.) in rats. Measurements were made one week after section of this branch. Intraperitoneal arginine enhanced both plasma insulin and glucagon concentrations; more in hepatic-vagotomized than in sham-vagotomized rats. The results suggest that inhibition of the secretion of insulin and glucagon after arginine stimulation is mediated by the hepatic branch of the vagus nerve. The existence of 'sensors' in the liver for arginine, or its derivatives, is proposed as an explanation for the inhibition of the secretion of insulin and glucagon by the hepatic vagus nerve.     

Evidence that exercise-induced heat storage is dependent on adrenomedullary secretion

To investigate the influence of medullary adrenal secretion on thermoregulation during exercise, Phy (Eserine, 5x10(-3) M) was injected into the lateral cerebral ventricle of normal (INT) or bilaterally adrenodemedullated (ADM) untrained rats. Body temperature (Tb) and metabolic rate were measured in the rats while they were exercising on a treadmill (20 m min(-1), 5% inclination) until fatigue or while they were at rest after drug injection. In resting rats, Phy increased oxygen consumption in both INT or ADM rats without any effect on core temperature. During the dynamic phase of exercise (first 20 min), ADM attenuated the exercise-induced increase in core temperature (0.86+/-0.12 degrees C ADM Sal vs 1.48+/-0.21 degrees C INT Sal), thus reducing heat storage (HS) levels. Icv injection of Phy in ADM rats significantly reduced the increase in Tb (0.012+/-0.10 degrees C min(-1) Phy vs 0.042+/-0.006 degrees C min(-1) Sal; p<0.02) and HS (65.8+/-56.1 cal Phy vs 207.7+/-32.7 cal Sal; p<0.04) compared to ADM Sal rats. In conclusion, the exercise-induced increase in heat storage was attenuated by adrenodemedullation in rats. Furthermore, the activation of heat loss mechanisms by the central cholinergic system during exercise occurs independently of adrenal medullary secretion suppression and can be improved by previous adrenodemedullation. Our data indicate the existence of a dual mechanism of heat loss control during the dynamic phase of exercise: one involving sympathoadrenal system activation that impairs heat loss and another that counteracts the increased sympathoadrenal activity through the hypothalamic cholinergic system to promote heat loss.     

Glucagon attenuates the action of insulin on glucose output in the liver of the Goto-Kakizaki rat perfused in situ

The effects of glucagon and insulin on glucose production were explored directly using the isolated perfused liver of the Goto-Kakizaki (GK) rat, an animal model of type-2 diabetes. In the perfused liver of control rats, infusion of glucagon (0.06-1.0 nM) into the portal vein dose-dependently increased glucose output. In the GK rat liver, in which the intracellular distribution of glycogen was heterogeneous, basal glucose output during perfusion was significantly higher than in control, whereas the effect of glucagon on the maximum glucose output was not different. Infusion of insulin inhibited the glucagon-induced hepatic glucose output by 30-40% in control livers, but had no effect on that from the GK rat liver. The increase in hepatic cAMP content after glucagon infusion was antagonized by insulin in control livers, but not in the livers of GK rats. These results indicate that the antagonistic effect of insulin on glucagon-induced hepatic glucose production was attenuated in the isolated liver of the GK rat and suggest that this insulin resistance appeared in the signal transduction process of glucagon upstream from cAMP production.     

Effect of endurance training on liver cAMP response to prolonged submaximal exercise

Endurance-trained rats utilize liver glycogen at a reduced rate during exercise compared to nontrained rats. We have compared liver cAMP responses to exercise in trained and nontrained rats in an attempt to elucidate the mechanism of this adaptation. Rats were trained on a motor-driven rodent treadmill 5 days/wk for 12 wk. On the day of the test, trained and nontrained rats were quickly anesthetized after running at 21 m/min up a 15% grade for periods up to 90 min. After 45 min of running, liver cAMP had increased from 0.60 +/- 0.01 to 0.90 +/- 0.03 pmol/mg in nontrained rats whereas no significant increase had occurred in livers of trained rats. Plasma glucagon and norepinephrine levels were significantly lower in trained rats at this point. At the end of 90 min hepatic cAMP was 1.28 +/- 0.12 in nontrained compared to 0.83 +/- 0.06 pmol/mg in trained rats. Plasma glucagon was markedly elevated in nontrained but not in trained rats at this time. The lower rate of liver glycogen utilization in trained rats is consistent with the lower cAMP levels maintained early in exercise.     

Regulation of glycogen resynthesis in muscles of rats following exercise.

Following a strenuous bout of exercise, glycogen repletion occurred most rapidly in the fast-twitch red type of muscle, least rapidly in fast-twitch white, and at an intermediate rate in slow-twitch red muscle. There was a linear correlation between glycogen synthase I activity and the rate of glycogen synthesis in the three types of muscle. This finding helps explain the differences between the rates of glycogen resynthesis in the three muscle types, and supports the view that glycogen synthase activity is the most important factor determining the rate of glycogen synthesis when substrate supply is adequate. There was an inverse correlation between muscle glycogen concentration and percent glycogen synthase I. Plasma insulin concentration was low and norepinephrine and glucagon concentrations were elevated in the postexercise period. The finding that rapid glycogen synthesis occurred despite a hormonal milieu conducive to glycogenolysis provides evidence that a low glycogen concentration is a potent stimulus to glycogen synthesis that overrides the effects of low insulin, and high norepinephrine and glucagon levels.     

Regulation of adrenal chromaffin cell development by the central monoaminergic system: differential control of norepinephrine and epinephrine levels and secretory responses

In the mature rat, reflex sympathetic stimulation by insulin-induced hypoglycemia resulted in profound depletion of adrenal epinephrine, and to a lesser extent, norepinephrine. In the developing rat, insulin evoked little or no secretory response from the adrenals prior to 1 week of age. By 7 days, a moderate depletion of epinephrine was seen and the magnitude of the response increased with age. In contrast, during the first 3 weeks of postnatal life, insulin failed to deplete norepinephrine from the adrenal medulla and in fact, produced an increase. This chiefly resulted from de novo biosynthesis of the amine, as the rise was blocked by alpha-methyl-p-tyrosine. These results suggest that the ontogeny of the two chromaffin cell types (norepinephrine and epinephrine-containing) in the adrenals and the maturation of their secretory responses are under differential regulation. Because descending supraspinal catecholaminergic and serotonergic systems have been implicated to play key roles in regulating adrenomedullary function, the ontogeny of the sympatho-adrenomedullary axis was evaluated after neonatal central lesioning with 6-hydroxydopamine or 5,7-dihydroxytryptamine. 6-Hydroxydopamine resulted in a preferential elevation of epinephrine in the developing adrenals as well as an increase in the responsiveness of the adrenals to reflex stimulation by insulin; the mature secretory pattern was obtained as early as at 4 days postnatally for epinephrine and 9 days for norepinephrine. In contrast, 5,7-dihydroxytryptamine led to a preferential reduction of basal adrenal norepinephrine content.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of influence of glucagon on glucose homeostasis after prolonged exercise in rats

Summary The significance of glucagon for post-exercise glucose homeostasis has been studied in rats fasted overnight. Immediately after exhaustive swimming either rabbit-antiglucagon serum or normal rabbit serum was injected by cardiac puncture. Cardiac blood and samples of liver and muscle tissue were collected before exercise and repeatedly during a 120 min recovery period after exercise. During the post-exercise period plasma glucagon concentrations decreased but remained above pre-exercise values in rats treated with normal serum, while rats treated with antiglucagon serum had excess antibody in plasma throughout. Nevertheless, all other parameters measured showed similar changes in the two groups. Thus after exercise the grossly diminished hepatic glycogen concentrations remained constant, while the decreased blood glucose concentrations were partially restored. Simultaneously concentrations in blood and serum of the main gluconeogenic substrates, lactate, pyruvate, alanine and glycerol declined markedly. During the post-exercise period NEFA concentrations in serum and plasma insulin concentrations remained increased and decreased, respectively, while plasma catecholamines did not differ from basal values. Muscle glycogen concentrations decreased slightly. These findings suggest that in the recovery period after exhaustive exercise the increased glucagon concentrations in plasma do not influence gluconeogenesis.     

PNMT inhibition decreases exercise performance in the rat.

The purpose of this investigation was to examine the effect of phenylethanolamine N-methyltransferase (PNMT) inhibition on the regulation of peripheral metabolic and hormonal responses during treadmill exercise in the rat. Changes in plasma catecholamine (epinephrine, norepinephrine, and dopamine), glucagon and glucose, and the glycogen content of the liver and two skeletal muscles were studied in four groups of rats. Two groups of rats were studied at rest: one group had been treated with LY134046, an inhibitor of PNMT, and the second group was treated with physiological saline. A third group treated with LY134046 was studied after treadmill exercise (28 m.min-1 and 8% slope). In this group of rats, exhaustion came after 37.5 +/- 7.9 minutes of exercise. In order to make appropriate comparisons, a fourth group of rats treated with physiological saline was exercised for 37.5 min. Running endurance during the treadmill exercise was thus reduced in LY134046-treated rats. Plasma epinephrine and glucagon concentrations and other metabolic (plasma glucose and gastrocnemius lateralis and superficial vastus lateralis muscles and liver glycogen contents) responses were similar between LY134046- and saline-treated rats at rest and after exercise. These results suggest that PNMT inhibition in epinephrine brain neurons might be the principal factor involved in the LY134046-induced reduction of exercise endurance.     

Mobilization of glucose from the liver during exercise and replenishment afterward.

The liver is anatomically well situated to regulate blood glucose. It is positioned downstream from the pancreas, which releases the key regulatory hormones glucagon and insulin. It is also just downstream from the gut, permitting efficient extraction of ingested glucose and preventing large excursions in systemic glucose after a glucose-rich meal. The position of the liver is not as well situated from the standpoint of experimentation and clinical assessment, as its primary blood supply is impossible to access in conscious human subjects. Over the last 20 years, to study hepatic glucose metabolism during and after exercise, we have utilized a conscious dog model which permits sampling of the blood that perfuses (portal vein, artery) and drains (hepatic vein) the liver. Our work has demonstrated the key role of exercise-induced changes in glucagon and insulin in stimulating hepatic glycogenolysis and gluconeogenesis during exercise. Recently we showed that portal venous infusion of the pharmacological agent 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside leads to a marked increase in hepatic glucose production. Based on this, we propose that the concentration of AMP may be a component of a physiological pathway for stimulating hepatic glucose production during exercise. Insulin-stimulated hepatic glucose uptake is increased following exercise by an undefined mechanism that is independent of liver glycogen content. The fate of glucose taken up by the liver is critically dependent on hepatic glycogen stores, however, as glycogen deposition is greatly facilitated by prior glycogen depletion.     

Effect of leukocytic endogenous mediators on endocrine pancreas secretory responses.

Crude mediators from stimulated rabbit peritoneal leukocytes (LEM) engender numerous physiologic alterations in rats, which are similar to those observed during infection. One hour after the intraperitoneal injection of crude LEM, plasma insulin and glucagon concentrations are elevated; at 2 h the hormonal alterations are manifested by a 30% increase in hepatic cyclic adenosine 3',5'-monophosphate (cAMP), glycogen depression, and uptake of 14C-labeled nonmetabolizable amino acid analogues (AA). Plasma hormone concentrations reach maximum levels by 5 h and decline by 24 h. The hepatic concentrations of AA parallel the insulin and glucagon responses and correlate with the inverse of insulin/glucagon molar ratio. In spite of mobilization of hepatic glycogen evident at 5 h, plasma glucose concentrations were transiently depressed. Plasma insulin, glucagon, and hepatic AA concentrations were dose dependent. Plasma insulin and glucagon responses to crude LEM may explain increases in hepatic cAMP, uptake of AA, and glycogenolysis as well as hypoglycemia. These data partially characterize the role of crude LEM, provide an explanation for the stimuli-inducing hyperglucagonemia and hyperinsulinemia during infection. They implicate the endocrine pancreas as a factor regulating the host's metabolic response to infection.     

Exercise training prevents hyperinsulinemia, muscular glycogen loss and muscle atrophy induced by dexamethasone treatment

This study investigated whether exercise training could prevent the negative side effects of dexamethasone. Rats underwent a training period and were either submitted to a running protocol (60% physical capacity, 5 days/week for 8 weeks) or kept sedentary. After this training period, the animals underwent dexamethasone treatment (1 mg/kg per day, i.p., 10 days). Glycemia, insulinemia, muscular weight and muscular glycogen were measured from blood and skeletal muscle. Vascular endothelial growth factor (VEGF) protein was analyzed in skeletal muscles. Dexamethasone treatment evoked body weight loss (?24%), followed by muscular atrophy in the tibialis anterior (?25%) and the extensor digitorum longus (EDL, ?15%). Dexamethasone also increased serum insulin levels by 5.7-fold and glucose levels by 2.5-fold compared to control. The exercise protocol prevented atrophy of the EDL and insulin resistance. Also, dexamethasone-treated rats showed decreased muscular glycogen (?41%), which was further attenuated by the exercise protocol. The VEGF protein expression decreased in the skeletal muscles of dexamethasone-treated rats and was unaltered by the exercise protocol. These data suggest that exercise attenuates hyperglycemia and may also prevent insulin resistance, muscular glycogen loss and muscular atrophy, thus suggesting that exercise may have some benefits during glucocorticoid treatment.     

Control of hepatic glycogen metabolism in the rhesus monkey: effect of glucose, insulin, and glucagon administration.

The effects of intravenous glucose, insulin and glucagon admininistration on the hepatic glycogen synthase and glycogen phosphorylase systems were assessed in the anesthetized rhesus monkey. Results were correlated with measurements of hepatic cyclic AMP (cAMP) concentrations and plasma glucose, insulin, and glucagon concentrations. Both glucose and insulin administration promoted significant inactivation of phosphorylase by 1 min, which was followed by more gradual activation of synthase. Neither glucose nor insulin caused significant changes in hepatic cAMP. Marked hyperglucagonemia resulting from insulin-induced hypoglycemia did not cause increases IN in hepatic cAMP, suggesting that the elevated insulin levels possibly inhibited glucagon action on the hepatic adenylate cyclase-cAMP system. Glucagon administration caused large increases in hepatic cAMP and activation of phosphorylase within 1 min, followed by more gradual inactivation of synthase when it had been previously activated by glucose. Concomitant glucose infusion, with resulting increased plasma insulin concentrations, markedly diminished the duration of hepatic cAMP elevations following glucagon adminstration, again suggesting an insulin inhibition of glucagon action on the hepatic adenylate-cAMP system.