Differential response of rat cardiac and skeletal muscle glycogen to glucocorticoids.

Though glucocorticoids were previously implicated in the support of myocardial glycogen supercompensation after exercise, it was unclear why skeletal muscle glycogen did not simultaneously supercompensate since it was also exposed to the exercise-induced glucocorticoid increases. The current study shows that glucocorticoids differentially affect cardiac and skeletal muscle glycogen. Following dexamethasone administration (400 micrograms i.p.) myocardial glycogen peaked at 6 h while glycogen in the soleus, red vastus lateralis, and white vastus lateralis increased more slowly and reached the highest values 17 h postinjection. Concurrently, blood glucose, insulin, and glucagon remained at control levels. Liver glycogen increased within 2 h and continued to rise with a peak value at 17 h. Plasma free fatty acid (FFA) levels increased and remained high throughout the 26-h experimental period. High FFA levels inhibit glycogenolysis and thus could be partially responsible for glucocorticoid-induced glycogen increases. It is postulated that glycogen supercompensation does not readily occur in skeletal muscles after exercise because of the brevity of the corticosterone and FFA increases and the slowness of the skeletal muscle glycogen response to glucocorticoids.

Substrate changes during fasting and refeeding contrasted in old and young rats.

Carbohydrate and lipid substrate changes associated with fasting were similar in aged (over 24 months), 1-year-old and young (about 4 months old) rats. In all three age-groups fasting reduced liver and skeletal muscle glycogen, elevated myocardial glycogen and plasm free fatty acid (FFA) levels, but did not significantly affect blood glucose. With refeeding, the myocardium from aged and 1-year-old rats lacked the glycogenesis observed in young rats. Less glycogenesis was also observed in aged soleus muscles during refeeding than in soleus muscles from young or 1-year-old rats. This depressed glycogenesis in the old rats could not be attributed to any change in the tissue triglyceride or plasma FFA response to refeeding, but was accompanied by a slightly greater elevation of glucagon in the aged rats. Though its etiology is unclear, the depressed glycogenesis indicates that aging affects aspects of carbohydrate metabolism in addition to the known decrease in glucose tolerance.

Somatostatin neutralization stimulates glucagon and insulin secretion from the avian pancreas.

Using the isolated perfused chicken pancreas, somatostatin antiserum was infused to neutralize the effects of endogenous somatostatin secretion on neighboring endocrine cells. At normal and high glucose concentrations, somatostatin antiserum significantly stimulated both glucagon and insulin secretion. These findings suggest that somatostatin continuously inhibits A and B cell output, and that glucose suppression of glucagon release is partially dependent upon local somatostatin secretion.

Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia.

Streptozotocin (SZ) was given to 2-day-old neonatal rats, and, during their subsequent development, the interrelationships between plasma glucose, plasma insulin, pancreatic islet morphology, and hormone content were examined. At 4 days of age, a peak of hyperglycemia was observed (SZ, 349 plus or minus 8 mg/dl versus control (C), 127 plus or minus 2) that was associated with a marked reduction of B-cell numbers (SZ, 26.5 plus or minus 2.6% B-cell per islet versus C, 72.8 plus or minus 0.8%). By 10 days of age the SZ animals became normoglycemia with partial recovery of the B-cell number (SZ, 39.6 plus or minus 2.1% versus, C, 64.0 plus or minus 2.6%). By six weeks hyperglycemia returned (SZ, 345 plus or minus 5.2 mg/dl versus C, 171 plus or minus 6.2) with B-cell number of the SZ being 72% of the C (SZ, 48.8 plus or minus 2.4% versus C, 67.5 plus or minus 1.5%). This hyperglycemia and reduced B-cell number persisted to at least 13 wk age. Despite a marked reduction of pancreatic insulin content observed during development, there was little effect upon glucagon or somatostatin content. At 6 wk of age, the plasma insulin concentration was only 30% of C, which suggests as insulin secretory defect beyond that which could be accounted for by the modest B-cell reduction. The present study indicates that even though active regeneration of B-cells occurred after early injury, the capacity for ultimate normalization was limited. The resultant moderate reduction in B-cell number may be associated with a functional defect in glucose-stimulated insulin secretion.

Effects of exogenous insulin, glucagon, and somatostatin on islet hormone secretion in the perfused chicken pancreas.

The effects of exogenous insulin were examined in the isolated perfused chicken pancreas with the duodenum excluded. At low background glucose (50 mg/dl), exogenous insulin infused at a concentration of 20,000 microU/ml elicited clear stimulation of somatostatin secretion while simultaneously inhibiting glucagon release. When the background glucose concentration was elevated to 750 mg/dl, exogenous insulin, had no effect on either somatostatin or glucagon release. When graded doses of exogenous insulin were infused into the chicken pancreas at low background glucose, low concentrations (200 microU/ml) had little effect on somatostatin or glucagon release, but higher concentrations (2000 and 20,000 microU/ml) had clear effects on both somatostatin and glucagon secretion. Glucagon infused at 100 ng/ml stimulated both insulin and somatostatin release. When somatostatin was infused at 25 ng/ml, clear inhibition of glucagon was seen with insulin inhibited to a lesser extent. This study supports the notion of a negative feedback relation between B and D-cells of the pancreatic islets and suggests a paracrine mediation.

Acetylcholine stimulates insulin, glucagon, and somatostatin release in the perfused chicken pancreas.

To evaluate the possible cholinergic control of islet hormone secretion, acetylcholine (10 microM) was perfused into the isolated chicken pancreas-duodenum, with perfusate concentrations of 2.8, 14, or 42 mM glucose. Prompt and significant stimulation of insulin, glucagon, and somatostatin secretion was seen when the glucose concentration was 14 mM, and this stimulation was blocked by preinfusion of atropine sulfate (50 microM). Similar stimulation of all three peptides was seen when the perfusate concentration of glucose was 42 mM. When the perfusate glucose concentration was 2.8 mM, the insulin response to acetylcholine was absent and the response by glucagon could not be discerned, perhaps because release was close to maximal. The somatostatin response, however, was only slightly diminished from that seen at higher glucose levels. The B cell response to acetycholine in the chicken was considerably greater than the weak responses seen to high glucose or arginine, suggesting a dominant role for cholinergic control of avian insulin secretion. In addition, the parasympathetic nervous system may also play a role in the secretory control of A- and D cells.

Insulin, glucagon, and somatostatin secretion from isolated perfused rat and chicken pancreas-duodenum.

Insulin, glucagon, and somatostatin secretion were evaluated in the following isolated perfused models: rat pancreas-duodenum (both normal and streptozotocin-diabetic animals) and the chicken pancreas with and without duodenum. Insulin secretion in response to glucose or arginine was greater from the normal rat than either the diabetic rat or the chicken. Glucagon release from both species was suppressed by glucose and stimulated by arginine except that poor inhibition by glucose was found in the diabetic rat. Somatostatin could be measured in the effluent from both normal and diabetic rats, but the responses to glucose and arginine were variable and modest. Clear increases of secretion in the rat were only observed in response to a combination of glucose, arginine, theophylline, and isoproterenol. In contrast, the chicken somatostatin secretion was markedly stimulated by glucose and by arginine. In conclusion, the perfused chicken pancreas-duodenum has been shown to secrete large amounts of somatostatin in comparison to the rat and should prove to be a useful system for the study of D-cell regulation.

The determinants of insulin extraction in the isolated perfused rat liver.

The effect of hepatic blood flow and portal insulin concentration on insulin extraction during one passage through the isolated perfused rat liver was studied. The percentage of insulin extracted was constant over the physiological range of blood flows (4 to 28 ml/min). The total amount of insulin extracted increased as the input concentration was raised from 48 to 4860 microU/ml with the highest level of extraction being approximately 700 microU of insulin per gram of liver per minute. When square wave input pulses of 243 to 4860 microU/ml were presented, about 5% of this insulin was retained and then released by the liver for periods up to 15 minutes after the cessation of the input. The possible roles of glucose and glucagon as regulators of insulin extraction were studied. Glucose (300 mg/dl), as compared with no glucose, led to a significant reduction of insulin extraction (22% vs. 38%, p less than 0.001). Glucagon had no effect on insulin extraction in the presence of constant levels of glucose. It is concluded, therefore, that glucose may increase circulating insulin levels not only by its well known stimulation of insulin secretion by the pancreas, but also by inhibiting insulin extraction by the liver.