Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antiprotozoal drug pentamidine can be toxic to islet cells in vivo and in vitro. Rat islets were exposed to pentamidine (mesylate and isethionate salts) and six other structurally related diamidines. The beta-cell response to arginine + theophylline was suppressed by pentamidine (10(-2) mmol/l) while the glucagon and somatostatin secretions persisted. All diamidines tested suppressed the beta-cell function, with a log-dose-response proportionality, the mesylate compound being more potent than pentamidine isethionate, and the lipophilic analogs more than the hydrosoluble diamidines. Electron microscopy revealed distinct morphological alterations in islets exposed to pentamidine, the intensity of these changes being dose-and time-dependent, and the beta cells more severely damaged than the non-beta cells. 51Cr-labelled islet cells and RIN 5 F cells consistently appeared more sensitive to pentamidine cytotoxicity than rat fibroblasts, myeloma cells and hepatocytes. The pentamidine-induced suppression of beta-cell function was not, in conditions tested, affected by the presence of nicotinamide and the hexose concentration in the medium. The kinetics of islet damage were slower than those of streptozotocin and alloxan-induced islet damage. The present study confirms that pentamidine is selectively toxic to islet beta cells, with some features distinct from the alloxan and streptozotocin toxicities to these cells. The mechanism of this process and its precipitating factors in vivo need clarification.
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PMID:Functional and morphological modifications induced in rat islets by pentamidine and other diamidines in vitro. 389 20

Subdiabetogenic doses of alloxan injected into the hepatic portal vein of rats abolished glucagon-induced inhibition of feeding (glucagon satiety) both in daytime tests using a palatable food and in nighttime tests using their standard pelleted diet. In contrast, inhibition of food intake by cholecystokinin and epinephrine and stimulation of feeding by 2-deoxy-D-glucose were not impaired by alloxan. Alloxan-induced deficits in glucagon satiety did not appear to result from generalized hepatocellular necrosis, because satiety deficits outlasted histological signs of toxicity and because furosemide, which produced a similar degree of hepatotoxicity, did not impair glucagon satiety. In addition, alloxan's effects were not associated with impaired glycogen storage or mobilization. Recovery of glucagon satiety occurred in some animals but not until 3-6 mo after alloxan. The degree of recovery was inversely related to alloxan dose. Our results indicate that, when administered into the hepatic portal vein, alloxan may be a relatively specific toxin for cells involved in the mediation of glucagon satiety. The specificity of the deficit and the time course of recovery suggest that the alloxan-sensitive cells may be hepatic vagal neurons.
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PMID:Glucagon-induced inhibition of feeding is impaired by hepatic portal alloxan injection. 396 37

We have previously shown that, in alloxan-diabetic dogs, the adjunction of sodium 2-chloropropionate (2-CP) with insulin injections resulted in a reduction of both hyperglycemia and hyperglucagonemia. The present studies were designed to more closely examine the glucagon-lowering effect of 2-CP. We investigated whether 2-CP was able to reduce elevated glucagon secretion both in vivo in streptozocin (STZ)-diabetic rats, and in vitro in the isolated, perfused rat pancreas. 2-CP (1 mmol/kg or 108 mg/kg) was given during 2 mo through esophageal tube to diabetic rats deprived of exogenous insulin. The drug induced a significant reduction of hyperglucagonemia (P less than 0.05) of blood lactate and alanine levels (P less than 0.02) and of plasma triglyceride levels (P less than 0.001). Furthermore, 2-CP markedly decreased glucosuria (P less than 0.005). In the isolated rat pancreas perfused with 2.8 mmol/L glucose, the continuous perfusion of 2-CP (1 mmol/L) starting before an infusion of arginine or alanine (5 mmol/L) considerably reduced the hypersecretion of glucagon evoked by these amino acids (P less than 0.001). These experiments show that sodium 2-chloropropionate can reduce glucagon hypersecretion in the diabetic rat not only in vivo, but acts also directly in vitro on the isolated, perfused pancreas of normal rats.
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PMID:Effect of sodium 2-chloropropionate on glucagon secretion in the rat. 400 81

1. The activities of NMN adenylyltransferase and of NAD(+) kinase have been measured in the livers of adrenalectomized or alloxan-diabetic rats and in the livers of rats treated with glucagon, pituitary growth hormone or thyroxine. 2. The activities of these enzymes have been compared with the effects of the same treatments on the nicotinamide nucleotide concentrations in the liver. 3. Alloxandiabetes (+37%) and thyroxine (+27%) both increased the activity of NMN adenylyltransferase. The other treatments were without effect on this enzyme. 4. Only thyroxine increased the activity of NAD(+) kinase significantly (+26%) although both adrenalectomy and glucagon tended to increase its activity. 5. The activity of NAD(+) glycohydrolase was measured in the livers of diabetic rats, and in the livers of rats treated with either growth hormone or thyroxine. Of these treatments, only growth hormone altered the enzyme activity (+26%, calculated on a total hepatic activity basis). 6. Female rats had a greater hepatic NAD(+)-kinase activity than males but there was no sex difference with respect to NMN adenylyltransferase. 7. The lack of correlation between the maximum potential activity of these three enzymes and the known changes of the nicotinamide nucleotides in each of the hormone conditions is discussed.
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PMID:The activities of nicotinamide mononucleotide adenylyltransferase and of nicotinamide-adenine dinucleotide kinase in the livers of rats subjected to different hormonal treatments. 437 8

In conscious dogs intravenously infused somatostatin (3.3 mug per min for 1 h) caused prompt and sustained declines in mean plasma insulin and glucagon, even during alanine infusion and intraduodenal casein hydrolysate feeding; plasma glucose declined, but not significantly. 6.7 mug per min of somatostatin significantly lowered pancreatoduodenal vein glucagon and insulin within 2.5 min and profoundly suppressed their secretion throughout the infusion. Consistent bihormonal suppression occurred at rates as low as 24 ng per kg per min, but was variable at 12 and 2.4 ng per kg per min. When somatostatin-induced (3.3 mug per min) hypoglucagonemia was corrected by exogenous glucagon, hyperglycemia occurred. In dogs with long-standing insulin-requiring alloxan diabetes 3.3 mug per min of somatostatin suppressed glucagon to 55 pg per ml throughout the 30-min infusion and lowered glucose by 36.4+/-6.1 mg per dl, about 1 mg per dl per min. Glucagon suppression was maintained despite alanine infusion, and glucose, which rose 29 mg per dl during alanine infusion without somatostatin, declined 58 mg per dl in the somatostatin-treated diabetic dogs despite alanine. Continuous infusion of somatostatin for 24 h in five insulin-requiring alloxan-diabetic dogs suppressed glucagon and lowered glucose significantly, usually to below normal. It is concluded that in normal dogs pharmacologic doses of somatostatin virtually abolish insulin and glucagon secretion in the basal state and during hyperaminoacidemia. Hyperglycemia occurs during somatostatin-induced insulin lack only if hypoglucagonemia is corrected. Somatostatin suppresses glucagon in diabetic dogs and lowers their plasma glucose approximately 1 mg per dl per min, even when the gluconeogenic substrate alanine is abundant. Glucagon suppression can be maintained for several hours in such dogs and hyperglycemia is thereby reduced.
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PMID:Somatostatin-induced changes in insulin and glucagon secretion in normal and diabetic dogs. 443 39

Highly purified secretin, infused endoportally in five conscious mongrel dogs at a rate of 10 clinical units per min for 20 min, caused a prompt and statistically significant reduction in the pancreaticoduodenal vein level of pancreatic glucagon from a control average of 1130 pg/ml (SEM+/-312) to a nadir of 492 pg/ml (SEM+/-194) 15 min later (P < 0.01). During modest hyperglycemia of about 130 mg/100 ml, induced by glucose infusion, the infusion of secretin at the same rate elicited even more dramatic suppression of pancreaticoduodenal glucagon levels to virtually unmeasurable concentrations. At a lower rate of infusion (5 U priming injection followed by 1 U/min for 20 min) significant suppression of glucagon secretion during hyperglycemia was also observed. Stimulation of endogenous secretin release by the intraduodenal administration of 14 mEq of HCl in 10 dogs during intravenous glucose infusion was followed by a decline in pancreaticoduodenal vein glucagon from 130 pg/ml (SEM+/-34) to a nadir of 99 pg/ml (SEM+/-32) 5 min later (P < 0.05). The infusion of secretin at a rate of 10 U/min in alloxan-diabetic dogs was associated with a significant decline in peripheral venous plasma glucagon, from a mean preinfusion level of 272 pg/ml (SEM+/-39) to a nadir of 128 pg/ml (SEM+/-22) (P < 0.01). It was concluded that exogenous secretin in the doses employed in this study is a potent suppressor of glucagon secretion, particularly during hyperglycemia. HCl-stimulated endogenous secretin also suppresses glucagon secretion. The ability of secretin to augment the glucagon-suppressing effect of ingested glucose qualifies it uniquely for a physiologic role as a modifier of the islet cell response to ingested glucose. The fact that it lowers the hyperglucagonemia of alloxan-diabetic dogs suggests that its glucagon-suppressing activity may not be insulin dependent.
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PMID:Suppressive effect of secretin upon pancreatic alpha cell function. 455 84

In acute experimental diabetes in animals, alpha-cell unresponsiveness to hyperglycemia can be promptly corrected by insulin, but in human diabetes, even massive doses of insulin have little effect. To determine if this inability of insulin to correct the alpha-cell abnormality in man is merely the consequence of the long duration of the diabetic state (rather than of a difference in mechanism), the effect of insulin was studied in alloxan diabetes of long duration. Alloxan-diabetic dogs were maintained for 7-18 mo and treated daily with insulin. When glucose was infused without insulin, glucagon did not decline but rose paradoxically. However, when insulin was infused at a rate of 9 mU/kg/min together with glucose, a prompt decline in glucagon from a base-line average of 171 pg/ml SEM+/-34 to a nadir of 41 pg/ml SEM+/-9 was observed. This decline indicated that alpha-cell responsiveness to hyperglycemia is completely restored by large quantities of insulin. To determine if small amounts of insulin would similarly restore alpha-cell responsiveness in long-standing experimental diabetes, 1.4 mU/kg/min was infused. By the time the mean insulin level had risen 43 muU/ml, glucagon had declined significantly and ultimately fell to a nadir of 44 pg/ml. It is concluded from these studies that alpha-cell responsiveness to hyperglycemia can be fully restored in long-standing alloxandiabetic dogs as readily as in acutely diabetic dogs. Its ineffectiveness in restoring alpha-cell responsiveness to hyperglycemia in human diabetes may not, therefore, be related to duration of the diabetic state, and may reflect a primary alpha-cell defect.
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PMID:The effect of insulin on the alpha-cell response to hyperglycemia in long-standing alloxan diabetes. 459 97

Rat liver l-serine-pyruvate aminotransferase activity exceeds markedly the normal adult value (a) in the neonatal period, (b) after glucagon injection and (c) after alloxan injection, observations that reinforce the suggestion from comparative findings that the aminotransferase has a role in gluconeogenesis. Some findings, however, argue in favour of l-serine dehydratase as the enzyme of gluconeogenesis from l-serine.
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PMID:Increased liver L-serine-pyruvate aminotransferase activity under gluconeogenic conditions. 472 29

Suppression of pancreatic glucagon secretion by hyperglycemia is a characteristic of normal alpha cell function. However, in diabetic subjects, plasma glucagon is normal or high despite hyperglycemia. It seemed possible that the presence of glucose or its metabolites within the alpha cell might be essential for suppression of glucagon secretion, and that in diabetes an intracellular deficiency of glucose secondary to insulin lack might be responsible for the nonsuppressibility. The present study was designed to determine the effect upon glucagon secretion of blockade of glucose metabolism and of experimental insulin deficiency. Blockade of glucose metabolism was induced in dogs by administration of 2-deoxyglucose or mannoheptulose. A striking rise in glucagon was observed despite accompanying hyperglycemia and hyperinsulinemia, which, in the case of mannoheptulose, was induced by infusing crystalline insulin. To determine if insulin lack also causes paradoxical hyperglucagonemia, dogs were made severely diabetic by alloxan. Fasting glucagon levels ranged from 3 to 22 times normal despite severe hyperglycemia, and were quickly restored to normal by infusing insulin. Diabetes induced in rats by anti-insulin serum was also associated with significant elevation in plasma glucagon. However, diazoxide-induced insulin lack did not increase glucagon in dogs. It is concluded that normal suppression of glucagon secretion by hyperglycemia does not occur when glucose metabolism is blocked or when severe insulin deficiency is produced. It is suggested that normal glucose metabolism within the alpha cell may be an insulin-requiring process without which hyperglycemic suppression of glucagon release cannot occur.
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PMID:The effect of experimental insulin deficiency on glucagon secretion. 493 45

Plasma glucose, free fatty acid, ketone, and triglyceride concentrations were measured at frequent intervals after the administration of alloxan to rats. Hepatic triglyceride levels were determined in the same animals. During the second 24-hr period after alloxan administration, severe ketoacidosis developed and triglyceride concentrations in the liver became markedly elevated. This finding was incompatible with the thesis that enhanced ketogenesis under circumstances of increased free fatty acid delivery to the liver requires diminished triglyceride synthesis. Plasma insulin and glucagon concentrations were determined at each time point. Initial changes in plasma glucose, ketones, free fatty acids, and triglycerides were accompanied by a fall in insulin concentrations, but no change occurred in glucagon levels. However, concentrations of the latter hormone increased dramatically in the second 24 hr after alloxan treatment and probably contributed to the development of the extreme hyperglycemia observed during this time period.
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PMID:Studies of the development of diabetic ketosis in the rat. 501 3


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