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)

Evidence is presented that modulation of the maximum velocity of a particulate low K-m cyclic adenosine 3':5'-monophosphate (cyclic AMP) phosphodiesterase by thyroid hormones is one mechanism for the regulation of the responsiveness of rat epididymal adipocytes to lipolytic agents such as epinephrine and glucagon. Fat cells of propylthiouracil-induced hypothyroid rats are unresponsive to lipolytic agents and the V-max of particulate low K-m cyclic AMP phosphodiesterase of these cells is elevated above normal. In vivo treatment of hypothyroid rats with triiodothyronine restores to control values both the lipolytic response of the fat cells to epinephrine and the V-max of the particulate bound low K-m cyclic AMP phosphodiesterase. No similar correlation is found with the soluble high K-m cyclic AMP phosphodiesterase. The phosphodiesterases of fat cells from normal and hypothyroid rats respond identically in vitro to propylthiouracil, triiodothyronine, methylisobutylxanthine, or theophylline, although the particulate low K-m cyclic AMP phosphodiesterase is inhibited to a greater extent than soluble cyclic guanosine 3':5'-monophosphate phosphodiesterase activity. Protein kinase of fat cells from hypothyroid rats can be stimulated by cyclic AMP to the same total activity as observed in fat cells of normal rats. However, less of the protein kinase in fat cells from hypothyroid rats was in the cyclic AMP-independent form. This shift in the equilibrium of protein kinase forms is consistent with an increased activity of low K-m cyclic AMP phosphodiesterase and probably results from a lowering of the lipolytically significant pool of cyclic AMP.
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PMID:Cyclic nucleotide phosphodiesterases and thyroid hormones. 16 41

Insulin has been shown to lower cyclic AMP (cAMP) levels in hormonally sensitive tissue. The mechanism by which this lowering occurs has not yet been fully defined. We studied the effects of insulin on rat adipose tissue cyclic nucleotide phosphodiestrase (PDE) in an incubation system. The adipose tissue used was from both normal animals and animals rendered diabetic by intravenous injections of streptozotocin. Rat epididymal fat pads were incubated in a Krebs-Ringer bicarbonate-4% albumin system with O, 100, 1,000 or 10,000 PU/ml insulin (INS); epinephrine (EPI) or glucagon (GLU) at several different concentrations. After 15 min of incubation, each tissue was homogenized, centrifugated, and the supernatant assayed for cAMP PDE activity using the breakdown of (3-H)cAMP. The data was used to characterize cAMP PDE into apparent high and low K-m PDE components. In the normal animals, INS increased Vmax of the low Km PDE components; 100 pU/ml INS, 30%, 1000 p1/ML INS, 40; and 10,000 pU/ml INS, 20%. In contrast, streptoxotocin diabetes lowered this Vmax by 30%. In the diabetic animals, INS also increased Vmax by 30%. In the diabetic animals, INS also increased Vmax of the low Km PDE component; 100 pU/ml INS, 30%; 1000 pU/ml INS, 50% and 10,000 pU/ml INS, 100%. Epinephrine at 1, 10, and 100 pg/ml stimulated low Km cAMP PDE activity by 67%, 73% and 44% respectively. The stimulatory effect of EPI on both the low and high Km cAMP PDE activity was neutralized by propranolol or adenosine. In comparison to EPI, GLU at very low concentrations, 10-9M, stimulated low Km cAMP PDE. These studies suggest that some of the biologic actions of insulin, an antilipolytic substance, are mediated through activation of low Km PDE. Furthermore, this enzymatic activity is lower in experimental diabetes. The stimulation of low Km PDE by lipolytic hormones may reflect a long-range protective action of these agents.
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PMID:Effect of insulin and lipolytic hormones on cyclic AMP phosphodieterase activity in normal and diabetic rat adipose tissue. 16 58

The possibility has been explored that decreases of adenylate cyclase may explain diminished hormone sensitivity of adipose tissue with aging. Isolated cells were prepared from epididymal fat pads of rats 1-, 2-, 6-, 12-, and 24-mo old, fixed in OSO4, and sized and counted with a Coulter apparatus. Adenylate cyclase was assayed in cell membranes (ghosts) using [alpha-32P] ATP as substrate and expressed as cyclic [32P] AMP/10 min per mg protein or per 10(6) cells. Enzyme activity was determined for the basal state and in the presence of varying concentrations of glucagon, ACTH, epinephrine, and fluoride. Basal activity per cell increased in threefold between 1 and 2 mo with a comparable increase in cell surface area, suggesting synthesis of enzyme along with new cell membrane. Although epinephrine stimulated adenylate cyclase 8-fold and fluoride 12-fold throughout the life-span of the rat, stimulated activity paralleled basal levels, decreasing 60% between 2 and 24 mo per mg protein and 40% between 6 and 24 mo per cell. Glucagon stimulated adenylate cyclase 4.5-fold relative to basal in the 1-mo-old rat, but its effect then rapidly decreased and was absent by 12 mo. The fourfold stimulation by ACTH noted in the 1-mo-old animals decreased gradually with age but was still twice basal at 24 mo. Since no significant change of cell size occurred after 6 mo, diminished hormone sensitivity with senescence cannot be related to cell size. Similar age-related patterns of hormonal activation were evoked by 5'-guanylyl-imidodiphosphate [GMP-P(NH)P], a nucleotide analogue which increased both basal- and hormone-activated enzyme at all ages studied. Dose-response curves to hormones, fluoride, and GMP-P (NH)P were not affected by age. High Mg++ (50 mM) in the presence of GMP-P-(NH)P stimulated adenylate cyclase to levels greater than with fluoride, but a similar loss of activity with aging was still observed. Loss of hormone receptors may partially explain the age-related decreases of glucagon and ACTH-sensitive adenylate cyclase, but decreased basal-, epinephrine-, fluoride-, and GMP-P-(NH) P-stimulated responses suggest loss of the catalytic component of the adenylate cyclase enzyme complex in the aging fat cell membranes.
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PMID:Hormone-sensitive fat cell adenylate cyclase in the rat. Influences of growth, cell size, and aging. 17 40

A glucagon-saline solution (0.1 ml, 10(7) mole/100 g body weight) was injected via the portal vein into nonfasted Wistar and carbohydrate-sensitive BHE rats. Levels of liver and epididymal fat pad cyclic-AMP were observed after 6 and 24 minutes. When compared to sham injected rats at 6 minutes, glucagon injected rats of both strains had twice the level of cyclie-AMP in liver and fat pad tissue. By 24 minutes, the cyclic-AMP levels of the Wistar rats had decreased to those observed in their sham injected counterparts, and the concentration of liver cyclic-AMP in both sham injected and glucagon injected BHE rats had decreased to levels significantly below those observed in the Wistar rats. This observation suggests that a lipolytic-lipogenic imbalance may reside in the livers of rats of the BHE strain.
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PMID:Rat strain differences in cyclic-AMP levels in liver and epididymal fat pad tissue as influenced by glucagon. 18 45

Normal male rats were made chronically diabetic by injection of alloxan or acutely diabetic by injection of anti-insulin serum. The concentration of cyclic AMP in epididymal adipose tissue was increased approximately 2 1/2-fold 24 h after alloxan administration and up to 7-fold 72 h post-alloxan. Treatment of alloxan-diabetic rats with insulin for 4 h completely suppressed lipolysis but only partially suppressed cyclic AMP levels; 6 h following insulin treatment cyclic AMP levels were normal. When segments of the epididymal fat bodies were incubated in vitro the high cyclic AMP levels were not maintained but instead decreased spontaneously. Addition of insulin to the incubation media decreased lipolysis in tissues of diabetic rats to levels measured in tissues of normal rats and accelerated the decline in cyclic AMP levels but did not return cyclic AMP levels to normal. Rats rendered acutely insulin deficient by injection of anti-insulin serum showed increased plasma glucose and free fatty acid levels and increased adipose tissue free fatty acid, and cyclic AMP levels 30 min following injection of the antiserum. Plasma glucagon levels increased but not until 2 h following anti-insulin serum, thereby excluding the possibility that an increment in plasma glucagon is the primary stimulus for the acceleration of lipolysis in diabetes. These data are consistent with the view that control of adipose tissue cyclic AMP levels in situ is an important physiologic action of insulin.
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PMID:Adenosine 3',5'cyclic monophosphate in adipose tissue of diabetic rats. 18 24

The effect of elevated body temperatures on the concentrations of epididymal cyclic AMP levels in non-diabetic, diabetic and hypophysectomized rats was studied. Cyclic AMP levels were increased during hyperthermia in all animals examined. This increase in epididymal cyclic AMP concentration was not seen in animals that had been supplemented with exogenous insulin prior to the experiment. The effect of pituitary lipolytic hormones on epididymal cyclic AMP levels was also investigated. Significant elevations of epididymal cyclic AMP levels were observed in hypophysectomized rats during hyperthermia indicating that pituitary hormones are not essential in causing these increases. Extrapituitary hormones, such as glucagon, might be responsible for epididymal cyclic AMP increases. Increases in epididymal cyclic AMP levels may therefore be the result of the reduction of blood insulin and concomitant increases of lipolytic hormones of both pituitary and extrapituitary origins.
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PMID:Effect of hyperthermia on epididymal cyclic AMP levels in diabetic non-diabetic and hypophysectomized rats. 19 89

Glycerol release from epididymal fat fragments of young adult (3-month old) ob/ob mice was three times lower than normal, on a tissue weight basis. Dose-response curves in response to isoproterenol and ACTH-(1--24) indicated that the capacity of the lipolytic process was reduced. However, the sensitivity to both hormones was normal, i.e. greater for ACTH than for isoproterenol. The burst of cyclic AMP observed at 7 minutes was affected even more than the lipolytic capacity in adipose tissue from obese mice. This was already observed in 1-month old animals, i.e. at a time when total body weight was still normal. It is concluded that the adenylate cyclase system is defective in adipose tissue of ob/ob mice. Besides, glucagon, vasoactive intestinal polypeptide, and secretin failed to stimulate glycerol release and cyclic AMP accumulation in both ob/ob, ob+/ob+, and HA-ICR mice, suggesting that mouse adipose tissue does not possess receptors for this group of hormones.
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PMID:Lipolysis and cyclic AMP levels in epididymal adipose tissue of obese-hyperglycaemic mice. 20 30

This study was performed in order to evaluate the effects of somatostatin on insulin releasing mechanisms and on glucose uptake in peripheral tissues using isolated pancreatic islets, isolated rat diaphragms and epididymal fat pads. Insulin release by various concentrations of glucose were examined, and it was found that 100 ng/ml of somatostatin significantly inhibited insulin release at the glucose concentration of 200 mg/dl. Somatostatin also significantly inhibted insulin release by the administration of 5microgram/ml of glucagon with 200 mg/dl of glucose concentration and 20 mM of orginine with 200mg/dl of glucose concentrations. But at the glucose concentration of 50mg/dl, no significant inhibition of somatostatin on insulin release was observed even when various concentrations of glucagon or arginine were added. The influence of somatostatin on peripheral tissues was examined in vitro, and no significant change on glucose uptake compared with the control group was shown in either tissues. The results indicated that somatostatin directly inhibited insulin release from rat pancreatic islets but had no effect on glucose uptake in peripheral tissues. The inhibitory effect of somatostatin on insulin release may act through the common mechanism of both glucose and other substances in leading to insulin release.
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PMID:[Effects of somatostatin on pancreatic isolated islets and peripheral tissues of rats]. 33 84

Specific modification of the single lysine residue (Lys-12) in glucagon with O-methylisourea has been effected by blocking the reactivity of the amino terminal histidine with copper, providing a method for obtaining [12-homoarginine]glucagon. It was found that as a side reaction, under the conditions of the modification reaction, Cu(II) catalyzed cleavage of the polypeptide chain between Asp-9 and Tyr-10, and between Lys-12 and Tyr-13. This observation may be of value for development of a sequence-specific peptide cleavage procedure. The dilute solution conformations of glucagon and [12-homoarginine]-glucagon were compared by circular dichroism, fluorescence, phosphorescence, energy transfer, and optical detection of magnetic resonance. The results indicate that conversion of Lys-12 to homoarginine does not alter the helix content the side chain conformation in the vicinity of the tyrosine and tryptophan residues, or the relative distances and orientations between these residues. However, the modification reduces the hormone potency towards activation of lipolysis in isolated rat epididymal fat cells by a factor of seven. We attribute the loss of potency to an interference with a specific interaction between the lysine residue and the fat cell hormone receptor, and not to a change in the solution conformation of the hormone.
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PMID:[12-Homoarginine]glucagon: synthesis and observations on conformation, biological activity, and copper-mediated peptide cleavage. 42 94

Metabolic adaptations to cyclic patterns of food intake were studied in genetically lean and obese Zucker rats. Twenty-four lean and 24 obese rats were exposed to 12 hours of light and 12 hours of dark and allowed food ad libitum. Both groups of rats ate more during the dark period of the cycle. The obese consumed nearly twice as much food as the lean during the light period of the cycle. At 4-hour intervals, rats were killed and liver and epididymal fat pads were removed for metabolic studies. Adipose tissue from lean rats demonstrated marked changes in rates of lipogenesis during the 24-hour cycle whereas adipose tissue from obese rats maintained a relatively steady rate of lipogenesis. Glucose incorporation into the glycerol moiety of triacylglycerol was nearly 3-fold higher in adipose tissue from obese rats. Liver lipogenesis in lean and obese rats followed their food intake pattern. Liver lipogenic rate (expressed per organ) was 3- to 5-fold higher in obese than lean rats during most of the 24-hour cycle. These data support the concept that the excessive fatty acids produced in the liver of obese rats are being esterified by adipose cells. Lipolytic response to glucagon was found in adipose tissue from obese rats during the dark and light periods, but only during the dark period for lean rats. These data suggest, in comparison to lean rats, that obese rats do not enter a relative catabolic state during a 24-hour cycle. A constant anabolic state in the genetically prone individual may lead to excessive lipid deposition and obesity.
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PMID:Diurnal changes in adipose and liver tissue metabolism of lean and obese Zucker rats. 57 Oct 11


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