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)

Pancreatic islet cell vacuolization, hyperglycemia, and glucose intolerance develop in rats after oral administration of cyproheptadine (CPH). In order to determine whether these effects were associated with abnormal insulin secretion, pancreas segments from CPH-treated and control rats were compared for their ability to secrete insulin in response to several stimuli. Oral administration of CPH (45 mg/kg/day) to rats for 1 or 8 days inhibited glucose-mediated insulin secretion from pancreas segments obtained 3 and 24 hr after the last dose of the drug. Insulin secretion had returned to normal by 48 hr after drug administration. Intraperitoneal administration of the drug was less effective than oral administration in inhibiting in vitro insulin secretion. Other stimuli for insulin secretion (tolbutamide, glucagon, L-leucine, and dibutyryl 3',5'cyclic AMP), like glucose, were incapable of releasing normal amounts of insulin from pancreas segments of CPH-treated rats. CPH and a metabolite, desmethyl-CPH, inhibited glucose-stimulated insulin secretion when added in vitro to pancreas segments from control rats. This suggests that the inhibition of insulin secretion in pancreas segments taken from animals treated with CPH could be due, at least in part, to the presence of drug and its metabolite in the tissue. A previously observed reduction in the pancreatic content of insulin in CPH-treated rats may also contribute to the abnormal insulin release in animals given the drug.
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PMID:Cyproheptadine and beta cell function in the rat: insulin secretion from pancreas segments in vitro. 17 78

1. Studies were performed to investigate the metabolic fate of dipeptides when administered intravenously in rats. Glycyl-leucine, glycylglycine or glycylsarcosine was injected into the jugular vein. The plasma disappearance rate after the peak plasma concentrations was most rapid for glycyl-leucine and least rapid for glycylsarcosine. 2. During urine collection for 40 min, trace amounts of glycyl-leucine and glycylglycine and 13% of the injected glycylsarcosine were excreted. 3. Neither glycylglycine nor glycyl-leucine was detected in the liver, muscle, intestinal mucosa or renal cortex, but concentrations of glycine or leucine, or both, in these tissues were increased after each injection. In contrast, glycylsarcosine was recovered in all these tissues with concentrations in the renal cortex being far greater than in any other tissue, but sarcosine was found only in the renal cortex and intestinal mucosa. 4. The changes in plasma concentrations of free amino acids, glucose and glucagon, and tissue concentrations of free amino acids, were similar after the intravenous administration of glycyl-leucine and an equimolar mixture of free glycine and leucine. However, the amount of insulin secreted during the 40 min after glycyl-leucine injection was 1-6 times that produced after the injection of the corresponding amino acid mixture. 5. Results show that, within the present experimental conditions, the intravenous administration of dipeptides is as effective as that of the corresponding free amino acids in enriching the tissue pools of amino acids. It is suggested that efficient hydrolysis by cellular enzymes prohibits accumulation of intact dipeptides in body tissues.
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PMID:Metabolism of intravenously administered dipeptides in rats: effects on amino acid pools, glucose concentration and insulin and glucagon secretion. 40 46

The effects of L-leucine, D-leucine, and L-isoleucine upon the secretion of glucagon and insulin were investigated using the isolated, perfused rat pancreas. All experiments were conducted in the presence of 5.6 mM D-glucose. Ten-minute perfusions of 2, 5, and 10 mM L-leucine induced the release of glucagon and insulin in a dose-related manner. The removal of L-leucine was followed by renewed release of insulin ("off-response") but not of glucagon. The magnitude of the off-response was greater when L-leucine was perfused over longer periods. L-Isoleucine evoked the release of both glucagon and insulin. When L-leucine was administered during perfusion of L-isoleucine, L-leucine-induced release of glucagon was inhibited, that of insulin was augmented, and the insulin off-response prevailed. When the perfusion of L-leucine immediately preceded that of L-isoleucine, L-isoleucine-induced release of glucagon was abolished and that of insulin was augmented. D-Leucine evoked the release of glucagon but not of insulin, and no off-response occurred. When the perfusion of D-leucine followed that of L-leucine, D-leucine-induced glucagon release was inhibited; the insulin off-response to L-leucine was not altered. We reached the following conclusions. 1) Glucagon release induced by L-leucine, D-leucine, or L-isoleucine is likely to be related to the occupancy by these analogous amino acids of transport and/or receptor sites which they share. 2) The insulin off response to L-leucine seems to be evoked by events which take place during the period of administration of L-leucine; these events are not likely to be the release of insulin that occurs during perfusion of L-leucine or the transport of L-leucine into or out of the beta cell. 3) Structurally or chemically similar compounds which are secretagogues both for glucagon and insulin affect the release of these hormones in different ways; these differences are likely to be due to dissimilar mechanisms governing the secretion of the two hormones.
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PMID:L-Leucine-induced secretion of glucagon and insulin, and the "off-response" to L-leucine in vitro. I. Characterization of the dynamics of secretion. 74 40

The effect of glucose and glucose plus glucagon on the incorporation of H-3-L-leucine into proinsulin and insulin was examined in isolated islets of twenty-one-day old fetal and five- and ten-day old newborn rats. Maximal stimulation of (pro-) insulin biosynthesis was achieved with 100 mg. per cent of glucose in isolated islets of twenty-one-day old fetal rats. No additional effect was observed with 300 mg. per cent of glucose. On the other hand, in islets of five- and ten-day old newborn rats the incorporation of H-3-L-leucine into proinsulin and insulin was gradually augmented by glucose up to concentrations of 300 mg. per cent. Addition of glucagon to the various glucose concentrations only enhanced the synthesis of insulin in ten-day old newborn islets, whereas it had no effect on the islets of the younger age groups. The results show a different pattern of insulin biosyntheses in fetal and newborn islets, which may be related to the varied plasma glucose concentrations of the perinatal period.
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PMID:Insulin biosynthesis in isolated pancreatic islets of fetal and newborn rats. 109 13

Leucine has been reported to be an important regulator of protein metabolism. We investigated the effect of intravenous infusion of L-leucine versus saline on amino acid metabolism in eight healthy human subjects. Plasma concentrations of amino acids were measured and protein turnover was estimated using L-(1-13C)lysine and L-(3,3,3,-2H3)leucine as tracers. Glucose kinetics were measured using D-(6,6-2H2)glucose as a tracer. Leucine infusion increased the plasma leucine concentration from 103 +/- 8 to 377 +/- 35 mumol/L (P less than .01). Plasma concentrations of essential amino acids, including threonine, methionine, isoleucine, valine, tyrosine, and phenylalanine were significantly decreased by leucine infusion. Leucine infusion did not change lysine flux significantly (108 +/- 4 during saline v 101 +/- 4 mumol/kg/h-1 during leucine infusion), but decreased lysine oxidation (13.2 +/- 0.9 v 10.7 +/- 1 mumol/kg/h, P less than .05) and endogenous leucine flux (from 128 +/- 4 to 113 +/- 7 mumol/kg/h, P less than .05) when plasma (2H3) ketoisocaproate (KIC) was used for calculation. During leucine infusion, the (2H3) KIC to (2H3) leucine plasma enrichment ratio increased from 0.76 +/- 0.02 to 0.88 +/- 0.01 (P less than .001), while estimation of leucine flux using plasma (2H3) leucine showed no change in endogenous leucine flux. Leucine infusion decreased hepatic glucose production and metabolic clearance of glucose, but did not change plasma concentrations of glucose, insulin, C-peptide, glucagon, epinephrine, norepinephrine, or free fatty acids. We conclude that leucine spares glucose and lysine catabolism and decreases plasma concentrations of essential amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of leucine on amino acid and glucose metabolism in humans. 164 Aug 50

Mild hyperglycemia was induced in normal rats by oral administration of both diazoxide and D-glucose. After 48 hours of such a treatment, the insulin and glucagon secretory responses of the perfused pancreas to alpha- and beta-D-glucose (3.3 mM) were examined in the presence of 10.0 mM L-leucine. The output of insulin, but not that of glucagon, and the perfusion pressure were higher in treated than control rats. The alpha-anomer of D-glucose was a more potent insulin secretagogue than beta-D-glucose in both control and treated rats. However, the alpha/beta ratio in insulin output was twice higher in control than treated rats. By analogy with other experimental models of diabetes, the attenuation in the anomeric difference of glucose-stimulated insulin output in the treated rats could reflect an altered secretory response to alpha- rather than beta-D-glucose. These findings suggest that hyperglycemia provokes, as a function of its severity and duration, first attenuation and then suppression, if not inversion, of the anomeric preference for alpha-D-glucose in insulin release. They are also compatible with the hypothesis that the anomeric malaise, associated with B-cell glucotoxicity, is caused by a progressive accumulation of glycogen in this cell.
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PMID:Attenuated anomeric difference of glucose-induced insulin release in the perfused pancreas of diazoxide-treated rats. 191 34

Ligation of the pancreatic duct in rabbits provokes a decrease in the insulin and glucagon content of the pancreas, and may lead to chronic hyperglycemia. The insulin secretory behavior of the perfused pancreas is perturbed in duct-ligated animals, and this is illustrated in several respects: 1. The steady-state insulin output evoked by L-leucine (10 mM) is higher in duct-ligated than control rabbits; 2. In the presence of the amino acid, the response to D-glucose is characterized by a delayed onset, the absence of an early secretory peak, and a sluggish return towards basal value upon removal of the hexose from the perfusate; and 3. Whereas control rabbits display a higher secretory response to alpha- than beta-D-glucose, such is no more the case in duct-ligated rabbits. The perturbation of the anomeric specificity in secretory response is most obvious in diabetic duct-ligated rabbits, in which case beta-D-glucose stimulates insulin release more efficiently than alpha-D-glucose. In both control and duct-ligated rabbits, however, the alpha-anomer is more potent than the beta-anomer in suppressing leucine-stimulated glucagon secretion. These findings are compatible with the view that chronic hyperglycemia leads to alteration in the anomeric preference of the pancreatic B-cell for alpha-D-glucose, possibly as a result of the nonenzymatic glycation of glycolytic enzymes in insulin-producing, but not glucagon-producing, islet cells.
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PMID:Altered anomeric specificity of glucose-induced insulin release in rabbits with duct-ligated pancreas. 203 26

In the isolated perfused rat pancreas, D,L-difluoromethylornithine, tested at a concentration of 3 mmol/L, failed to affect the release of glucagon and insulin caused, over 15 min stimulation, by either L-arginine or L-ornithine (2.0, 5.0 or 10.0 mmol/L) in the presence of either 3.3 or 5.6 mmol/L D-glucose. The inhibition of ornithine decarboxylase also failed to affect the release of glucagon provoked by either L-leucine (2 or 3 mmol/L) or L-glutamine (2 mmol/L) and the secretion of insulin stimulated by a rise in glucose concentration from 5.6 to 10.6 mmol/L. These data are interpreted to suggest that the rapid generation of polyamines from either L-arginine or L-ornithine does not play any significant role in the immediate glucagonotropic and insulinotropic action of these cationic amino acids.
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PMID:Stimulus-secretion coupling of arginine-induced insulin release. Resistance of arginine- and ornithine-stimulated glucagon and insulin release to D,L-alpha-difluoromethylornithine. 240 45

Two small peptide antigens, glucagon and enkephalin (5-L-leucine), were covalently immobilised using either glutaraldehyde or bis-(sulphosuccinimidyl) suberate to an adsorbed layer of phenylalanine-lysine copolymer (PL) or partially acetylated PL (APL) on polystyrene. Both copolymers formed stable layers, particularly APL after adsorption from solution in distilled water. Adsorption of the copolymers under these conditions and subsequent coupling of the antigens yielded solid phases with low non-specific immunoglobulin binding characteristics in an enzyme-linked immunosorbent assay (ELISA) to detect peptide-specific antibodies in rabbit serum. The signal-to-noise ratio in this ELISA was dependent on the combination of copolymer, antigen and coupling reagent employed. Removal from the solid-phase of weakly bound antigen by washing with solutions containing Tween 20 or sodium dodecyl sulphate (SDS) increased assay sensitivity, which was 2-4-fold greater than when simple antigen adsorption was utilised. In the ELISA, the coefficient of variation was lower when covalent antigen coupling was employed.
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PMID:Solid-phase immunoassay of serum antibodies to peptides. Covalent antigen binding to adsorbed phenylalanine-lysine copolymers. 249 9

Compounds with a reported in vivo and in vitro effect on the diabetogenicity of alloxan were studied with regard to the uptake of calcium in mouse islet mitochondria, with the aim of obtaining information on the susceptibility and selectivity of alloxan toxicity. A strong correlation was found between the uptake of calcium in mouse islet mitochondria, which is believed to be associated with the activation of oxidative enzymes involved in energy production and secretion of insulin, and the protection afforded by the injection of D-glucose, D-mannose, L-leucine and glucagon, and by the in vitro administration of cyclic AMP, L-glutamine and L-leucine. The effect of D-glucose was abolished by D-mannoheptulose. A correlation was also seen between reduced mitochondrial uptake of calcium and the potentiation of alloxan cytotoxicity afforded by 1.25-dihydroxycholecalciferol, methylene blue and menadione. The observations suggest an association between functional activity and alloxan cytotoxicity. The selectivity of the cytotoxic action of alloxan is believed to be dependent on a reduced mitochondrial uptake of calcium and an associated reduction of the energy production at low functional activity in the B-cells (e.g. in starvation which is well-known to potentiate the alloxan effect).
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PMID:Alloxan diabetogenicity: determinants of potentiation, protection and B-cell selectivity. 254 7


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