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 effect of tolbutamide on pyridine nucleotides and insulin secretion stimulated by aminophylline, 3,5-AMP-dibutyrate or glucagon was studied in pancreatic islets of rats previously treated with 6-aminonicotinamide (6-AN), an inhibitor of pyridine nucleotide synthesis. After being incubated for 60 min in a Krebs-Ringer-Bicarbonate-Buffer in the absence of glucose, pancreatic islets of rats i.p. injected with 35 mg/kg of 6-AN 6 hrs before pancreas removal contained about 30% less NADP and NADPH than did islets of control rats. No changes of NDA or NADH were observed in islets of 6-AN-treated animals. Addition of 16.5 mM glucose led to an increase of NADH, NADPH and a decrease of NADP in islets of both groups of animals; NAD levels remained unchanged. In vitro addition of tolbutamide to islets of control rats did not affect the levels of NADPH or NADP in the presence of 5.5 mM glucose. When 16.5 mM glucose were present, a decrease of NADPH and an increase of NADP was obvious. No effect of tolbutamide on insular NADPH or NADP was observed in islets of rats previously treated with 6-AN be it in the presence of 5.5 or 16.5 mM glucose. In islets of 6-AN-treated rats insulin release in response to aminophylline or 3,5-AMP-dibutyrate in the presence of 5.5 mM glucose was significantly depressed, when compared to islets of untreated controls. Addition of tolbutamide increased insulin release due to aminophylline, 3,5-AMP-dibutyrate or glucagon islets of controls. Tolbutamide alone was without effect. In islets of 6-AN-treated rats aminophylline, 3,5-AMP-dibutyrate or glucagon stimulated insulin release only when tolbutamide was present. Our data suggest that there is no direct interference of tolbutamide with pyridine nucleotides of pancreatic islets, and that tolbutamide increases the secretory response of the beta-cell to aminophylline, 3,5-AMP-dibutyrate or glucagon when insulin release due to these agents is inhibited during decrease of insular NADP and NADPH, caused by 6-AN.
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PMID:Effect of tolbutamide on aminophylline-, 3,5-AMP-dibutyrate- or glucagon-induced insulin release from pancreatic islets after impairment of pyridine nucleotide metabolism caused by 6-aminonicotinamide (6-AN). 24 43

This paper reports the synthesis and the biological activities of six new glucagon analogues. In these compounds N-terminal modifications of the glucagon sequence were made, in most cases combined with changes in the C-terminal region which had been shown previously to enhance receptor affinity. The design of these analogues was based on [Lys17,18,Glu21]glucagon,1 a superagonist, which binds five times better than glucagon to the glucagon receptor, and on the potent glucagon antagonist [D-Phe4,Tyr5,Arg12]glucagon, which does not stimulate adenylate cyclase system even at very high concentrations. The N-terminal modifications involved substitution of His1 by the unnatural conformationally constrained residue, 4,5,6,7-tetrahydro-1H-imidazo[c]pyridine-6-carboxylic acid (Tip) and by desaminohistidine (dHis). In addition we prepared two analogues (6 and 7), in which we deleted the Phe6 residue, which was suggested to be part of a hydrophobic patch and involved in receptor binding. The following compounds were synthesized: [Tip1, Lys17,18,Glu21]glucagon (2); [Tip1,D-Phe4,Tyr5,Arg12,Lys17,18,Glu21]glucagon (3); [dHis1,D-Phe4,Tyr5,Arg12,Lys17,18,Glu21]glucagon (4); [dHis1,Asp3,D-Phe4,Tyr5,Arg12,Lys17,18,Glu21+ ++]glucagon (5); des-Phe6-[Tip1,D-Phe4,Tyr5,Arg12,Glu21]glucagon (6); des-Phe6-[Asp3,D-Phe4,Tyr5,Arg12,Glu21]glucagon (7). The binding potencies of these new analogues relative to glucagon (= 100) are 3.2 (2), 2.9 (3), 10.0 (4), 1.0 (5), 8.5 (6), and 1.7 (7). Analogue 2 is a partial agonist (maximum stimulation of adenylate cyclase (AC) approximately 15% and a potency 8.9% that of glucagon, while the remaining compounds 3-7 are antagonists unable to activate the AC system even at concentrations as high as 10(-5) M. In addition, in competition experiments, analogues 3-7 caused a right-shift of the glucagon stimulated adenylate cyclase dose-response curve.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthetic glucagon antagonists and partial agonists. 166 20

In rats, oral administration of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate), a dihydropyridine derivative, Ca2+-channel activator, lowers fasting glycaemia and improves glucose tolerance to carbohydrate loading without elevating peripheral plasma insulin. To study the hypoglycaemic mechanism of this compound, we have examined its effects on glucose production by isolated rat hepatocytes and on hormone secretion by the perfused rat pancreas. Incorporation of BAY K 8644 (0.2-10 microM) into the hepatocyte incubation medium failed to significantly modify glycogenolysis, gluconeogenesis or L-lactate production. Hepatocyte glycogen phosphorylase a (EC 2.4.1.1) activity and fructose 2,6-bisphosphate levels were also unaffected by BAY K 8644. In the perfused rat pancreas, BAY K 8644 markedly stimulated insulin release without modifying glucagon or somatostatin output. Thus, the possibility that this compound exerts its hypoglycaemic effect by provoking insulin secretion should be further investigated.
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PMID:In vitro effects of BAY K 8644, a dihydropyridine derivative with hypoglycaemic properties, on hepatic glucose production and pancreatic hormone secretion. 245 69

The effect of a specific alpha 2-adrenergic antagonist 2-[2-(4,5-dihydro-1.H-imidazol-2-yl)-1-phenyl-ethyl] pyridine dihydrochloride sesquihydrate (DG5128), on the glucose output by epinephrine and/or glucagon was studied using the perfused rat liver. The administration of DG5128 alone did not affect the glucose output. However, DG5128 produced a significant inhibition of the increased glucose output when induced by 10(-6) M epinephrine alone or 10(-6) M epinephrine plus 1.4 x 10(-10) M glucagon. There were no significant changes of the glucose output by 1.4 x 10(-10) M or 7.0 x 10(-11) M glucagon alone. On the other hand, addition of 1 mU/ml insulin to the perfusate suppressed the 7.0 x 10(-11) M glucagon-induced glucose output, but failed to decrease the 1.4 x 10(-10) M glucagon effect. DG5128 suppressed further the glucagon (7.0 x 10(-11) M)-induced increase of glucose output in the presence of insulin. These results suggest that DG5128 produces a hypoglycemic effect partly through an inhibition of the increased hepatic glucose output elicited by epinephrine and glucagon.
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PMID:Effect of DG5128 on epinephrine and glucagon induced glucose output from the isolated perfused rat liver. 333 74

Midaglizole (DG-5128), 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, is a novel alpha 2-adrenoceptor antagonist. Its effects on plasma glucose, immunoreactive insulin (IRI), and immunoreactive glucagon (IRG) in healthy male volunteers were investigated. Volunteers received single oral administrations of midaglizole (150-500 mg), multiple increasing oral administration on 3 separate days (150-300 mg 3 times daily), or successive daily oral administration for 1 wk (200 mg 3 times daily). The hypoglycemic action of midaglizole was observed within 0.5-1.0 h after its administration and thereafter for 5 h. The maximum hypoglycemic effect was found 1.0-1.5 h after administration. Midaglizole decreased postprandial hyperglycemia in a dose-dependent manner. In the fasting state, midaglizole significantly increased IRI secretion and suppressed IRG secretion. Midaglizole inhibited epinephrine-induced platelet aggregation after successive administration for 1 wk (200 mg 3 times daily). The plasma half-life of midaglizole was only 3 h, and the drug was rapidly excreted into the urine and feces, with greater than 80% in its unchanged form, within 24 h. Midaglizole did not affect the results of any clinical or laboratory tests performed. Our data indicate that midaglizole is a possible hypoglycemic agent. Further clinical investigations are required to confirm its effects on diabetes mellitus.
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PMID:Studies of midaglizole (DG-5128). A new type of oral hypoglycemic drug in healthy subjects. 354 46

The Ca2+ selective fluorescent indicator, Quin-2, was employed to monitor continuously the concentration of free cytosolic Ca2+ [ Ca2+ ]i in isolated rat hepatocytes. Epinephrine (10(-6) M) and phenylephrine (10(-5) M), acting via alpha 1-adrenergic receptors, increases [ Ca2+ ]i from a basal concentration of approximately 0.2 microM to approximately 0.6 microM. This increase in [ Ca2+ ]i is evident as early as 1 to 1.5 s, the earliest time so far reported for any hepatic alpha 1-adrenergic event. Vasopressin (10(-8) M), after a lag which is 2 to 3 s longer, increases [ Ca2+ ]i to the same extent and at the same rate as the alpha 1-adrenergic agonists. Glucagon (10(-8) M) also increases [ Ca2+ ]i but at a significantly slower rate and only after a lag of about 10 s. All of these agents also induce an increase in the fluorescence of control cells. This Quin-2 independent fluorescence, which is due to an increased reduction of pyridine nucleotides, must be corrected for before the maximum change in [ Ca2+ ]i can be calculated but is sufficiently slow so as not to contribute to the initial rate of increase in the Quin-2-dependent fluorescence.
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PMID:Changes in free cytosolic Ca2+ in hepatocytes following alpha 1-adrenergic stimulation. Studies on Quin-2-loaded hepatocytes. 613 32

The effects of glucagon on the respiratory function of mitochondria in situ were investigated in isolated perfused rat liver. Glucagon at the concentrations higher than 20 pM and cyclic AMP (75 microM) stimulated hepatic respiration, and shifted the redox state of pyridine nucleotide (NADH/NAD) in mitochondria in situ to a more reduced state as judged by organ fluorometry and beta-hydroxybutyrate/acetoacetate ratio. The organ spectrophotometric study revealed that glucagon and cyclic AMP induced the reduction of redox states of cytochromes a(a3), b and c+c1. Atractyloside (4 micrograms/ml) abolished the effects of glucagon on these parameters and gluconeogenesis from lactate. These observations suggest that glucagon increases the availability of substrates for mitochondrial respiration, and this alteration in mitochondrial function is crucial in enhancing gluconeogenesis.
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PMID:Effects of glucagon on the redox states of cytochromes in mitochondria in situ in perfused rat liver. 632 76

Treatment of isolated hepatocytes with the alpha 1-adrenergic agonist norepinephrine induced a dose-dependent increase in free cytosolic Ca2+, as judged by fluorescence increases, in cells loaded with the Ca2+ indicator (2-[(2-bis[carboxymethyl]amino-5-methylphenoxy)methyl]-6-methoxy-8 -bis [carboxymethyl]aminoquinoline (quin-2). Pretreatment with either glucagon or dibutyryl cAMP increased the rate and magnitude of the quin-2 fluorescence response in hepatocytes treated with submaximal doses of norepinephrine and increased the cell sensitivity such that a physiological concentration of norepinephrine (7.5 nM) was able to provoke a quin-2 fluorescence response. Similar enhancement of norepinephrine-induced phosphorylase activation and pyridine nucleotide reduction in isolated hepatocytes and Ca2+ efflux from the perfused liver was also observed in the presence of glucagon. These potentiated responses correlated with a cAMP-dependent increase (mediated by glucagon, dibutyryl cAMP, or forskolin) in the binding of [3H]norepinephrine or [3H]epinephrine to sites present on isolated hepatocytes bearing the characteristics of alpha 1-adrenergic receptors. The data suggest that a cAMP-dependent mechanism is involved in the regulation of alpha 1-agonist binding to liver cells and, thereby, in the control of hepatic carbohydrate metabolism in response to catecholamines.
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PMID:Potentiation of alpha 1-adrenergic responses in rat liver by a cAMP-dependent mechanism. 633 Jul 49

Two chemically unrelated inhibitors of lipolysis were used in order to differentiate between the effect of FFA depression and a possible FFA-unrelated drug effect, respectively, on the plasma concentrations of GH, cortisol, and glucagon. Saline infusion served as a control experiment. In eight healthy male volunteers, a similar FFA depression by either iv infusion of nicotinic acid (3-pyridine-carboxylic acid, NA) or oral intake of an adenosine derivative, N(6)-allyl-N(6)-cyclohexyl-adenosine (AD-D), was followed by a significant GH increase (to 22.1 +/- 6.2 and 9.6 +/- 2.9 ng/ml at 240 and 270 min, respectively). Due to the large scatter of the GH concentrations during NA infusion, these responses were not significantly different. No GH increase occurred when the FFA depression was prevented by addition of a lipid infusion. In contrast, plasma cortisol and glucagon both increased significantly (by 107.4 micrograms/liter at 270 min and by 48.4 pg/ml at 60 min, respectively) during NA- but not during AD-D-induced FFA depression. Addition of the lipid infusion abolished the cortisol increase during NA infusion but had no influence on basal cortisol concentrations during AD-D intake. It lowered glucagon to values slightly below basal concentrations when added to the NA infusion and more markedly during AD-D administration. The results provide evidence that 1) depression of plasma FFA per se stimulates the secretion of GH, and 2) the increase of cortisol and glucagon during NA infusion is probably unrelated to the FFA depression. Hence, the stimulatory effect of FFA lack on glucagon secretion needs to be reconsidered.
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PMID:Growth hormone, cortisol, and glucagon concentrations during plasma free fatty acid depression: different effects of nicotinic acid and an adenosine derivative (BM 11.189). 634 70

Menadione and NH4Cl were reported to lower the islet content of reduced pyridine nucleotides. They were used to investigate the possible significance of NAD(P)H in the regulation of glucagon release by glucose and arginine. Menadione (10-25 mumol/l) enhanced arginine-stimulated glucagon release at a low glucose concentration (3.3 mmol/l), but failed both to affect glucagon secretion in the sole presence of glucose (3.3 mmol/l) and to suppress the inhibitory action of glucose 11.1 mmol/l upon glucagon output. In contrast to menadione, NH4Cl inhibited arginine-stimulated glucagon release at the low glucose concentration. The inhibitory action of glucose in high concentration upon glucagon release was not suppressed by NH4Cl. These findings do not permit to extrapolate to the A2-cell the concept that reduced pyridine nucleotides represent a major coupling factor in the nutritional regulation of hormonal release.
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PMID:Evidence for a limited role of NAD(P)H in the nutritional regulation of glucagon release: studies with menadione and NH4Cl. 699 42


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