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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central nervous system myelin basic protein (MBP) stimulates the release of several peptide hormones including insulin and glucagon. This could be associated with the development of hyperglycaemia in neurological disorders such as stroke, in which MBP is known to leak into blood circulation. In the present study the mechanism of insulin and glucagon release was investigated by using short-term incubation of isolated rat pancreatic islets. Incubation with MBP in the absence of Ca2+ resulted in approx. 11-fold stimulation of insulin and glucagon release. The stimulation dwindled with increasing Ca2+ concentration and was 6.5-fold at 0.5 mM and 2-fold at 2.5 mM Ca2+. When MBP and glucose at various concentrations were simultaneously present in the incubation mixture, stimulation of insulin release was the sum of the stimulation induced by these two agents separately both at the 0.5 and 2.5 mM Ca2+ concentrations. Glucose at concentrations of 10 or 15 mM did not suppress MBP-stimulated glucagon release. Caffeine-evoked increase in intracellular Ca2+ was without effect on MBP-stimulated insulin or glucagon release but enhanced glucose-induced insulin release. The Ca2+ channel blocker diltiazem had no effect on MBP-stimulated insulin release at concentrations where glucose-stimulated release was inhibited. Ruthenium red inhibited both MBP- and glucose-stimulated insulin release as well as MBP-induced glucagon release. Staurosporine (inhibitor of protein kinase C) had no effect on MBP-induced insulin release, although it partially inhibited glucose-stimulated release. Maleylation of MBP abolished its insulin- and glucagon-releasing activity by approx. 90%. These results suggest that MBP exerts its insulin-releasing effect by mechanisms different from those of glucose-stimulated insulin release and does not require Ca2+ channels or protein kinase C. The relation of MBP-induced insulin and glucagon release to Ca2+ concentration is probably explained by enhanced self-aggregation of MBP or by increased ability of MBP to interact with islet cell membranes in the absence of Ca2+, or both. It is concluded that MBP-induced hormone release appears to be mediated by membrane fusion and oligomerization of MBP. The mechanism thus resembles that of various toxins and other cytotoxic agents.
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PMID:Mechanism of the myelin basic protein-induced insulin and glucagon release from isolated rat pancreatic islets. 754 15

The effects of parenteral glucose, cyclic AMP and caffeine on the breakdown of glycogen in the lysosomes of newborn rat hepatocytes, were studied by using biochemical assays, electron microscopy and quantitative morphometry. Glucose prevented the normal postnatal increase in lysosomal volume, acid alpha 1,4 glucosidase activity and lysosomal glycogen breakdown. On the contrary, cyclic AMP and caffeine promoted this increase. There was a positive correlation between liver cyclic AMP concentration and acid glucosidase activity (R = 0.84, p < 0,001). Cyclic AMP also induced a change in the shape of lysosomes. The postulation that glucagon secreted after birth is the natural stimulus for the cyclic AMP-mediated postnatal increase in acid glucosidase activity and mobilization of the lysosomal glycogen in rat hepatocytes, is supported by these experimental findings.
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PMID:The breakdown of glycogen in the lysosomes of newborn rat hepatocytes: the effects of glucose, cyclic 3',5'-AMP and caffeine. 789 41

1. In postganglionic sympathetic neurones and adrenal chromaffin cells, catecholamines are co-stored in vesicles with soluble peptides, including chromogranin A (CgA) and neuropeptide Y (NPY), which are subject to exocytotic co-release with catecholamines. 2. Plasma catecholamine, CgA and NPY responses to stimulators and inhibitors of sympatho-adrenal catecholamine storage and release were measured in humans. Short-term, high-intensity dynamic exercise, prolonged low-intensity dynamic exercise, and assumption of the upright posture, in decreasing order of potency, predominantly stimulated noradrenaline (NA) release from sympathetic nerve endings. Only high-intensity exercise elevated CgA and NPY, which did not peak until 2 min after exercise cessation. Stimulated NA correlated with plasma CgA 2 min after exercise, and with NPY 5 min after exercise. 3. Insulin-evoked hypoglycaemia and caffeine ingestion, in decreasing order of potency, predominantly stimulated adrenaline (AD) release from the adrenal medulla. During insulin hypoglycaemia AD and CgA rose, but NPY was unchanged. Neither NPY nor CgA were altered by caffeine. The rise in CgA after intense adrenal medullary stimulation was greater than its rise after intense sympathetic neuronal stimulation (1.4-versus 1.2-fold, respectively). 4. Infusion of tyramine, which disrupts sympathetic neuronal vesicular NA storage, elevated systolic blood pressure and NA, while NPY and CgA were unchanged. After reserpine, another disruptor of neuronal NA storage, NA transiently rose and then fell; NPY and CgA were unaltered. After the non-exocytotic adrenal medullary secretory stimulus glucagon. AD rose while NA, CgA and NPY did not change. After amantadine, an inhibitor of protein endocytosis, both CgA and fibrinogen rose, while NA and NPY remained unaltered. Neither CgA, NPY, nor catecholamines were altered by the catecholamine uptake and catabolism inhibitors desipramine, cortisol, and pargyline. 5. Human sympathetic nerve contained a far higher ratio of NPY to catecholamines than human adrenal medulla, while adrenal medulla contained far more CgA than sympathetic nerve. 6. It is concluded that peptides are differentially co-stored with catecholamines, with greater abundance of CgA in the adrenal medulla and NPY in sympathetic nerve. Activation of catecholamine release from either the adrenal medulla or sympathetic nerves, therefore, results in quite different changes in plasma concentrations of the catecholamine storage vesicle peptides CgA and NPY. Only profound, intense stimulation of chromaffin cells or sympathetic axons measurably perturbs plasma CgA or NPY concentration; lesser degrees of stimulation perturb plasma catecholamines only. Neither CgA nor NPY are released during non-exocytotic catecholamine secretion.
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PMID:Sympatho-adrenal secretion in humans: factors governing catecholamine and storage vesicle peptide co-release. 792 73

The effect of various doses of i.p. injection of the adenosine receptor agonist (R)-phenylisopropyladenosine (R-PIA), ranging from nanomolar to micromolar concentrations, on plasma levels of free fatty acids, glucose, insulin, glucagon, ACTH, and corticosterone was examined in 200-g male rats. At the lowest dose of R-PIA (0.005 mumol/kg), a marked decrease in plasma insulin and free fatty acids was observed. This effect on free fatty acids persisted up to the highest concentration of R-PIA (50 mumol/kg). The insulin response showed a similar pattern except at the highest concentration, when the plasma levels were within normal ranges. A 100% increase in plasma glucose was found, but only with doses of 0.5 mumol/kg and above, suggesting an A2 receptor influence, possibly related to the elevation of plasma glucagon observed with the same doses of R-PIA. It has been shown that caffeine, an antagonist of adenosine, stimulates the pituitary--adrenal axis. Surprisingly, it was shown that R-PIA produces the same effect, as evidenced by the marked elevation of both plasma ACTH and corticosterone at concentrations of 0.5 mumol/kg and higher. It is suggested that this centrally mediated effect is due to a primary peripheral action.
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PMID:Hormonal dose-response to an adenosine receptor agonist. 805 50

It has been recently shown that the physiological processing of glucagon into its C-terminal (19-29) fragment, miniglucagon, by cardiac cells was essential for the contractile positive inotropic effect of the hormone. However, the mechanisms underlying the effects of miniglucagon remained undetermined. In the present study, we assessed the effects of miniglucagon on Ca2+ homeostasis in embryonic chick ventricular myocytes. In quiescent cells, short-term applications of 0.1 nmol/L miniglucagon markedly increased the accumulation of 45Ca into intracellular compartments resistant to digitonin lysis and sensitive to caffeine. Ca2+ accumulation into the sarcoplasmic reticular (SR) store was further attested by fura 2 imaging studies on quiescent or prestimulated cells: miniglucagon potentiated Ca2+ release from the SR compartment triggered by caffeine and evoked a rise in cytosolic Ca2+ when applied on cells pretreated with 1 mumol/L thapsigargin, a specific inhibitor of the SR Ca2+ pump. Glucagon alone produced a small cytosolic Ca2+ signal that was considerably amplified by miniglucagon. The action of glucagon was mimicked by 8-bromo-cAMP and was blocked by isradipine, suggesting that it relied on the activation of L-type Ca2+ channels, via phosphorylation. We conclude that the combined actions of miniglucagon and glucagon on Ca2+ accumulation into SR stores and Ca2+ release from the same stores are likely to support the positive inotropic effect elicited in vivo by glucagon on heart contraction.
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PMID:Synergistic actions of glucagon and miniglucagon on Ca2+ mobilization in cardiac cells. 860 92

Recent experiments indicate that the calcium store (e.g., endoplasmic reticulum) is involved in electrical bursting and [Ca2+]i oscillation in bursting neuronal cells. In this paper, we formulate a mathematical model for bursting neurons, which includes Ca2+ in the intracellular Ca2+ stores and a voltage-independent calcium channel (VICC). This VICC is activated by a depletion of Ca2+ concentration in the store, [Ca2+]cs. In this model, [Ca2+]cs oscillates slowly, and this slow dynamic in turn gives rise to electrical bursting. The newly formulated model thus is radically different from existing models of bursting excitable cells, whose mechanism owes its origin to the ion channels in the plasma membrane and the [Ca2+]i dynamics. In addition, this model is capable of providing answers to some puzzling phenomena, which the previous models could not (e.g., why cAMP, glucagon, and caffeine have ability to change the burst periodicity). Using mag-fura-2 fluorescent dyes, it would be interesting to verify the prediction of the model that (1) [Ca2+]cs oscillates in bursting neurons such as Aplysia neuron and (2) the neurotransmitters and hormones that affect the adenylate cyclase pathway can influence this oscillation.
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PMID:Modeling slowly bursting neurons via calcium store and voltage-independent calcium current. 869 30

The time course of effects of caffeine on plasma glucose and non-esterified fatty acids (NEFA) were measured and related to various hormonal responses associated with substrate mobilization and utilization. Participation of the sympatho-adrenal system (SAS) in the metabolic and hormonal actions of caffeine was also investigated by the use of ganglionic blockade. Following 50 mg kg-1 i.p. injections of caffeine in rats, plasma glucose increased 25% and NEFA 40%, and these actions were parallelled by an elevation of plasma insulin, ACTH and corticosterone, without changes in glucagon. It is suggested that the insulin response is related to the plasma glucose increase and possibly also to an action of cAMP. When caffeine was injected in rats previously treated with the ganglionic blocker, hexamethonium, none of the responses mentioned above were modified. These results show that the glucose and NEFA responses are independent of glucagon secretion and are due not only to SAS activation but also to other mechanisms such as the increased ACTH and corticosterone secretion. It is also suggested that the mobilization of substrates by caffeine is mediated, through these various mechanisms, by the activation of cAMP and by phosphodiesterase inhibition.
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PMID:Metabolic and hormone-related responses to caffeine in rats. 874 42

Glucose was found to induce large amplitude oscillations of cytoplasmic Sr2+ and Ca2+ in individual pancreatic beta-cells exposed to the respective cation. Subsequent addition of 20 nM glucagon or other agents raising cAMP triggered pronounced transients superimposed upon the large amplitude oscillations. Hyperpolarization with diazoxide prevented both the large amplitude oscillations and the superimposed transients. After short exposure to carbachol or ATP there was a temporary, and after addition of the Ca2+-ATPase inhibitor thapsigargin a permanent, disappearance of the transients with persistence of the glucose-induced large amplitude oscillations. The Ca2+ channel blocker methoxyverapamil exhibited opposite specificity in preventing the large amplitude oscillations under conditions when the transients often remained. In the presence of methoxyverapamil the transients disappeared during diazoxide hyperpolarization and were restored by subsequent K+ depolarization, which also elevated the content of inositol 1,4,5-trisphosphate (IP3) by 45%. The glucagon-induced transients were obliterated by 12-O-tetradecanoylphorbol 13-acetate, insensitive to ryanodine and paradoxically inhibited by high concentrations of caffeine. The IP3-mediated intracellular ion mobilization induced by carbachol was amplified by glucagon. The results indicate that depolarization-dependent formation of IP3 causes intracellular Ca2+ mobilization in individual beta-cells when the IP3 receptors are sensitized by cAMP. This mechanism may be an important determinant for the electrophysiological burst activity in intact pancreatic islets due to the presence of endogenous glucagon.
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PMID:Crosstalk between the cAMP and inositol trisphosphate-signalling pathways in pancreatic beta-cells. 890 Apr 4

Recent studies have shown that glucagon is processed by cardiac cells into its COOH-terminal (19-29) fragment, mini-glucagon, and that this metabolite is an essential component of the contractile positive inotropic effect of glucagon (Sauvadet, A., Rohn, T., Pecker, F. and Pavoine, C. (1996) Circ. Res. 78, 102-109). We now show that mini-glucagon triggers arachidonic acid (AA) release from [3H]AA-loaded embryonic chick ventricular myocytes via the activation of a phospholipase A2 sensitive to submicromolar Ca2+ concentrations. The phospholipase A2 inhibitor, AACOCF3, prevented mini-glucagon-induced [45Ca2+] accumulation into the sarcoplasmic reticulum, but inhibitors of lipoxygenase, cyclooxygenase, or epoxygenase pathways were ineffective. AA applied exogenously, at 0. 3 microM, reproduced the effects of mini-glucagon on Ca2+ homeostasis and contraction. Thus AA: (i) caused [45Ca2+] accumulation into a sarcoplasmic reticulum compartment sensitive to caffeine; 2) potentiated caffeine-induced Ca2+ mobilization from cells loaded with Fura-2; 3) acted synergistically with glucagon or cAMP to increase both the amplitude of Ca2+ transients and contraction of electrically stimulated cells. AA action was dose-dependent and specific since it was mimicked by its non-hydrolyzable analog 5,8,11,14-eicosatetraynoic acid but not reproduced by other lipids such as, arachidic acid, linolenic acid, cis-5,8,11,14,17-eicosapentaenoic acid, cis-4,7,10,13,16, 19-docosahexaenoic acid, or arachidonyl-CoA, even in the micromolar range. We conclude that AA drives mini-glucagon action in the heart and that the positive inotropic effect of glucagon on heart contraction relies on both second messengers, cAMP and AA.
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PMID:Arachidonic acid drives mini-glucagon action in cardiac cells. 913 91

An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*, S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)pr opyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC50 of 0.13 microM in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5- to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 microM) and in primary human hepatocytes (2.1 microM IC50). In vivo, oral administration of CP-91149 to diabetic ob/ob mice at 25-50 mg/kg resulted in rapid (3 h) glucose lowering by 100-120 mg/dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob/ob mice pretreated with 14C-glucose to label liver glycogen, CP-91149 administration reduced 14C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic flux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.
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PMID:Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. 946 93


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