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)

In order to analyse further the pathophysiology of pentamidine effects on blood glucose regulation, the following experimental models were established in rats: impairment of the renal function, bile duct ligation, inhibition of the P450 cytochrome enzyme system. In otherwise intact rats, 7.5 mg/day pentamidine was well tolerated whereas doses of 15 mg/day induced severe, relapsing and eventually lethal hypoglycaemia within a few days. Induction of a renal insufficiency of graded severity by treatment with gentamycin, subtotal nephrectomy and total bilateral nephrectomy resulted in repetitive, severe (sometimes lethal) hypoglycaemia, alternating with hyperglycaemia, glucosuria and ketonuria in pentamidine-treated rats (7.5 mg/d). No long-standing insulin-dependent diabetes was observed. In the dysglycemic animals, plasma insulin levels were inappropriate to the concomitant glycaemia; no stimulation was obtained by i.v. glucose. Glucagon levels were higher than normal, suppressible by i.v. glucose, responsive to IV arginine and to hypoglycaemia. Dysglycemic events were more frequent and marked in the rats with the most severe renal functional derangement. They were more frequent in the rats treated with pentamidine mesylate than in those treated with the isethionate salt. Control uremic rats (free of pentamidine) remained euglycaemic. The islets of Langerhans displayed severe vascular congestion and degranulation and necrosis of the B cells, while the non B cells (and particularly the A cells) were intact. Exocrine pancreatitis was occasionally observed in the most severely uremic rats. In contrast with uremic rats, neither surgical ligation of choledocus, nor treatment by P450 cytochrome inhibitors (particularly ketoconazole) precipitated dysglycaemia in the pentamidine-treated rats. These experimental data: 1) strengthen the concept of inappropriate insulin release from pentamidine-lesioned islet B cells due to pentamidine accumulation; 2) indicate a predominant role for renal insufficiency in determining the accumulation of this drug; 3) emphasize the clinical importance of renal insufficiency as a risk factor for pentamidine-induced dysglycaemia. Association with ketoconazole does not appear to be a risk factor.
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PMID:Pentamidine-induced dysglycaemia: experimental models in the rat. 833 59

We have recently demonstrated an alteration in the levels of G-proteins and their correlation with adenylyl cyclase in spontaneously hypertensive rats (SHR). In the present studies we examined if the other models of hypertensive rats, such as DOCA-salt hypertensive rats (HR), also exhibit the similar alterations in G-protein and in adenylyl cyclase activity. We have determined the adenylyl cyclase activity stimulated and inhibited by hormones, as well as the levels of G-proteins using specific antibodies and cDNA probes in the hearts from DOCA-salt HR and their sham-operated controls after 2 and 4 weeks of treatment. Adenylyl cyclase activity stimulated by GTP gamma S, isoproterenol, and glucagon was significantly decreased in heart sarcolemma from DOCA-salt HR as compared to their controls after 2 and 4 weeks of treatment. In addition, the inhibitory hormones inhibited the enzyme activity to a greater extent in hypertensive rats than controls. Furthermore, the levels of Gi alpha-2 and Gi alpha-2 mRNA, as determined by immunoblotting and Northern blotting techniques, respectively, were higher in hearts from DOCA-salt HR. However, the levels of G8 alpha 45 were decreased in these rats. These results indicate that, similar to SHR, the hearts from DOCA-salt HR exhibit the increased expression of Gi, however unlike SHR, the expression of G8 was decreased. It is suggested that the altered expression of G-proteins may partly be responsible for the decreased responsiveness of adenylyl cyclase to hormone stimulation and increased responsiveness to hormone inhibition in DOCA-salt hypertension.
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PMID:DOCA-salt hypertensive rat hearts exhibit altered expression of G-proteins. 842 65

The effect has been studied of various media, hormones and of amino acids on the membrane potential of rat hepatoma cells in culture measured by microelectrode impalement. Cells in Eagle's minimal essential medium plus 5% serum had a value which varied daily from about 5-8 mV, inside negative. The membrane potential of rat hepatocytes was measured to be 8.7 +/- 0.2 mV, inside negative. The membrane potential of the hepatoma cells was decreased by insulin and increased by glucagon. Membrane potential was unaffected by change of medium to Hanks' or Earle's balanced salt solutions or deprivation of serum. It was, however, reduced in cells in phosphate-buffered saline and by reduction of pH. The former effect was shown to be due to the higher [Na+] of phosphate-buffered saline as opposed to the other media. Addition of alanine, glycine, serine, proline and methylaminoisobutyrate all reduced membrane potential by 2-3 mV. Smaller decreases were seen with methionine, leucine and phenylalanine, but none with glutamine, threonine, BCH (2-aminonorborane-2-carboxylic acid) and D-alanine. The results are compared with the effects of similar conditions on aminoisobutyrate uptake. Whilst there was a correlation under some conditions there was not under others. It is concluded that for the hepatoma cells factors additional to the membrane potential must exert some influence on the capacity for amino acid transport.
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PMID:Membrane potential of rat hepatoma cells in culture: influence of factors affecting amino acid transport. 856 68

The binding properties of hepatic aldolase (B) were determined in digitonin-permeabilized rat hepatocytes after the cells had been preincubated with either glycolytic or gluconeogenic substrates. In hepatocytes that had been preincubated in medium containing 5 mM glucose as sole carbohydrate substrate, binding of aldolase to the hepatocyte matrix was maximal at low KCl concentrations (20 mM) or bivalent cation concentrations (1 mM Mg2+) and half-maximal dissociation occurred at 50 mM KCl. Preincubation of hepatocytes (for 10-30 min) with glucose or mannose (10-40 mM), fructose, sorbitol, dihydroxyacetone or glycerol (1-10 mM), caused a leftward shift of the salt dissociation curve (maximum binding at 10 mM KCl; half-maximum dissociation at 35 mM KCl) but did not affect the proportion of bound enzyme at low or high KCl concentrations. Galactose and 2-deoxyglucose had no effect on aldolase binding. Inhibitors of glucokinase (mannoheptulose and glucosamine) suppressed the effects of glucose but not the effects of sorbitol, glycerol or dihydroxyacetone. Glucagon suppressed the effects of glucose, fructose and dihydroxyacetone but not glycerol. Poly(ethylene glycol) (PEG) (2-10%), added to the permeabilization medium, increased aldolase binding and caused a rightward shift in the salt dissociation curve. In the presence of PEG (6-8%), the effects of substrates on aldolase dissociation were shifted to higher salt concentrations (50-100 mM versus 35 mM KCl). The effects of substrates (added to the intact cell) on aldolase binding to the permeabilized cell could be mimicked by addition of the phosphorylated derivatives of these substrates to the permeabilized cell. Of the intermediates tested dihydroxyacetone phosphate and fructose 1,6-bisphosphate were the most effective at dissociating aldolase (A50 values of 20 microM and 40 microM respectively). Other effective intermediates in order of decreasing potency were fructose 1-phosphate, glycerol 3-phosphate, glucose 1,6-bisphosphate/fructose 2,6-bisphosphate. These results show that aldolase B binds to the hepatocyte matrix by a salt-dependent mechanism that is influenced by macromolecular crowding and metabolic intermediates. Maximum binding occurs when hepatocytes are incubated in the absence of glycolytic and gluconeogenic substrates and minimum binding occurs in the presence of substrates that are precursors of either fructose 1,6-bisphosphate or triose phosphates. Since the bound form of aldolase represents a kinetically less active state it is proposed that aldolase binding and dissociation may be a mechanism for buffering the concentrations of metabolic intermediates.
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PMID:Substrate modulation of aldolase B binding in hepatocytes. 861 43

Bile flow rates and composition are subject to a wide variety of neural, endocrine and paracrine influences. The effects of these multiple factors may be different in the diseased liver compared to the response produced in the normal liver. As prostanoids may have a therapeutic role in liver disease it was intended to evaluate the effects of two principal therapeutic prostanoids, prostaglandin E2 and prostacyclin, on bile flow in dogs with a normal liver and in dogs with hepatotoxin-induced liver injury. Initially, in awake animals with chronic biliary and gastric fistulas the bile flow response to prostaglandin E2 and prostacyclin was evaluated and compared to the response produced by bile salt infusion alone and to that produced by the standard choleretic hormones, secretin and glucagon. The animals were then fed alpha-naphthylisothiocyanate (ANIT) and the studies repeated. ANIT is a hepatoxin that produces bile duct cell hyperplasia which was confirmed in dogs by demonstrating that ANIT increased [3H]thymidine incorporation by isolated canine bile duct cells. In normal dogs, the prostanoids, secretin, and glucagon increased hepatic bile flow. 10 days of ANIT feeding produced a hypercholeresis. While secretin was able to stimulate the hyperplastic biliary epithelium and increase bile flow over values produced by the hyperplastic biliary epithelium alone, neither prostaglandin E2, prostacyclin, or glucagon appeared to stimulate the hyperplastic biliary epithelium. As ANIT produced evidence of cholestasis and hepatocellular damage, only secretin would seem to have a potential therapeutic role in increasing bile flow in cholestatic liver disorders associated with bile duct cell hyperplasia.
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PMID:The effect of prostanoids on hepatic bile flow in dogs with normal liver and bile duct cell hyperplasia. 880 23

Glucagon-like peptide (GLP)-1-(7-36) amide and its pancreatic receptors are important for control of blood glucose levels. However, rat GLP-1 receptors are also localized in the brain, in hypothalamus, and in areas without a blood-brain barrier. When rats were kept on a food restriction schedule, intracerebroventricular injection of GLP-1 just before food was offered inhibited food intake. However, peripheral GLP-1 administration by intraperitoneal injection had little effect. GLP-1 effects on water intake and output were also investigated. Intracerebroventricular GLP-1 profoundly inhibited angiotensin II-induced drinking behavior in rats, and water intake was suppressed by exogenous GLP-1 in rats habituated to a water restriction schedule. These effects were reproduced by intraperitoneal administration of GLP-1. Furthermore, intracerebroventricular GLP-1 stimulated urinary excretion of water and sodium. The centrally elicited effects were blocked by the GLP-1 antagonist exendin-(9-39) amide, whereas the N-terminally extended and inactive GLP-1-(1-36) amide had no effect on feeding and drinking. GLP-1 had no effect in behavioral assays measuring exploratory locomotor activity and conditioned taste aversion. In conclusion, GLP-1 may play a physiological role in regulation of both ingestion and the water and salt homeostasis.
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PMID:Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. 889 73

The purpose of the study was to evaluate renal functional reserve [RFR is the difference between glomerular filtration rate (GFR) at rest and maximal GFR after stimulation] in a controlled study in normal pigs. Our basic hypothesis was that a decreased RFR may be used as an early indicator of renal deterioration, i.e. a test to disclose significant obstruction as opposed to simple dilatation in hydronephrosis. During various forms of stimulation (amino acids, captopril and dopamine), we measured changes in GFR, renal plasma flow (RPF), tubular reabsorption of sodium and water, net uptake from plasma to the kidney of three salt and water homeostatic hormones (angiotensin II, aldosterone and atrial natriuretic peptide) and of glucagon, which is thought to play a key role as mediator of the GFR increase during amino acid infusion. We found the largest GFR increase during combined infusion of amino acids and dopamine (+13%), but compared with a non-stimulated control group, the GFR increase was statistically non-significant. RPF increased by 57% during stimulation with amino acids plus dopamine (P < 0.001), while tubular reabsorption of sodium and water, and renal uptake of angiotensin II, aldosterone and atrial natriuretic peptide showed no significant differences between control and stimulation groups. The renal uptake of glucagon increased significantly during amino acid stimulation with no concomitant GFR increase. We conclude that in this experimental, non-obstructed model, RFR is a very insensitive measure, which cannot be used to discriminate between obstruction and simple dilatation in hydronephrosis. Further, our study does not support the hypothesis that glucagon is involved in GFR changes after amino acids.
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PMID:Renal functional reserve in pigs: renal haemodynamics, renal tubular function and salt and water homeostatic hormones during amino acid and dopamine stimulation. 901 58

We have recently shown an enhanced expression of inhibitory guanine nucleotide regulatory proteins Gi alpha-2 and Gi alpha-3 and their respective mRNA in hearts from DOCA-salt hypertensive rats. However, it is not known whether these changes are due to the expressed hypertrophy or hypertension. The present studies were therefore undertaken to investigate this possibility. Hypertension in Sprague-Dawley rats was induced by the oral administration of the arginine analog N(omega)-nitro-L-arginine methyl ester (L-NAME) in their drinking tap water for a period of 4 weeks. The control rats were given plain tap water only. L-NAME-treated rats showed an enhanced blood pressure (190 +/- 9.23 mm Hg; n = 20) compared to control rats (121 +/- 6.3 mm Hg; n = 20). However, heart to body weight ratio was not different in the two groups. Guanosine 5'-o-(3-thiotriphosphate) (GTPgammaS) stimulated adenylyl cyclase activity in heart membranes from both groups, but the extent of stimulation was significantly decreased in L-NAME-treated rats. Similarly, stimulations exerted by isoproterenol, glucagon, NaF, and forskolin on adenylyl cyclase were also diminished in L-NAME-treated rats. On the other hand, the inhibitory effect of low concentrations of GTPgammaS on forskolin-stimulated enzyme activity was significantly enhanced. The extent of oxotremorine-mediated inhibition of adenylyl cyclase was unaltered in both control and L-NAME-induced hypertensive rats. The levels of Gi alpha-2 and Gi alpha-3, but not of stimulatory guanine nucleotide regulatory protein Gs alpha, as determined by immunoblotting, were significantly augmented in L-NAME-treated rats. Northern blot studies revealed a significant increase in Gi alpha-2 and Gi alpha-3 mRNA with no changes in Gs alpha mRNA. These results suggest that the altered expression of Gi alpha proteins and adenylyl cyclase activity in L-NAME-treated rats may be attributed to hypertension and not to hypertrophy.
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PMID:Nitric oxide synthase inhibition by N(omega)-nitro-L-arginine methyl ester modulates G-protein expression and adenylyl cyclase activity in rat heart. 912 16

To study the regulation of growth and differentiated function of insulin-secreting cells, the rat insulinoma cell line INS-1 was cultured in a defined serum-free medium containing prolactin, IGF-I, and triiodothyronine, which was originally reported to maintain insulin secretion of islet cells. Growth and viability, as well as cellular insulin content of INS-1 cells in the defined medium, were comparable to the control cells cultured in the complete medium containing 10% fetal calf serum. However, after a 3-day culture in this medium, insulin secretion in response to glucose, pyruvate, and leucine was markedly blunted compared with the control cells (-78, -68, and -56%, respectively), whereas the response to 30 mmol/l K+ was only slightly decreased. In these cells: 1) nutrient metabolism assessed by tetrazolium salt reduction was reduced in response to pyruvate and leucine, which are mainly metabolized in the mitochondria; 2) oxidation of both [3,4-(14)C]glucose and [1-(14)C]pyruvate was decreased (-22 and -32%, respectively); 3) glucose failed to depolarize the membrane potential, whereas tolbutamide was fully active; 4) video imaging analysis of cytosolic Ca2+ showed a decrease in the population of glucose-responsive cells, while the response to 30 mmol/l K+ was preserved; 5) serum replenishment for 3 days restored glucose-induced insulin secretion. Interestingly, conditioned serum-free medium from rat islets maintained the insulin secretory function of INS-1 cells, although glucagon, somatostatin, and some other factors failed to restore the function. In contrast, conditioned media from HepG2, PC12, and human umbilical vein endothelial cells did not substitute for serum. Thus, the impaired insulin secretion of the cells cultured in the defined medium is best explained by defective mitochondrial metabolism. Islet cells, but not INS-1 cells, produce factors required for normal signal generation by nutrient secretagogues.
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PMID:Glucose-induced insulin secretion in INS-1 cells depends on factors present in fetal calf serum and rat islet-conditioned medium. 928 42

Recent research has provided new concepts in our understanding of renal magnesium handling. Although the majority of the filtered magnesium is reabsorbed within the loop of Henle, it is now recognized that the distal tubule also plays an important role in magnesium conservation. Magnesium absorption within the cTAL segment of the loop is passive and dependent on the transepithelial voltage. Magnesium transport in the DCT is active and transcellular in nature. Many of the hormonal (PTH, calcitonin, glucagon, AVP) and nonhormonal (magnesium-restriction, acid-base changes, potassium-depletion) influences that affect magnesium transport within the cTAL similarly alter magnesium absorption within the DCT. However, the cellular mechanisms are different. Actions within the loop affect either the transepithelial voltage or the paracellular permeability. Influences acting in the DCT involve changes in active transcellular transport either Mg2+ entry across the apical membrane or Mg2+ exit from the basolateral side. These transport processes are fruitful areas for future research. An additional regulatory control has recently been recognized that involves an extracellular Ca2+/Mg(2+)-sensing receptor. This receptor is present in the basolateral membrane of the TAL and DCT and modulates magnesium and calcium conservation with elevation in plasma divalent cation concentration. Further studies are warranted to determine the physiological role of the Ca2+/Mg(2+)-sensing receptor, but activating and inactivating mutations have been described that result in renal magnesium-wasting and hypermagnesemia, respectively. All of these receptor-mediated controls change calcium absorption in addition to magnesium transport. Selective magnesium control is through intrinsic control of Mg2+ entry into distal tubule cells. The cellular mechanisms that intrinsically regulate magnesium transport have yet to be described. Familial diseases associated with renal magnesium-wasting provide a unique opportunity to study these intrinsic controls. Loop diuretics such as furosemide increase magnesium excretion by virtue of its effects on the transepithelial voltage thereby inhibiting passive magnesium absorption. Distally acting diuretics, like amiloride and chlorothiazide, enhance Mg2+ entry into DCT cells. Amiloride may be used as a magnesium-conserving diuretic whereas chlorothiazide may lead to potassium-depletion that compromises renal magnesium absorption. Patients with Bartter's and Gitelman's syndromes, diseases of salt transport in the loop and distal tubule, respectively, are associated with disturbances in renal magnesium handling. These may provide useful lessons in understanding segmental control of magnesium reabsorption. Metabolic acidosis diminishes magnesium absorption in MDCT cells by protonation of the Mg2+ entry pathway. Metabolic alkalosis increases magnesium permeability across the cTAL paracellular pathway and stimulates Mg2+ entry into DCT cells. Again, these changes are likely due to protonation of charges along the paracellular pathway of the cTAL and the putative Mg2+ channel of the DCT. Cellular potassium-depletion diminishes the voltage-dependent magnesium absorption in the TAL and Mg2+ entry into MDCT cells. However, the relationship between potassium and magnesium balance is far from clear. For instance, magnesium-wasting is more commonly found in patients with Gitelman's disease than Bartter's but both have hypokalemia. Further studies are needed to sort out these discrepancies. Phosphate deficiency also decreases Mg2+ uptake in distal cells but it apparently does so by mechanisms other than those observed in potassium depletion. Accordingly, potassium depletion, phosphate deficiency, and metabolic acidosis may be additive. The means by which cellular potassium and phosphate alter magnesium handling are unclear. Research in the nineties has increased our understanding of renal magnesium transport and regulation, but there are many in
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PMID:Renal magnesium handling: new insights in understanding old problems. 935 Jun 41


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