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)

Adult rat hepatocytes have been previously isolated and maintained in monolayer culture, but attempts to stimulate DNA synthesis have been unsuccessful. Hormonal conditions are now described which induce DNA synthesis in cultured hepatocytes from partially hepatectomized rats. DNA synthesis was determined autoradiographically by the incorporation of [3H]thymidine into nuclei of morphologically distinct hepatocytes. Insulin (4-4000 nM) or epidermal growth factor (10 ng/ml) alone caused significant increases in the labeling index. The two hormones together acted synergistically to produce labeling indices of 35-50% on the third day of culture, compared with 2-7% in control cultures. The addition of glucagon (400 nM) further increased the labeling indes. Dexamethasone (80 ng/ml) inhibited DNA synthesis but, under certain conditions, enhanced cell attachment. Growth hormone and triiodothyronine had no significant effect on DNA synthesis. The mixture of epidermal growth factor, insulin, and glucagon also stimulated incorporation of [3H]thymidine into phenol-extracted DNA. Although DNA synthesis was stimulated, cell division occurred infrequently. These data suggest a prominent role for epidermal growth factor in promoting hepatic DNA synthesis by acting in concert with insulin and glucagon.
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PMID:Hormonal stimulation of DNA synthesis in primary cultures of adult rat hepatocytes. 106 71

Effects of liver denervation on bile formation were studied in eight dogs prepared with chronic biliary fistulas. The animals were studied in the basal state, after feeding, and during infusion of glucagon 50 ng/kg/min, secretin 2 U/kg/hr, or somatostatin 200 ng/kg/min. After this first set of experiments the animals underwent a total hepatic denervation that consisted of section of the hepatic ligaments and a careful dissection of the portal vein, hepatic artery, and common duct with stripping of all the surrounding connective tissue and topical application of phenol. The above experiments were then repeated. Denervation did not modify bile flow, or bile salts, cholesterol, or phospholipid concentration or output. Biliary response to glucagon and secretin was similar before and after denervation. Somatostatin had an anticholerectic effect in both intact and denervated animals, but significantly reduced bile salt output only in the intact dogs. Feeding had a choleretic effect pre- and postdenervation, and the infusion of somatostatin following feeding decreased bile flow to the same degree before and after denervation. In the intact animals the output of all three biliary lipids was reduced by somatostatin after feeding but they were unaffected by somatostatin after denervation. Moreover, cholesterol and phospholipid outputs were stable after feeding in intact animals, but significantly decreased after denervation. 14C-erythritol clearance studies indicated no change in the canalicular component of bile flow with denervation, except again during somatostatin suppression of feeding. These data indicate that basal bile flow is normal after denervation but that innervation may play an important role in the modulation of responses to somatostatin and more complex stimuli such as feeding.
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PMID:The effects of liver denervation on the regulation of hepatic biliary secretion. 135 20

Cats were prepared with chronically implanted catheters in the portal and femoral vein for administration of glucose. A femoral arterial catheter was used for blood sampling. After at least 5 days following the implantations, cats received an infusion of 3 mg/kg/min into the portal vein and the insulin and glucagon responses were compared with a similar infusion into the femoral vein. The hypothesis predicted that glucose receptors in the liver would result in greater pancreatic hormonal responses than would be seen with the femoral infusions of glucose. This did not occur. There was no statistically significant difference between the rise in insulin and the decrease in glucagon elicited by the glucose infusion into the two alternate infusion sites. A sham-denervated series showed similar responses. A group of cats that underwent hepatic denervation using topical phenol application to the hepatic plexus near the hilum of the liver was tested. The responses of the denervated group were similar to those for the control and sham-operated groups, confirming that hepatic glucose receptors do not serve as an afferent limb of a hepato-pancreatic reflex controlling insulin and glucagon release in conscious cats. In all experiments, a bolus of glucose (500 mg) was injected i.v. to represent a tolerance test. The responses of blood glucose levels, pancreatic insulin and glucagon and recovery from the stimulus were similar in all groups which suggests that hepatic nerves are not essential for a normal hepatic response to intravenously infused glucose. It is suggested, however, that hepatic nerves may be important in producing normal hepatic responses to oral glucose loads.
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PMID:The effect of intraportal and intravenous glucose infusion and an intravenous glucose tolerance test on insulin and glucagon levels in conscious cats with normal and chronically phenol-denervated livers. 608 37

Topical application of 90% phenol around the bile duct, portal vein, and hepatic artery, as well as along each of the three hepatic ligaments was tested for effectiveness of rapid and chronic denervation in cats. Because phenol produces nonselective nerve degeneration, it was assumed that proof of functional sympathectomy was adequate proof of disruption of parasympathetic and afferent nerves as well. Functional sympathetic neurons were evaluated by measuring physiological responses to direct electrical stimulation of the anterior hepatic plexus. Acute or rapid denervation was assessed by the degree of rise in portal blood pressure produced by nerve stimulation. Complete denervation appeared within 20 min and was still present by 80 min postapplication. Chronic denervation was tested by applying the phenol and recovering the cats for 6-14 days. An equal number (n = 6) of sham-denervated cats were compared. Phenol denervation did not alter basal glucose, insulin or glucagon levels, hematocrit, blood pressure, or hepatic glycogen levels. These variables are a good index of stress and metabolic status. Nerve stimulation in the chronic sham group raised portal pressure, arterial pressure, and blood glucose levels, whereas the chronic-denervated group showed no responses. The health of the two groups appeared normal with the sole difference being that the painted tissues were mildly discolored and more adhesions appeared in the phenol-denervated set. Thus phenol is a useful tool for producing hepatic denervation. It is less traumatic, faster, and more certain than surgical denervation. In addition, the hepatic lymphatics can be preserved using the topical application of phenol.
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PMID:Evaluation of topical phenol as a means of producing autonomic denervation of the liver. 649 14

Several peptides have been proposed as regulators of nutrient release from the stomach and subsequent uptake from the gut. Using a phenol red gavage method, we compared the potencies of subcutaneously preinjected amylin, glucagon-like peptide-1 (7-36)amide (GLP-1), cholecystokinin octapeptide (CCK-8), gastric inhibitory peptide (GIP), glucagon, and pancreatic peptide on slowing the release of an acaloric gel from rat stomach. The latter three peptides did not fully inhibit gastric emptying at subcutaneous doses up to 100 micrograms. Amylin, GLP-1, and CCK-8 fully inhibited gastric emptying, with ED50s of 0.42 +/- 0.07, 6.1 +/- 0.12, and 8.5 +/- 0.20 nmol/kg +/- SE of log, respectively.
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PMID:Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. 854 64

The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6 yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume was determined by a dye dilution technique using phenol red. In randomized order, GLP-1-(7-36) amide (1.2 pmol/kg.min; Saxon Biochemicals) or placebo (0.9% NaCl with 1% human serum albumin) was infused between -30 and 240 min. In the control experiment, gastric emptying was completed within 120 min, and plasma glucose, insulin, C-peptide, GLP-1-(7-36) amide, and glucagon concentrations transiently increased. With exogenous GLP-1-(7-36) amide (plasma level, approximately 70 pmol/L), gastric volume remained constant over the period it was measured (120 min; P < 0.0001 vs. placebo), and plasma glucose fell to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion. At the degree observed, inhibition of gastric emptying, however, must be overcome by tachyphylaxis, reduction in dose, or pharmacological interventions so as not to interfere with the therapeutic use of GLP-1-(7-36) amide in type 2 diabetic patients.
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PMID:Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. 855 Jul 73

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.
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PMID:Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM. 896 Aug 41

Glucagon-like peptide 1 (GLP-1) has been shown to inhibit gastric emptying of liquid meals in type 2 diabetic patients. It was the aim of the present study to compare the action of physiological and pharmacological doses of intravenous GLP-1-(7-36) amide and GLP-1-(7-37) on gastric emptying in normal volunteers. Nine healthy subjects participated (26 +/- 3 yr; body mass index 22.9 +/- 1.6 kg/m2; hemoglobin A1C 5.0 +/- 0.2%) in five experiments on separate occasions after an overnight fast. A nasogastric tube was positioned for the determination of gastric volume by use of a dye-dilution technique (phenol red). GLP-1-(7-36) amide (0.4, 0.8, or 1.2 pmol.kg-1.min-1), GLP-1-(7-37) (1.2 pmol.kg-1.min-1), or placebo was infused intravenously from -30 to 240 min. A liquid meal (50 g sucrose, 8% amino acids, 440 ml, 327 kcal) was administered at 0 min. Glucose, insulin, and C-peptide were measured over 240 min. Gastric emptying was dose dependently slowed by GLP-1-(7-36) amide (P < 0.0001). Effects of GLP-1-(7-37) at 1.2 pmol.kg-1.min-1 were virtually identical. GLP.1 dose dependently stimulated fasting insulin secretion (-30 to 0 min) and slightly reduced glucose concentrations. After the meal (0-240 min), integrated incremental glucose (P < 0.0001) and insulin responses (P = 0.01) were reduced (dose dependently) rather than enhanced. In conclusion, 1) GLP-1-(7-36) amide or -(7-37) inhibits gastric emptying also in normal subjects, 2) physiological doses (0.4 pmol.kg-1.min-1) still have a significant effect, 3) despite the known insulinotropic actions of GLP-1-(7-36) amide and -(7-37), the net effect of administering GLP-1 with a meal is no change or a reduction in meal-related insulin responses. These findings suggest a primarily inhibitory function for GLP-1 (ileal brake mechanisms).
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PMID:Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. 937 85

Glucagon-like peptide 1 (GLP-1) has been proposed to act as an incretin hormone due to its ability to enhance glucose-stimulated insulin secretion. Because GLP-1 also decelerates gastric emptying, it physiologically reduces rather than augments postprandial insulin secretory responses. Therefore, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 +/- 4 years, BMI 25.0 +/- 4.9 kg/m2) were studied with an infusion of GLP-1 (0.8 pmol.kg(-1).min(-1) from -30 to 240 min) or placebo. On separate occasions, the prokinetic drugs metoclopramide (10 mg), domperidone (10 mg), cisapride (10 mg, all at -30 min per oral), or erythromycin (200 mg intravenously from -30 to -15 min) were administered in addition to GLP-1. A liquid test meal (50 g sucrose and 8% mixed amino acids in 400 ml) was administered at 0 min. Capillary and venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1, glucagon, gastric inhibitory polypeptide (GIP), and pancreatic polypeptide (specific immunoassays). Gastric emptying was assessed by the phenol red dilution technique. Statistical analyses were performed using repeated-measures ANOVA and Duncan's post hoc test. GLP-1 significantly decelerated the velocity of gastric emptying (P < 0.001). This was completely counterbalanced by erythromycin, whereas the other prokinetic drugs used had no effect. Postprandial glucose concentrations were lowered by GLP-1 (P < 0.001 vs. placebo), but this effect was partially reversed by erythromycin (P < 0.05). Insulin secretory responses to the meal were lower during GLP-1 administration (P < 0.05 vs. placebo). However, when erythromycin was added to GLP-1, insulin concentrations were similar to those in placebo experiments. The suppression of meal-related increments in glucagon secretion by GLP-1 was reversed by erythromycin (P < 0.001). The time course of GIP secretion was delayed during GLP-1 administration (P < 0.05), but when erythromycin was added, the pattern was similar to placebo experiments. GLP-1 administration led to a reduction in pancreatic polypeptide plasma concentrations (P < 0.05). In contrast, pancreatic polypeptide levels were markedly increased by erythromycin (P < 0.001). Intravenous erythromycin counteracts the deceleration of gastric emptying caused by GLP-1, probably by interacting with the parasympathetic nervous system (pancreatic polypeptide responses). Despite augmented rises in insulin secretion, the glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance of this facet of the multiple antidiabetic actions of GLP-1.
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PMID:Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. 1598 24

The objective of this study was to investigate the effects of cyclooxygenase-2 (COX-2) inhibitor (celecoxib) on delayed gastric emptying and gastric dysrhythmia induced by glucagon. The study was performed in six healthy female dogs implanted with four pairs of gastric serosal electrodes, and a duodenal fistula for the assessment of gastric emptying. Each dog was studied in three randomized sessions: control, glucagon and COX-2 inhibitor (celecoxib). Gastric emptying was assessed every 15 min via a duodenal cannula by calculating the amount of collected phenol red which mixed with the test meal and gastric slow waves were recorded at the same time. We found that: (i) glucagon significantly and substantially decreased gastric emptying of liquids (P < 0.001, anova), increased blood glucose (BG) levels, and induced gastric dysrhythmias. The delayed gastric emptying was correlated with the BG level (R = -0.77, P < 0.001) and (ii) celecoxib improved glucagon-induced delayed gastric emptying at 30, 45, 60 and 75 min after feeding. Celecoxib did not blocked dysrhythmic action of glucagon (P > 0.05, anova). In conclusion, glucagon induces delayed gastric emptying partially via COX-2-derived prostaglandins. However, COX-2-derived prostaglandins are not involved in glucagon-evoked gastric dysrhythmia. Selective COX-2 inhibitors may provide a possible therapeutic option for diabetic gastroparesis.
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PMID:Effects of cyclooxygenase-2 inhibitor on glucagon-induced delayed gastric emptying and gastric dysrhythmia in dogs. 1724 69


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