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 addition to its insulinotropic action, exogenously administered glucagon-like peptide (GLP-1) inhibits gastropancreatic motility and secretion via central pathways. The aims of the present study were to evaluate the effects of exogenous GLP-1-(7-36) amide on fecal output and to investigate the role of endogenous GLP-1 on stress-induced colonic activity. With the use of a stereotaxic instrument, adult male Sprague-Dawley rats weighing 200-250 g were fitted with stainless steel cerebroventricular guide cannulas under ketamine anesthesia. A group of rats were placed in Bollman-type cages to induce restraint stress. Fecal output monitored for 2 h was increased significantly by intracerebroventricular GLP-1 to 500, 1, 000, and 3,000 pmol/rat (P < 0.05-0.01), whereas intraperitoneal GLP-1 had no effect. Intracerebroventricular administration of the GLP-1 receptor antagonist exendin-(9-39) (10 nmol/rat) reversed the increases induced by GLP-1 (500 pmol/rat; P<0.01). Similar results were also observed with the injection of corticotropin-releasing factor receptor antagonist astressin (10 microg/rat icv). The significant increase in fecal pellet output induced by restraint stress was also decreased by both intracerebroventricular exendin (10 nmol/rat) and astressin (10 microg/rat; P<0.01-0.001). These results suggest that GLP-1 participates in the central, but not peripheral, regulation of colonic motility via its own receptor and that GLP-1 is likely to be a candidate brain-gut peptide that acts as a physiological modulator of stress-induced colonic motility.
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PMID:Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats. 1085 22

Diabetes is caused by a failure of the pancreas to produce insulin in amounts sufficient to meet the body's needs. A hallmark of diabetes is an absolute (type 1) or relative (type 2) reduction in the mass of pancreatic beta-cells that produce insulin. Mature beta-cells have a lifespan of approximately 48-56 days (rat) and are replaced by the replication of preexisting beta-cells and by the differentiation and proliferation of new beta-cells (neogenesis) derived from the pancreatic ducts. Here, we show that the insulinotropic hormone glucagon-like peptide (GLP)-1, which is produced by the intestine, enhances the pancreatic expression of the homeodomain transcription factor IDX-1 that is critical for pancreas development and the transcriptional regulation of the insulin gene. Concomitantly, GLP-1 administered to diabetic mice stimulates insulin secretion and effectively lowers their blood sugar levels. GLP-1 also enhances beta-cell neogenesis and islet size. Thus, in addition to stimulating insulin secretion, GLP-1 stimulates the expression of the transcription factor IDX-1 while stimulating beta-cell neogenesis and may thereby be an effective treatment for diabetes.
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PMID:Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. 1090 82

The pancreatic hormone glucagon hyperpolarizes the liver cell membrane under various conditions. Here we investigated the physiological relevance of this effect by testing the influence of infusions of glucagon antiserum on the liver cell membrane potential in vivo. Intracellular microelectrode recordings of liver cells (up to 60/rat over 2 h) were done in anesthetized male rats. Livers were fixed in place, and recordings were done 10-30 min after intraperitoneal injections of glucagon or hepatic portal vein infusions of glucagon or specific polyclonal glucagon antibodies raised in rabbits. The isotonic lactose vehicle was used as a control for glucagon, and equal amounts of nonimmunized rabbit IgG were used as a control for glucagon antibodies. Intraperitoneal glucagon (400 microg/kg) hyperpolarized the liver cell membrane up to 12 mV, and intraportal glucagon (10 or 60 microg/kg) dose dependently hyperpolarized the liver cell membrane by 3-7 mV. Intraportal infusion of glucagon antiserum (in vitro binding capacity of 4 ng glucagon/rat) significantly depolarized the liver cell membrane by approximately 2.5 mV. The effects of both glucagon and glucagon antiserum reversed after 60-90 min. We conclude that glucagon is a physiologically important modulator of the liver cell membrane potential.
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PMID:Physiological effect of circulating glucagon on the hepatic membrane potential. 1164 Nov 26

This study investigated the hypotheses that dietary proteins suppress food intake partly through the glucagon-like peptide-1 (GLP-1) signaling pathway, and that this effect is mediated by products of protein digestion. The GLP-1 receptor agonist, Exendin-4 (Ex-4) (0.5 micro g/rat), was given intraperitoneally to male Wistar rats, and food intake was measured when Ex-4 was given alone or with preloads of intact whey and casein proteins, their hydrolysates and amino acid mixtures (0.5 g x 4 mL(-1) x rat(-1)). Both Ex-4 and the preloads suppressed food intake (P < 0.05), but the effect of Ex-4 on food intake was reduced when coadministered with the preloads (P < 0.05). Because the effect of Ex-4 was reduced by the protein hydrolysates and by the amino acid preloads, the results support a role for the end products of protein digestion and GLP-1 release in the suppression of food intake in response to protein ingestion. We concluded that the GLP-1 signaling pathway, activated by the release of products of protein digestion, is another mechanism accounting for the reduction of food intake after protein ingestion.
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PMID:Exendin-4, a GLP-1 receptor agonist, interacts with proteins and their products of digestion to suppress food intake in rats. 1284 Feb 1

Recently, islet transplantation in patients with type 1 diabetes has had greater success than in the past, but the important question of whether the kinetics of islet secretion are able to accommodate the metabolic demands of special conditions such as exercise remains unanswered. Syngeneic rat islets (4,000 islet equivalents/rat) were transplanted into the liver, kidney, and peritoneal cavity (encapsulated or nonencapsulated) of rats with streptozocin-induced diabetes. Normoglycemic transplanted rats and age-matched controls were subjected to 30 min of moderate exercise on a treadmill 5 weeks after transplantation. Although control rats maintained near normoglycemia during and after exercise, the rats with islet transplants had significantly lower blood glucose levels. For the rats with islets in the liver, increased C-peptide levels were found at 30 min (790 +/- 125 and 1,450 +/- 250 pmol/l at 0 and 30 min, respectively; P < 0.01), whereas a decrease was found in controls and in rats with islets transplanted into the peritoneal cavity or under the kidney capsule. Moreover, increased glucagon levels were found after exercise in the rats with islets transplanted into the liver (62 +/- 6, 165 +/- 29, 155 +/- 27, and 97 +/- 13 pg/ml at 0, 30, 60, and 90 min, respectively; P < 0.05), whereas no changes in glucagon levels were observed in controls. In conclusion, moderate exercise caused hypoglycemia in rats with islet transplants in different sites including liver, kidney, and peritoneal cavity. C-peptide and glucagon responses to exercise were very different in rats with transplanted islets compared with controls. This islet dysfunction led to exercise-induced hypoglycemia.
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PMID:Exercise induces hypoglycemia in rats with islet transplantation. 1474 86

Protein ingestion after injection of the glucagon-like peptide-1 receptor agonist Exendin-4 (Ex-4) causes hyperglycemia in rats. The objectives of this study were to determine the components of protein digestion responsible for this effect and to associate it with changes in the concentrations of other metabolites and hormones. Two experiments were conducted. In the first experiment, food-deprived rats were gavaged with intact whey (WP) or albumin protein, their hydrolysates, amino acid mixtures (1 g/2.5 ml), or water 5 min after injection of either PBS or Ex-4 (0.5 microg/rat). Tail vein blood was analyzed for glucose over 2 h. In the second experiment, food-deprived rats were gavaged with WP with or without Ex-4. Groups of conscious rats were killed by decapitation either before, or at selected times after gavage. Plasma concentrations of glucose, amino acids, free fatty acids (FFA), glycerol, insulin, glucagon, and leptin were measured. In experiment 1, blood glucose was higher when intact proteins and protein hydrolysates, but not amino acid mixtures, were given with than without Ex-4 (P < 0.05). In experiment 2, concentrations of glucose, FFA, and the ratio of tyrosine to branched-chain amino acid were higher (P < 0.01), but leptin and essential amino acid concentrations were lower (P < 0.05), and insulin, glucagon, and glycerol were similar when WP was given with or without Ex-4. We conclude that the hyperglycemia caused by the administration of Ex-4 concurrently with dietary protein arises from the action of peptides released during digestion and their interaction with Ex-4 in the regulation of glucose, fatty acid, and amino acid metabolism.
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PMID:Hyperglycemia after protein ingestion concurrent with injection of a GLP-1 receptor agonist in rats: a possible role for dietary peptides. 1587 53

The aims of the present study were: to characterize the mechanisms of hemodynamic alterations induced by GLP-2, and, to compare the responses elicited in the superior mesenteric artery (SMA) to other vascular beds. Anesthetized rats were infused at the doses of 0.9, 2.3, 4.6 and 9.3 nmol/kg into the jugular vein for 60 min. Blood flow in the various arteries was measured by the ultrasonic transit time technique. Some animals were pretreated with indomethacin (5 mg/kg, ip), L-NAME (9, 18, 36 and 72 micromol/kg, iv), atropine sulfate (1-2 mg/kg, iv), CCK-1 and CCK-2 receptor antagonists (L-364,718 and L-365,260, 1 mg/kg, iv), exendin (9-39) amide (35 nmol/kg, iv) and lidocaine (74 micromol/kg, iv) prior to the infusion of GLP-2 (4.6 nmol/kg). In another group, capsaicin was applied either systematically (125 mg/kg, sc) or vagally (1 mg/rat). GLP-2 administration at all doses significantly increased the SMA blood flow throughout the experiments. GLP-2 (4.6 nmol/kg) infusion significantly increased blood flow of inferior mesenteric artery and carotid artery but not in any other vessel measured. Only the pretreatments with L-NAME and lidocaine were ineffective in preventing the GLP-2-induced responses. These results implicate that GLP-2-induced blood flow alterations are most significant in the SMA and are not mediated by prostaglandins, muscarinic, GLP-1 or CCK receptors. Our results also suggest that the stimulatory effect of GLP-2 on SMA blood flow is NO-dependent and mediated via intrinsic, non-cholinergic enteric neurons.
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PMID:Mediators of glucagon-like peptide 2-induced blood flow: responses in different vascular sites. 1734 12

Leptin interplays with other peptides to control feeding behaviour in humans and animals. Using exendin-4, an agonist of glucagon-like peptide-1, we investigated whether leptin modifies its effect on food intake in the rat. In the first series, exendin-4 alone (0.1, 2 or 10 microg per rat), leptin alone (0.1, 2, 10 or 100 microg per rat) or exendin-4 and leptin together (0.1 + 0.1, 2 + 2, 10 + 10, or 2 + 100 microg per rat, respectively) were injected once intraperitoneally. In the second series animals were injected either with exendin-4 (2 microg) alone, leptin (10 microg) alone, or leptin (10 microg) + exendin-4 (2 microg) daily for 5 subsequent days. At the lowest dose used, leptin and exendin-4 injected once together, but not separately, reduced significantly a 24-hour food intake. When used in higher doses, however, leptin did not change the exendin-4-dependent suppressory effect on food consumption. No significant differences in food intake were seen between rats treated repeatedly with exendin-4 only and animals injected with both drugs. Hence, leptin and exendin-4 may act additively to inhibit appetite when present in low concentrations while, at high leptin doses, this effect is abolished. The lack of synergistic effects of exendin-4 and high leptin concentrations on food intake may explain, at least in part, mechanisms responsible for leptin resistance in subjects with hyperleptinaemia.
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PMID:Interactions between leptin and exendin-4, a glucagon-like peptide-1 agonist, in the regulation of food intake in the rat. 1762 2

TRPM4 is a Ca(2+)-activated non-selective cation (CAN) channel that functions in cell depolarization, which is important for Ca(2+) influx and insulin secretion in pancreatic beta-cells. We investigated TRPM4 expression and function in the beta-cell lines HIT-T15 (hamster), RINm5F (rat), beta-TC3 (mouse), MIN-6 (mouse) and the alpha-cell line INR1G9 (hamster). By RT-PCR, we identified TRPM4 transcripts in alpha- and beta-cells. Patch-clamp recordings with increasing Ca(2+) concentrations resulted in a dose-dependent activation of TRPM4 with the greatest depolarizing currents recorded from hamster-derived cells. Further, Ca(2+) imaging experiments revealed that inhibition of TRPM4 by a dominant-negative effect significantly decreased the magnitude of the Ca(2+) signals generated by agonist stimulation compared to control cells. The decrease in the [Ca(2+)](i) resulted in reduced insulin secretion. Our data suggest that depolarizing currents generated by TRPM4 are an important component in the control of intracellular Ca(2+) signals necessary for insulin secretion and perhaps glucagon from alpha-cells.
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PMID:TRPM4 impacts on Ca2+ signals during agonist-induced insulin secretion in pancreatic beta-cells. 1906 36

Glucagon, a gut hormone, is one of the key regulatory elements in glucose homeostasis, and is clinically used for treatment of hypoglycemia and premedication in peroral endoscopy. Dry powder inhaler (DPI) form of glucagon is believed to be a promising new dosage form, and the present study aimed to develop a novel glucagon-DPI using absorption enhancer for improved pharmacological effects. The cytotoxicity of citric and capric acids, the potential absorption enhancers, at 1 and 10 mM was assessed by monitoring extracellular LDH levels in rat alveolar L2 cells, and a concentration- and time-dependent release of LDH was observed in capric acid, but not in citric acid-treated cells. DPI form of glucagon containing citric acid was prepared with a jet mill, and laser diffraction and cascade impactor analyses of the newly developed glucagon-DPI suggested high dispersion and deposition in the respiratory organs with an emitted dose and fine particle fraction of 99.5 and 25%, respectively. Addition of citric acid in glucagon-DPI improved the dissolution behavior, and did not impair the solid-state stability of glucagon-DPI. Intratracheal administration of glucagon-DPI (50 microg-glucagon/kg body weight of rat) containing citric acid led to 2.9-fold more potent hyperglycemic effect in rats, as compared to inhaled glucagon-DPI without citric acid. Based on these physicochemical and pharmacological characterization, the dry powder inhaler of glucagon with addition of citric acid would be of use as an alternative to injection form.
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PMID:Novel dry powder inhaler formulation of glucagon with addition of citric acid for enhanced pulmonary delivery. 1970 31


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