Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

GLP-1, an incretin hormone of the enteroinsular axis with insulinotropic and glucagonostatic activity, is secreted after nutrient ingestion. GLP-1 is mainly produced by intestinal L-cells in the lower gastrointestinal tract (GIT); simple carbohydrates are absorbed in the upper GIT and alpha-glucosidase inhibition leads to augmented and prolonged GLP-1 release in normal subjects. In a cross-over study, 100 mg acarbose or placebo was administered simultaneously with 100 g sucrose to 11 hyperglycaemic Type 2 diabetic patients poorly controlled with diet and sulphonylureas. Plasma levels of GLP-1, insulin, C-peptide, glugacon, GIP, glucose and H2-exhalation were measured over 6 h. Differences in the integrated responses over the observation period were evaluated by repeated measurement analysis of variance with fasting values used as covariates. With acarbose, sucrose reached the colon 60-90 min after ingestion as indicated by a significant increment in breath hydrogen exhalation (p = 0.005). After an early GLP-1 increment 15 min after sucrose under both conditions, GLP-1 release was prolonged in the acarbose group (p = 0.001; significant from 210 to 360 min.). Initially (0-150 min), glucose (p = 0.001), insulin (p = 0.001), and GIP (p < 0.001) were suppressed by acarbose, whereas later there were no significant differences. Glucagon levels were higher with acarbose in the last 3 h of the 6 h observation period (p = 0.02). We conclude that in hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a sucrose load leads to elevated and prolonged GLP-1 release.
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PMID:Prolonged and enhanced secretion of glucagon-like peptide 1 (7-36 amide) after oral sucrose due to alpha-glucosidase inhibition (acarbose) in Type 2 diabetic patients. 963 23

Insulin resistance syndrome has recently been described as a unifying hypothesis to explain the relationship between the many risk factors of coronary heart disease. Carbohydrate that is malabsorbed and fermented in the colon has been demonstrated to decrease insulin response to a glucose load and improve other risk factors associated with coronary heart disease, although the mechanism remains unclear. The object of the present study was to investigate whether this observation could be explained by the production of fermentation products induced by malabsorbed carbohydrate in the colon, or by stimulating the incretin glucagon-like peptide 1 (7-36) amide that is released from the large bowel. We used lactulose as a model for resistant starch carbohydrate. Ten insulin-resistant male volunteers, who had undergone previous coronary artery bypass grafting, volunteered to take part in the study and underwent 6 d of lactulose loading (15 g/d for 2 d and 30 g/d for 4 d). There was no significant change in insulin, glucose, free fatty acids, or glucagon-like peptide 1 (7-36) amide response to an oral glucose tolerance test following the lactulose despite a significant rise in breath hydrogen. Large bowel fermentation stimulated by lactulose appears to have no significant effect on insulin, glucose, free fatty acids, and glucagon-like peptide 1 (7-36) response in patients with coronary heart disease.
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PMID:Effect of large bowel fermentation on insulin, glucose, free fatty acids, and glucagon-like peptide 1 (7-36) amide in patients with coronary heart disease. 1067 37

Patients with serum calcium above 4.5 mmol/litre risk sudden death. Rehydration and frusemide may decrease calcium levels by 0.5-1 mmol/litre but result in a high renal filtered load of calcium which, if above 3.7 mmol/litre, causes calcium phosphate protein complexes to form giving rise to hypercalcaemic nephropathy. Current drugs namely clodronate, calcitonin and plicamycin take days to lower serum calcium and have disadvantages. Intravenous phosphate rapidly lowers serum calcium but when the calcium phosphate product rises above 4.6 mmol/litre the saturation point for the precipitation of calcium hydrogen phosphate is reached and tissue calcification occurs. Intravenous glucagon results in a steep reduction in serum phosphate within minutes and also lowers serum calcium, resulting in a marked fall in the calcium phosphate product to well below the critical level of 4.6 mmol/litre. If, in addition to glucagon, intravenous phosphate is now given, it should have a further calcium-lowering effect by inhibiting bone osteoclasts.
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PMID:Prevention of hypercalcaemic nephropathy and tissue calcification by glucagon during phosphate infusion. 1049 24

The small intestine's large capacity for glucose absorption and for adaptation seems to contradict the reported importance of carbohydrate malabsorption in short bowel (SB) patients. The aim of the present study was to investigate the occurrence of malabsorption in these patients ingesting realistic amounts of carbohydrates. We performed a dose-response study [ingestion of increasing amounts of glucose and complex carbohydrates (boiled rice and wheat bread), and the nonabsorbable disaccharide lactulose] in SB patients with an intact colon. The hydrogen (H2) -breath test and changes in serum acetate were used to evaluate colonic fermentation and, thus, indirectly, the lack of small intestinal carbohydrate assimilation. Blood glucose and plasma insulin were measured to evaluate absorption. Plasma concentrations of the ileal brake hormones--glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY)--were measured to test whether release of these hormones was related to colonic fermentation. Significant amounts of 25 g and 50 g glucose, and of the bread and rice meals were fermented rather than absorbed, as judged by the increases in end-expiratory H2. Serum acetate concentrations were significantly higher in SB patients than in healthy controls. The orocecal transit times of all test meals ranged from 15 to 120 min. GLP-1 and PYY releases in SB patients were significantly higher than in healthy volunteers. They were mutually parallel and paralleled the increase in insulin. They were not related to ongoing fermentation or to intraluminal carbohydrate content per se, but most probably to absorption of glucose in the distal bowel. In conclusion, well-adapted SB patients had pronounced small intestinal malabsorption of carbohydrate, even after ingestion of small amounts of easily absorbable carbohydrates. A fast small intestinal spreading of carbohydrates, once in the small intestine, and a spill-over to the colon seem to explain the data best.
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PMID:Importance of colonic bacterial fermentation in short bowel patients: small intestinal malabsorption of easily digestible carbohydrate. 1050 35

ABSTRACT. Despite the high incidence of acute metabolic acidosis, there are no reliable human data to enable physicians to accurately diagnose this disorder. In addition, there is uncertainty about the direction and magnitude of plasma potassium changes in acute metabolic acidosis. The systemic and renal acid-base, electrolyte, and endocrine response to acute acid loads (imposed by three timed NH(4)Cl infusions into the duodenum, 0.9 mmol of NH(4)Cl per kg of body weight over 30 min each) was characterized in six healthy male subjects in whom a metabolic steady-state had been established. Arterialized blood CO(2) tension decreased by 0.85 mmHg per mmol/L decrease in plasma bicarbonate concentration and blood hydrogen ion concentration increased by 0.45 nmol/L per mmol/L decrease in plasma bicarbonate concentration. Plasma potassium did not change significantly (+0.02 +/- 0.02 mmol/L per mmol decrease in plasma bicarbonate concentration). Plasma insulin increased and plasma glucagon levels decreased in acute metabolic acidosis, while catecholamines and aldosterone were not affected significantly. These data provide the first diagnostic criteria for the diagnosis of acute metabolic acidosis in humans. The finding of a hyperinsulinemic response in acute metabolic acidosis suggests that an insulin response counterregulates any acidemia-induced cellular potassium efflux, resulting in stable plasma potassium concentrations.
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PMID:Acute metabolic acidosis: characterization and diagnosis of the disorder and the plasma potassium response. 1515 80

This study investigated the blood glucose-lowering effect and antioxidant capacity of caffeic acid in C57BL/KsJ-db/db mice. Caffeic acid induced a significant reduction of the blood glucose and glycosylated hemoglobin levels than the control group. The plasma insulin, C-peptide, and leptin levels in caffeic acid group were significantly higher than those of the control group, whereas the plasma glucagon level was lower. Increased plasma insulin by caffeic acid was attributable to an antidegenerative effect on the islets. Caffeic acid also markedly increased glucokinase activity and its mRNA expression and glycogen content and simultaneously lowered glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities and their respective mRNA expressions, accompanied by a reduction in the glucose transporter 2 expression in the liver. In contrast to the hepatic glucose transporter 2, adipocyte glucose transporter 4 expression was greater than the control group. In addition, caffeic acid significantly increased superoxide dismutase, catalase, and glutathione peroxidase activities and their respective mRNA levels, while lowering the hydrogen peroxide and thiobarbituric acid reactive substances levels in the erythrocyte and liver of db/db mice. These results indicate that caffeic acid exhibits a significant potential as an antidiabetic agent by suppressing a progression of type 2 diabetic states that is suggested by an attenuation of hepatic glucose output and enhancement of adipocyte glucose uptake, insulin secretion, and antioxidant capacity.
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PMID:Antihyperglycemic and antioxidant properties of caffeic acid in db/db mice. 1664 2

Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potent inhibitors of liver glycogen phosphorylase a (IC(50) = 0.4-1.2 microM) and of basal and glucagon-stimulated glycogenolysis (IC(50) = 1-3 microM). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate and induce conformational changes that characterize the R-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Our findings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformational change to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor the T state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.
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PMID:Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition. 1697 Mar 95

Alzheimer's disease (AD) is the most common form of dementia. Glucagon-like peptide-1 (GLP-1) gives a new genre in therapeutic targets for intervention in AD with its neurotrophic and neuroprotective functions. In previous work, we identified that geniposide is a novel agonist for GLP-1 receptor, which shows neurotrophic characteristics to induce the neuronal differentiation of PC12 cells. The aim of this study is to determine whether geniposide prevents neurons from oxidative damage, and to explore its signaling pathways. The results demonstrated that geniposide increased the expression of anti-apoptotic proteins, including Bcl-2 and heme oxygenase-1 (HO-1), to antagonize the oxidative damage in PC12 cells induced by hydrogen peroxide. LY294002 (a PI3K inhibitor) inhibited the effect of geniposide increasing of Bcl-2 level by activation of MAPK, MEK and c-Raf phosphorylation in hydrogen peroxide treated PC12 cells. U0126 (a selective inhibitor of MEK) also attenuated the enhancement of geniposide on Bcl-2 level by inhibiting the phosphorylation of p90RSK in the hydrogen peroxide treated PC12 cells. All these data demonstrate that geniposide, an agonist for GLP-1 receptor, regulates expression of anti-oxidative proteins including HO-1 and Bcl-2 by activating the transcriptor of p90RSK via MAPK signaling pathway in PC12 cells.
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PMID:Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway. 1762 57

Low-glycemic index (GI) foods and foods rich in whole grain are associated with reduced risk of type 2 diabetes and cardiovascular disease. We studied the effect of cereal-based bread evening meals (50 g available starch), varying in GI and content of indigestible carbohydrates, on glucose tolerance and related variables after a subsequent standardized breakfast in healthy subjects (n = 15). At breakfast, blood was sampled for 3 h for analysis of blood glucose, serum insulin, serum FFA, serum triacylglycerides, plasma glucagon, plasma gastric-inhibitory peptide, plasma glucagon-like peptide-1 (GLP-1), serum interleukin (IL)-6, serum IL-8, and plasma adiponectin. Satiety was subjectively rated after breakfast and the gastric emptying rate (GER) was determined using paracetamol as a marker. Breath hydrogen was measured as an indicator of colonic fermentation. Evening meals with barley kernel based bread (ordinary, high-amylose- or beta-glucan-rich genotypes) or an evening meal with white wheat flour bread (WWB) enriched with a mixture of barley fiber and resistant starch improved glucose tolerance at the subsequent breakfast compared with unsupplemented WWB (P < 0.05). At breakfast, the glucose response was inversely correlated with colonic fermentation (r = -0.25; P < 0.05) and GLP-1 (r = -0.26; P < 0.05) and positively correlated with FFA (r = 0.37; P < 0.001). IL-6 was lower (P < 0.01) and adiponectin was higher (P < 0.05) at breakfast following an evening meal with barley-kernel bread compared with WWB. Breath hydrogen correlated positively with satiety (r = 0.27; P < 0.01) and inversely with GER (r = -0.23; P < 0.05). In conclusion, the composition of indigestible carbohydrates of the evening meal may affect glycemic excursions and related metabolic risk variables at breakfast through a mechanism involving colonic fermentation. The results provide evidence for a link between gut microbial metabolism and key factors associated with insulin resistance.
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PMID:Including indigestible carbohydrates in the evening meal of healthy subjects improves glucose tolerance, lowers inflammatory markers, and increases satiety after a subsequent standardized breakfast. 1835 28

The solution conformation of alpha-conotoxin GI and its two single disulfide analogues are simulated using a polarizable force field in combination with the molecular fragmentation quantum chemical calculation. The polarizability is explicitly described by allowing the partial charges and fragment dipole moments to be variables, with values coming from the linear-scaling energy-based molecular fragmentation calculations at the B3LYP/6-31G(d) level. In comparison with the full quantum chemical calculations, the fragmentation approaches can yield precise ground-state energies, dipole moments, and static polarizabilities for peptides. The B3LYP/6-31G(d) charges and fragment-centered dipole moments are introduced in calculations of electrostatic terms in both AmberFF03 and OPLS force fields. Our test calculations on the gas-phase glucagon (PDB code: 1gcn) and solvated alpha-conotoxin GI (PDB code: 1not) demonstrate that the present polarization model is capable of describing the structural properties (such as the relative conformational energies, intramolecular hydrogen bonds, and disulfide bonds) with accuracy comparable to some other polarizable force fields (ABEEM/MM and OPLS-PFF) and the quantum mechanics/molecular mechanics (QM/MM) hybrid model. The employment of fragment-centered dipole moments in calculations of dipole-dipole interactions can save computational time in comparison with those polarization models using atom-centered dipole moments without much loss of accuracy. The molecular dynamics simulations using the polarizable force field demonstrate that two single disulfide GI analogues are more flexible and less structured than the native alpha-conotoxin GI, in agreement with NMR experiments. The polarization effect is important in simulations of the folding/unfolding process of solvated proteins.
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PMID:Conformational simulations of aqueous solvated alpha-conotoxin GI and its single disulfide analogues using a polarizable force field model. 1878 21


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