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)

Administration of dehydroepiandrosterone (DHEA) to rats results in alterations in liver and serum factors. This study was undertaken to determine the earliest metabolic change(s) associated with DHEA treatment. Serum cholesterol, triacylglycerol, glucose, insulin, glucagon, thyroid hormones and hepatic glucose-6-phosphate dehydrogenase activity were, in general, unaltered in obese Zucker rats after 7 d and 24, 12 and 3 h of DHEA treatment. Malic enzyme, long-chain fatty acyl-coenzyme A hydrolase and catalase activities and peroxisomal beta-oxidation rates were elevated after 7 d and 24 h in DHEA treatment, but not after 12 h. Mitochondrial beta-oxidation was not altered. Hepatic mitochondrial state 3 respiration per g liver with glutamate-malate was elevated after 7 d and 24, 12 and 3 h in DHEA-treated rats and was elevated per mg protein except after 7 d. Succinate-supported state 3 respiration per g liver was also elevated after 7 d and 24 and 12 h of DHEA treatment. Mitochondria from rats treated for 7 d had lower levels of cardiolipin and phosphatidylethanolamine and an increase in phosphatidylcholine. Changes in fatty acid composition of these phospholipids occurred after 7 d and 24 h of DHEA treatment. In an additional study, rats were treated with DHEA or DHEA plus ethidium bromide for 3 d. Ethidium bromide inhibited the increase in mitochondrial protein and respiration associated with DHEA treatment. These findings indicate that mitochondrial respiration is the earliest factor affected by DHEA and may be associated with protein synthesis.
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PMID:Short-term effects of dehydroepiandrosterone treatment in rats on mitochondrial respiration. 182 28

In order to examine the effect of a single bout of exercise on hepatic mitochondrial function, starved untrained male rats swam at 34-35 degrees C with a tail weight (5% of body wt.) for 100 min. The rates of ADP-stimulated and uncoupled respiration were higher in the mitochondria isolated from the exercised rats regardless of the substrate utilized. Succinate-linked Ca2+ uptake was 48% greater in the exercised group; however, Ca2+ efflux was markedly depressed. The inhibition of Ca2+ uptake by Mg2+ was higher in the control group, so that the difference in Ca2+ uptake between the two groups was greater in the presence of Mg2+ than in its absence. The response of phosphorylating respiration and Ca2+ fluxes to exogenous phosphate and the pH of the assay medium differed in the exercise group. These observations with the exercised group were not related to non-specific stress. The exercise-induced mitochondrial-functional alterations are reminiscent of those obtained from mitochondria isolated from glucagon- or catecholamine-treated sedentary rats. Thus, adrenergic stimulation as well as other factors may be operating during exercise, leading to an alteration of mitochondrial function in vitro.
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PMID:Exercise-induced alterations of hepatic mitochondrial function. 716 27

The present study deals with the insulinotropic action of the dimethyl ester of succinic acid (SAD), considered as a potential tool for the treatment of non-insulin-dependent diabetes mellitus. In the perfused pancreas prepared from either euglycemic rats or animals first infused for 48 hours with a solution of D-glucose, SAD (10 mM) markedly enhanced insulin output evoked by a high concentration of D-glucose (16.7 mM), whether in the absence or presence of glimepiride (0.5 microM). The succinate ester failed, however, to affect glucagon secretion. Thus, SAD indeed displays favourable attributes for stimulation of insulin release in type 2 diabetes, with emphasis on its insulinotropic efficiency at high concentrations of D-glucose in an animal model of B-cell glucotoxicity.
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PMID:Enhancement by succinic acid dimethyl ester of insulin release evoked by D-glucose and glimepiride in the perfused pancreas of normoglycemic and hyperglycemic rats. 818 62

The glucagon-like peptide 1 (7-36) amide (GLP-1, 1.0 nM) was administered to isolated rat pancreases perfused either in the absence of exogenous nutrient or presence of 10 mM succinic acid dimethyl ester (SAD). In the absence of any exogenous nutrient, GLP-1 failed to affect either insulin or glucagon release. The administration of SAD caused a biphasic stimulation of insulin output and inhibited glucagon secretion. In the presence of SAD, GLP-1 still failed to affect glucagon release, but markedly enhanced insulin secretion. These findings indicate that GLP-1 is not truly a glucose-dependent, but rather nutrient-dependent insulin secretagogue. They also suggest that non-glucidic nutrients, such as SAD, could be used to optimalize the B-cell secretory response to GLP-1 in non-insulin-dependent diabetes mellitus.
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PMID:Potentiation of glucagon-like peptide 1 insulinotropic action by succinic acid dimethyl ester. 861 71

Glucagon-like peptide 1 (GLP-1) is often referred to as a glucose-dependent insulinotropic agent and is currently under investigation as a tool in the treatment of noninsulin-dependent diabetes. This report shows that, in the absence of glucose, a nonglucidic nutrient, namely succinic acid dimethyl ester (SAD), allows full expression of the insulinotropic potential of GLP-1 in the perfused pancreas from diabetic GK rats. Thus, whereas the insulin and glucagon responses to GLP-1 in GK rats differ from those previously documented in nondiabetic animals when tested in the absence of exogenous nutrient, the secretory response of the endocrine pancreas to GLP-1 is virtually normalized in the GK rats when SAD is incorporated into the perfusate. It is proposed, therefore, that nonglucidic nutrients, such as SAD, may optimalize the B-cell secretory response to GLP-1 in noninsulin-dependent diabetes mellitus.
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PMID:Potentiation of GLP-1 insulinotropic action by a nonglucidic nutrient in the pancreas of diabetic GK rats. 890

Most patients with type 2 (non-insulin-dependent) diabetes mellitus require pharmacotherapy, initially as monotherapy and subsequently in combination, as adjuncts to diet and exercise. Exogenous insulin is ultimately required in a substantial proportion, reflecting the progressive natural history of the disease. Sulphonylureas and biguanides have been employed for over 4 decades as oral antidiabetic agents, but they have a limited capacity to provide long term glycaemic control and can cause serious adverse effects. Thus, more efficacious and tolerable antidiabetic agents are required. Recent years have witnessed the introduction of agents with novel modes of action, that is, the alpha-glucosidase inhibitors acarbose and miglitol (which reduce postprandial hyperglycaemia) and the first of the thiazolidinedione insulinsensitising drugs--troglitazone and rosiglitazone. Although the former has been withdrawn in some countries due to adverse effects, another 'glitazone' pioglitazone is expected to be approved in the near future. Other recently introduced drugs include glimepiride and the meglitinide insulin secretagogue, repaglinide. Attention is also focusing increasingly on combination therapy using insulin together with sulphonylureas, metformin or troglitazone. Rapid-acting insulin analogues are now being used as alternatives to conventional insulins; their role in the management of type 2 diabetes mellitus is presently uncertain but reports of a reduced frequency of hypoglycaemia are encouraging. The development of new drugs aims to counter the principal metabolic defects of the disorder, respectively, relative insulin deficiency and insulin resistance. Novel classes of rapid-acting secretagogues under evaluation include the morphilinoguanide BTS 67582 and the meglitinides mitiglinide (KAD 1229) and senaglinide (A-4166). Succinate ester derivatives represent a potential novel approach to improving beta-cell function through enhancement of insulin biosynthesis and secretion. Enhancement of nutrient-induced insulin secretion is a mechanism with several putative targets within the beta-cell; potentiators of insulin secretion include glucagon-like peptide-1 and its analogues, phosphodiesterase inhibitors and the imidazoline derivative PMS 812 (S 21663). The amylin agonist pramlintide slows gastric emptying and suppression of glucagon secretion. Non-thiazolidinedione insulin-sensitising agents include the gamma-receptor agonist G 1262570X (GG 570) and D-chiro-inositol. Insulin analogues with prolonged action and inhaled insulin preparations are also under investigation. Insulin-mimetic agents include organic vanadium compounds. Whether newer agents will offer clinically relevant efficacy and tolerability advantages over existing therapies remains to be determined.
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PMID:Recent developments and emerging therapies for type 2 diabetes mellitus. 1082 Jun 47

D-mannoheptulose was recently proposed to be transported into cells by GLUT2, whereas its hexaacetate ester may cross the plasma membrane without requiring the intervention of a specific carrier system. In the light of these proposals, the effects of unesterified D-mannoheptulose and D-mannoheptulose hexaacetate upon hormonal secretion by the perfused rat pancreas were now investigated. Unesterified D-mannoheptulose (1.7 mM) inhibited insulin release and, in most cases, somatostatin output, whereas it augmented glucagon secretion by pancreases exposed to D-glucose (3.3 mM) in the presence of the dimethyl ester of succinic acid (SAD, 10.0 mM). The heptose failed, however, to affect hormonal secretion in the sole presence of SAD. D-mannoheptulose hexaacetate (also 1.7 mM) reproduced, within limits, the effects of unesterified D-mannoheptulose in pancreases exposed to both D-glucose and SAD. In addition, however, the ester displayed a positive effect upon the secretion of the three hormones, even in the sole presence of SAD. These findings support the view that monosaccharide esters may affect the secretion of pancreatic hormones in a dual manner, linked to both the metabolic response to their glucidic moiety and a direct effect of the ester itself. Moreover, they reveal that unesterified D-mannoheptulose is able to antagonize the effect of D-glucose upon hormonal secretion even in cells claimed not to contain GLUT2. The modality by which D-mannoheptulose apparently gains access to the cytosol of these cells remains to be elucidated.
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PMID:Effects of D-mannoheptulose and its hexaacetate ester on hormonal secretion from the perfused pancreas. 1089 57

It was recently proposed that suitable succinic acid esters could be used to potentiate the insulinotropic action of glucagon-like peptide 1 (GLP-1) in the treatment of type-2 diabetes mellitus. In such a perspective, the present study aimed mainly at investigating whether exendin-4 (Ex-4), a peptide structurally related to GLP-1(7-36)amide, and succinic acid dimethyl ester (SAD) also act synergistically upon insulin secretion in anaesthetized rats. Despite a higher plasma insulin concentration in SAD-infused rats (5.5+/-1.1 ng/ml) than in saline-infused animals (1.9+/-0.7 ng/ml), the intravenous injection of Ex-4 augmented to a greater extent the plasma concentration of insulin in the former rats (+7.4+/-2.5 ng/ml) than in the latter animals (+2.8+/-0.6 ng/ml). These findings document that the insulinotropic actions of Ex-4 and GLP-1 display comparable nutrient dependency, being both potentiated by a non-glucidic nutrient secretagogue such as SAD.
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PMID:Synergistic insulinotropic effects of succinic acid dimethyl ester and exendin-4 in anaesthetized rats. 1149 54

Glucagon-like peptide-1 (GLP-1) acts as a nutrient-dependent insulin-releasing agent, and its insulinotropic action is enhanced by nutrient secretagogues, such as the dimethyl ester of succinic acid (SAD). In the present study, a primed constant infusion of SAD (0.5 micromol followed by 0.25 micromol/min both per g of body wt) was found to increase plasma insulin concentration in fed anesthetized rats, to potentiate the B-cell secretory response to GLP-1 (0.5 pmol/g of body wt), and to unmask the hypoglycemic potential of the gastrointestinal hormone. In the SAD-infused rats, the infusion of exendin(9-39)amide (5.0 pmol/min per g of body wt), 1 min before and 3 min after GLP-1 injection, decreased plasma insulin concentration before GLP-1 injection, suppressed the B-cell secretory response to GLP-1, and both delayed and minimized its hypoglycemic action. It is proposed, therefore, that exendin (9-39)amide could represent a tool in the treatment of alimentary or reactive hypoglycemia.
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PMID:Suppression by exendin(9-39)amide of glucagon-like peptide-1 insulinotropic action in rats infused with dimethyl ester of succinic acid. 1176

We investigated the in vitro effects of therapeutical concentrations of S 21403 (a succinic acid derivative also known as KAD 1229 and mitiglinide) on insulin and glucagon secretion during a metabolic stimulus (glucose rising from 5 to 8.33 mM) or at a stable 2.22 mM glucose using the isolated perfused rat pancreas model, and we compared them with the patterns of repaglinide and glibenclamide. Control perfusions were also performed. During 8.33 mM glucose, insulin release peaked to 339.12+/-22.87 microU/ml in controls. S 21403 enhanced insulin release (first peak 413.02+/-14.90 microU/ml; P<0.03 vs. controls, P=ns vs. repaglinide, P<0.005 vs. glibenclamide). Repaglinide increased glucose-induced first peak secretion to 409.33+/-20.05 microU/ml within the eighth minute (P<0.05 vs. controls, P<0.01 vs. glibenclamide). Glibenclamide did not affect the first phase of glucose-induced insulin release (peak of 338.41+/-29.79 microU/ml) but potentiated and delayed the second phase. No drug affected glucagon release. In conclusion, S 21403 induces a faster, more physiological pattern of insulin release than the other drugs we tested.
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PMID:Effects of S 21403 on hormone secretion from isolated rat pancreas at different glucose concentrations. 1245 May 80


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