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)

The mechanisms involved in the rapid glucagon-like peptide-1 (GLP-1) release following glucose ingestion are poorly defined. Besides a direct intestinal stimulation of L cells, humoral and neuronal mechanisms have been discussed. We investigated the temporal pattern of GLP-1 release in five healthy men (aged 27.8 +/- 3.6 yr, body mass index, 23.4 +/- 1.2 kg/m2) after an overnight fast for 60 min under basal conditions and for 60 min after an oral glucose load (OGL; 100 g) in both the presence and absence of atropine (80 ng/kg min, iv). Blood was sampled every 2 min, and data were evaluated for the temporal pattern of GLP-1 secretion by several computer-assisted programs (deconvolution, Pulsar analysis, and Fourier transformation). With all methods a pulsatile pattern of plasma GLP-1 levels with a frequency of five to seven per h was detected; this remained unchanged in the different metabolic states and during atropine treatment. Glucose and GLP-1 plasma levels showed a parallel increase after OGL (OGL without atropine = control: 8.4 +/- 2.9 and 7.9 +/- 3.0 min, respectively). Atropine infusion delayed this increase significantly (16.8 +/- 8.07 and 17.4 +/- 6.61 min, respectively; P < 0.02). In contrast to plasma glucose concentrations (82.7 +/- 0.3% of control; P < 0.05), atropine infusion reduced the integrated GLP-1 pulse amplitude to 56.0 +/- 11.3% of the control levels (P < 0.05). In conclusion, GLP-1 is secreted in a pulsatile manner with a frequency comparable to that of pancreatic hormones. Mean GLP-1 plasma concentrations increase after OGL due to augmented GLP-1 pulse amplitudes but not frequency. The differential effect of atropine on glucose and GLP-1 plasma levels suggest a direct cholinergic muscarinic control of L cells.
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PMID:Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. 906 83

The effect of early phase insulin on postprandial levels of insulin, C-peptide, glucose, and glucagon was investigated in lean (n = 10) and obese (n = 12) subjects. Subjects underwent four conditions during ingestion of a meal (600 kcal): 1) saline infusion; 2) 10-min insulin infusion simultaneously with meal ingestion (0.24 U bolus, 15 mU. m(-2). min(-1)); 3) atropine infusion (0.4 mg/m(2) bolus, 0.4 mg. m(-2). h for 4 h); 4) insulin and atropine infusion. Blood samples were taken for 3.5 h. Insulin infusion had no effect on postprandial insulin levels in either population but significantly reduced postprandial glucose in the obese subjects (P < 0.05). Obese subjects with elevated postprandial glucose levels in the presence of muscarinic blockade exhibited a decline in glucose with insulin supplementation. Atropine reduced postprandial insulin levels in both groups, with a greater attenuation in the obese (P < 0.01), but postprandial glucose levels were also significantly reduced, suggesting that atropine inhibited gastric emptying. Thus the effects of muscarinic blockade on postprandial insulin levels cannot be evaluated. These data suggest that insulin supplementation during the preabsorptive time period may contribute to glucoregulation in the obese population.
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PMID:Early phase insulin infusion and muscarinic blockade in obese and lean subjects. 1040 74

Meal-induced insulin secretion is thought to be regulated primarily by absorbed nutrients and incretin hormones released from the gastrointestinal tract. In addition, the parasympathetic nervous system (PNS) is known to mediate preabsorptive, or cephalic phase, insulin secretion. Despite evidence that the PNS remains activated during the absorptive phase of the meal, its role in mediating postprandial insulin secretion has not been established. To study the role of the PNS in absorptive phase insulin release, we measured plasma concentrations of glucose as well as islet hormones and incretins in six healthy rhesus monkeys before and for 60 min after meals while they were infused with saline (control), atropine (muscarinic blockade), or trimethaphan (nicotinic blockade). During the infusion of saline, plasma levels of glucose, pancreatic polypeptide (PP), insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 increased promptly after meal ingestion and remained elevated throughout the 60 min of the study. The PP response was nearly abolished in animals treated with trimethaphan, indicating functional blockade of PNS input to the islet, and in contrast to the control study, there were minimal changes in plasma concentrations of glucose, incretin hormones, and insulin. Because trimethaphan inhibited glycemic and incretin stimuli in addition to blocking PNS input to the islet, it was not possible to discern the relative roles of these factors in the stimulation of insulin secretion. Atropine also significantly decreased PNS transmission to the islet, as reflected by PP levels similar to those observed with trimethaphan. Unlike the trimethaphan study, plasma glucose levels rose normally during atropine treatment and were similar to those in the control study over the course of the experiments (114 +/- 22 and 132 +/- 23 mmol/L.60 min, respectively). In addition, the rise in plasma glucagon-like peptide-1 following the meal was not suppressed by atropine, and the glucose-dependent insulinotropic polypeptide responses were only modestly decreased. Despite the significant increases in circulating glucose and incretins, plasma insulin levels were greatly attenuated by atropine, so that the 60 min responses were more comparable to those during trimethaphan treatment than to those in the control study (atropine, 3,576 +/- 1,284; trimethaphan, 4,128 +/- 2,616; control, 15,834 +/- 5,586 pmol/L.60 min; P: < 0.05). Thus, muscarinic blockade markedly suppressed the meal-induced insulin response despite normal postprandial glycemia and significant elevations of incretins. These results indicate that activation of the PNS during the absorptive phase of meals contributes significantly to the postprandial insulin secretory response.
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PMID:Activation of the parasympathetic nervous system is necessary for normal meal-induced insulin secretion in rhesus macaques. 1123 17

The effect of electrical field stimulation (EFS) on insulin (INS) and glucagon (GLU) secretion from normal and diabetic rat pancreas is poorly understood. In our study, EFS (5-20Hz, 50 V amplitude and 1.0 ms pulse width), when applied alone, resulted in a significant (p<0.05) increase in INS secretion from the pancreas of both normal and diabetic rats. Atropine (10(-5) M) did not inhibit the EFS (5 Hz)-evoked INS secretion in normal pancreas and failed to alter the effect of EFS (10-20 Hz) on INS secretion from the pancreas of both normal and diabetic rats. Propranolol (Prop) inhibited INS secretion to below basal level in the presence of EFS (5 Hz) but not at EFS (10- 20 Hz). Tetrodotoxin (TTX) also significantly (p = 0.002) inhibited INS secretion from normal pancreas in the presence of EFS (5-20 Hz). The decrease in insulin secretion observed when pancreatic tissue fragments were incubated in Prop and TTX in the presence of EFS was reversed by yohimbine (10(-5) M). In contrast, TTX did not significantly modify INS secretion from diabetic pancreas in the presence of EFS. EFS (5-20 Hz) significantly (p<0.05) increased GLU release from normal and diabetic rat pancreas when applied alone. Neither atropine, Prop nor TTX significantly modified GLU release from the pancreas of either normal or diabetic rats. This suggests that GLU secretion may be controlled through a different pathway. The EFS-evoked INS and GLU secretion is probably executed via different mechanisms. These mechanisms include 1) activation of cholinergic nerves by EFS; 2) EFS of alpha- and beta-adrenergic nerves; 3) activation of non-adrenergic non-cholinergic pathway by EFS; 4) EFS-induced depolarization and subsequent action potential in pancreatic endocrine cells and 5) electroporosity caused by EFS-induced membrane permeability. All of these effects may be summative. In conclusion, EFS (5-20 Hz), when applied alone, can evoke significant increases in INS and GLU secretion from the pancreas of both normal and diabetic rats. Insulin secretion is controlled via alpha-2 adrenergic (inhibition) and beta-adrenergic (stimulation) receptors. Glucagon secretion is enhanced by alpha2 adrenergic stimulation.
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PMID:Effect of electrical field stimulation on insulin and glucagon secretion from the pancreas of normal and diabetic rats. 1144 Feb 74

Leucine-enkephalin (Leu-Enk) has been shown to be present in endocrine cells of the rat pancreas and may play a role in the modulation of hormone secretion from the islets of Langerhans. Since little is known about the effect of Leu-Enk on insulin and glucagon secretion, it was the aim of this study to determine the role of Leu-Enk on insulin and glucagon secretion from the isolated pancreatic tissue fragments of normal and diabetic rats. Pancreatic tissue fragments of normal and streptozotocin-induced diabetic rats were incubated for 1 h with different concentrations of Leu-Enk (10(-12)-10(-6)M) alone or in combination with either atropine or yohimbine or naloxone. After the incubation period the supernatant was assayed for insulin and glucagon using radioimmunoassay techniques. Leu-Enk (10(-12 )-10(-6)M) evoked large and significant increases in insulin secretion from the pancreas of normal rats. This Leu-Enk-evoked insulin release was significantly (p < 0.05) blocked by atropine, naloxone and yohimbine (all at 10(-6)M). In the same way, Leu-Enk at concentrations of 10(-12)M and 10(-9)M induced significant (p < 0.05) increases in glucagon release from the pancreas of normal rats. Atropine, yohimbine but not naloxone significantly (p < 0.05) inhibited Leu-Enk-evoked glucagon release from normal rat pancreas. In contrast, Leu-Enk failed to significantly stimulate insulin and glucagon secretion from the pancreas of diabetic rats. In conclusion, Leu-Enk stimulates insulin and glucagon secretion from the pancreas of normal rat through the cholinergic, alpha-2 adrenergic and opioid receptor pathways.
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PMID:The role of leucine-enkephalin on insulin and glucagon secretion from pancreatic tissue fragments of normal and diabetic rats. 1188 Sep 25

Plasma levels of glucagon-like peptide-1 (GLP-1) rise rapidly after nutrient ingestion through an indirect mechanism triggered from the proximal intestine and involving the vagus nerve that stimulates the L cell in the distal gut. The role of muscarinic receptors in this pathway was thus investigated using the anesthetized rat and fetal rat intestinal cells (FRIC) in culture. GLP-1 secretion from the distal gut increased 5-fold after 3 ml corn oil were placed into the proximal duodenum (P < 0.001). Atropine (a nonspecific muscarinic receptor antagonist) completely inhibited fat-induced GLP-1 secretion in vivo (P < 0.01). Pirenzepine (an M1 muscarinic receptor antagonist) also inhibited fat-induced GLP-1 secretion in vivo, by 91 +/- 6% (P < 0.01). Gallamine (an M2 muscarinic receptor antagonist) and 4-diphenylacetoxy-N-methylpiperidine (an M3 muscarinic receptor antagonist) had no effect. Incubating FRIC cultures with bethanechol (a muscarinic receptor agonist) stimulated GLP-1 secretion to 200 +/- 22% of control (P < 0.01). Pirenzepine and gallamine significantly inhibited bethanechol-stimulated GLP-1 secretion, by 96 +/- 12% and 98 +/- 8%, respectively (P < 0.01). Unexpectedly, 4-diphenylacetoxy-N-methylpiperidine stimulated GLP-1 secretion by FRIC cells, to 324 +/- 52% of the control value (P < 0.01). Double immunofluorescent staining using GLP-1 and M1, M2, and M3 muscarinic receptor antibodies showed expression of the three subtypes of muscarinic receptors by the L cells in rat ileal sections and FRIC cultures. These results demonstrate the role of M1 muscarinic receptors expressed by L cells in the control of postprandial secretion of GLP-1. M2 muscarinic receptors also seem to play a role in controlling GLP-1 secretion by fetal, but not adult, L cells.
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PMID:Muscarinic receptors control postprandial release of glucagon-like peptide-1: in vivo and in vitro studies in rats. 1202 Dec 7

Amino acids (AA) and/or somatotropin (ST) were infused into a jugular vein of lactating cows receiving atropine to determine the effect on milk protein secretion. Atropine decreased milk protein yield by 35%. Plasma alpha-amino nitrogen, which was decreased by 31% due to atropine, was restored to control levels upon AA infusion. Plasma ST concentration was not affected by atropine and, upon ST infusion, increased by 236% in treated animals. Amino acids, ST, or the combination of the two were unable to return milk protein to control levels in atropine-treated animals. Plasma insulin concentration decreased by 37% in atropine-treated animals and was not significantly different for cows receiving atropine as well as ST, AA, or both ST and AA. Similarly, glucagon decreased by 36% in atropine-treated animals but was partially restored in cows receiving AA. Overall, the insulin-to-glucagon ratio was not significantly affected by treatment. Plasma glucose concentration was not affected by treatment. These data lend support to the importance of the insulin-to-glucagon ratio in terms of whole-body metabolism, with the exception of the mammary glands, which are glucagon-insensitive and, therefore, sensitive to the observed decrease in circulating insulin concentration.
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PMID:Delineating potential control mechanisms of mammary protein synthesis utilizing atropine. 1214 75

Muscarinic antagonists, particularly atropine, can inhibit myopia development in several animal models and also in children. However, the biochemical basis of the inhibition of axial eye growth remains obscure, and there are doubts whether muscarinic receptors are involved at all. Experiments in chickens and monkeys have shown that the synthesis of the transcription factor ZENK, also named Egr-1, in retinal glucagon amacrine cells is strongly associated with inhibition of axial eye growth (assumed to create a STOP signal). We have tested whether the muscarinic antagonists atropine, pirenzepine, oxyphenonium, gallamine, MT-3, himbacine, and 4-DAMP can stimulate ZENK expression so that the drugs' inhibitory effect on myopia development could be explained by an enhanced STOP signal. Because it is known that intravitreal quisqualic acid (QA) eliminates most cholinergic neurons in the retina within 6 or 7 days, in a second set of experiments, we tested whether these antagonists could still stimulate ZENK production, 6 days after QA was applied. Muscarinic antagonists, injected intravitreally at various concentrations, affected ZENK synthesis in various and unpredictable ways. Pirenzepine, oxyphenonium, and MT-3 increased the proportion of glucagon cells that were ZENK-immunoreactive, whereas himbacine decreased that proportion, and gallamine and 4-DAMP had no significant effect. Atropine caused an upregulation of ZENK only if all positive amacrine and bipolar cells were counted and therefore appeared to affect primarily cells other than glucagon amacrines. The pattern of results remained unchanged after ablation of most cholinergic neurons by QA. Our results suggest that at least some muscarinic antagonists do not activate cells that synthesize ZENK when they inhibit axial eye growth. Therefore, in line with other studies they also cast doubt on the assumption that muscarinic transmission is crucial, and they suggest that muscarinic antagonists may inhibit myopia through extraretinal target sites or through non-cholinergic retinal actions.
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PMID:Effects of muscarinic antagonists on ZENK expression in the chicken retina. 1614 26

The gut-born incretin hormone glucagon-like peptide-1 (GLP-1) delays gastric emptying. To elucidate the mechanisms by which GLP-1 affects gastroduodenal motility and glycaemia, we studied the effects of exendin(9-39), a potent GLP-1 receptor antagonist, on gastroduodenal motility and pancreatic hormones. In this randomized, double-blind, placebo-controlled, four-arm, cross-over trial, 10 healthy volunteers were studied during the interdigestive period followed by duodenal perfusion of a mixed liquid meal (250 kcal). On four separate days, exendin(9-39), atropine, exendin(9-39) + atropine or saline were infused intravenously. Antro-pyloro-duodenal and fundic motility were assessed. The compliance of the proximal stomach was determined by isobaric distensions. During fasting, exendin(9-39) did not influence proximal gastric volume, pyloric tone, and duodenal contractility. Exendin(9-39) significantly increased antral waves only in the absence of atropine. During duodenal meal perfusion, exendin(9-39) significantly reduced proximal gastric volume accommodation, abbreviated postprandial antral inhibition, reduced the postprandial increase in pyloric tone, and reduced gastric compliance. Atropine abolished the effects of exendin(9-39) on gastric volume accommodation but did not affect its effects on postprandial antroduodenal motility and on gastric compliance. Exendin(9-39) increased fasting and postprandial glycaemia and plasma glucagon but not insulin concentrations. Atropine did not affect GLP-1 secretion. Cholinergic mechanisms mediate the effects of GLP-1 on postprandial gastric accommodation but not on antro-pyloro-duodenal motility. GLP-1 reduces fasting and postprandial glycaemia, in part by reducing glucagon secretion.
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PMID:GLP-1 regulates gastroduodenal motility involving cholinergic pathways. 1922 Jul 54

This case report describes the first reported overdose of the dihydropyridine calcium channel blocker (CCB) lercanidipine. A 49 yr old male presented to the Emergency Department 3 hrs after the ingestion of 560 mg of lercanidipine. In the department he had a witnessed seizure within 15 minutes of arrival attributed to the overdose. Following immediate recovery of consciousness after the seizure, he had refractory hypotension and bradycardia which failed to respond to fluid resuscitation, glucagon therapy, and intravenous calcium. He went on to require vasopressor support with noradrenaline and was treated with high dose insulin therapy which was successful in achieving cardiovascular stability. Vasopressor therapy was no longer required within one half life of lercanidipine, and the total stay on intensive care was one day before transfer to a ward.Calcium channel blocker overdose is an uncommon but life-threatening overdose. Treatment for severe toxicity is similar to b-blocker overdose. Hypotension is treated with intravenous fluid therapy, intravenous calcium and possibly glucagon with vasopressor or inotropic support as required. Atropine is used to attempt reversal of bradycardia. High doses of intravenous insulin with intravenous dextrose as required (hyperinsulinaemic euglycaemia or HIET), has also been successfully reported. Experimental animal data suggests that HIET is of benefit and potentially superior to fluid therapy, calcium, glucagon and potentially vasopressor therapy. HIET effectively and sustainably reverses hypotension, bradycardia and improves myocardial contractility and metabolism. Current advice in calcium channel blocker overdose is to begin therapy early in toxicity, starting with a 1.0 IU/kg insulin bolus followed by an infusion of 0.5 IU/kg/hr of insulin and dextrose as required titrated to clinical response.
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PMID:Management of lercanidipine overdose with hyperinsulinaemic euglycaemia therapy: case report. 2125 26


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