Glucagon

(Glucagón)Glucagon is a hormone that raises the level of glucose (a type of sugar) in the blood. The pancreasproduces glucagon and releases it when the body needs more sugar in the blood for delivery to thecells. When someone with diabetes has a very low blood glucose level, a glucagon injection can helpraise the blood glucose quickly.-Is an importanthormoneinvolved incarbohydrate metabolism. Produced by thepancreas, it is released when theglucoselevel in the blood is low (hypoglycemia), causing theliverto convert stored glycogenintoglucoseand release it into the bloodstream. The action of glucagon is thus opposite to that of insulin, which instructs the body's cells to take in glucose from the blood. However, glucagonalso paradoxically stimulates the release of insulin, so that newly available glucose in the bloodstreamcan be uptaken and used by insulin-dependent tissues. An injectable form of glucagon is vital first aidin cases of severehypoglycemiawhen the victim is unconscious or for other reasons cannot takeglucose orally. The dose for an adult is typically 1 milligram, and the glucagon is given byintramuscular, intravenous or subcutaneous injection, and quickly raisesblood glucoselevels.Glucagon can also be administered intravenously at 0.25 - 0.5 unit.

Glucagon Description

glucagon for Injection (rDNA origin) is a polypeptide hormone identical to human Glucagon thatincreases blood glucose and relaxes smooth muscle of the gastrointestinal tract. Glucagon issynthesized in a special non-pathogenic laboratory strain of Escherichia coli bacteria that has beengenetically altered by the addition of the gene for Glucagon.Glucagon is a single-chain polypeptide that contains 29 amino acid residues and has a molecularweight of 3483.The empirical formula is C153H225N43O49S. The primary sequence of Glucagon is shown below.Crystalline Glucagon is a white to off-white powder. It is relatively insoluble in water but is soluble at apH of less than 3 or more than 9.5.Glucagon is available for use intravenously, intramuscularly, or subcutaneously in a kit that contains avial of sterile Glucagon and a syringe of sterile diluent. The vial contains 1 mg (1 unit) of Glucagonand 49 mg of lactose. Hydrochloric acid may have been added during manufacture to adjust the pH of the Glucagon. One International Unit of Glucagon is equivalent to 1 mg of Glucagon.1 The diluentsyringe contains 12 mg/mL of glycerin, Water For Injection, and hydrochloric acid.

Uses

An injectable form of glucagon is vital first aid in cases of severehypoglycemiawhen the victim isunconscious or for other reasons cannot take glucose orally. The dose for an adult is typically 1milligram, and the glucagon is given by intramuscular, intravenous or subcutaneous injection, andquickly raisesblood glucoselevels. Glucagon can also be administered intravenously at 0.25 - 0.5 unit.

Anecdotal evidence suggests a benefit of higher doses of glucagon in the treatment of overdose withbeta blockers; the likely mechanism of action is the increase of cAMP in themyocardium, effectively bypassing the inhibitory action of theβ-adrenergic second messenger system.

[4]

Glucagon acts very quickly: common side effects include headache and nausea.Drug interactions: Glucagon interacts only with oral anticoagulants increasing the tendency to bleed.

For use as a diagnostic aid:

Glucagon is indicated as a diagnostic aid in the radiologic examination of the stomach, duodenum,small bowel, and colon when diminished intestinal motility would be advantageous.Glucagon is as effective for this examination as are the anticholinergic drugs. However, the addition of the anticholinergic agent may result in increased side effects.

Glucagon secretion

is an immediate response to hypoglycemia, which leads torestoration of normal blood glucose levels by stimulating hepatic glucose production. The normalregulation of this hormone secretion by low glucose becomes progressively impaired in type 1 andsome type 2 diabetic patients, and the ensuing risk of developing severe hypoglycemia represents amajor obstacle to efficient insulin treatment of these diseases (1,2). The physiological mechanisms controlling glucagon secretion and how they become deregulated indiabetes are far from being elucidated. Experimental studies in animals and in humans have providedevidence for multiple systems controlling glucagon secretion. First, α cells may directly respond tochanges in glucose concentrations (3,4), and they express genes associated with glucose sensing such as glucokinase (5) and the Kir6.2 and SUR1 (6) subunits of the ATP-dependent K+ (K

ATP

) channelbut not glucose transporter type 2 (GLUT2) (7). A second level of control of glucagon secretion is byintraislet insulin levels (8, 9). Indeed, insulin is a negative regulator of glucagon secretion, and suppression of insulin secretion by low glucose relieves this inhibition. A major control of α cells’ secretory activity, however, occurs through both the sympathetic and parasympathetic branches of theautonomic nervous system and by the sympathoadrenal axis (10,11). The activation of the autonomic nervous system and sympathoadrenal axis by hypoglycemia dependson glucose sensing mechanisms, which are yet poorly defined but probably reside at severalanatomical sites, including the hepatoportal vein area, the brainstem, and the hypothalamus.Hepatoportal vein glucose sensors are linked by hepatic vagal afferents to brainstem nuclei, inparticular the nucleus of the tractus solitarius (NTS) and the lateral hypothalamus (12, 13). Their role in glucagon secretion is still debated, and they may not be critical for hypoglycemia-induced glucagonsecretion; however, their activation by portal glucose injection can suppress the glucagon response toinsulin-induced peripheral hypoglycemia (14,15). The role of hypothalamic nuclei in counterregulation has been explored through lesion studies andpharmacological or genetic interference with glucose detection systems (16). From these studies, theventromedial hypothalamic nucleus (VMH) appears to play a critical role. Indeed, hypoglycemia-induced glucagon secretion was suppressed by direct VMH injection of glucose (17) or of K

ATP

channelinhibitors (18). Inactivation of K

ATP

channel in Kir6.2

–/–

mice also led to impaired glucagon response,

which was correlated with a suppression of the glucose-regulated VMH neurons firing activity (19). Inaddition, glucoprivation by direct injection of 2-deoxy-D-glucose (2-DG) in the VMH induced glucagonsecretion (20).Whereas the above data support a role for the VMH in the control of glucagon secretion, otherpublished data indicate that glucose-sensing units located in the brainstem play an equally critical rolein the physiological control of glucagon secretion. For instance, when the cerebral acqueduct isobstructed, 2-DG induces a glucoregulatory response only when injected in the fourth but not thelateral ventricle (21). Also, localization of 2-DG–activated neurons by c-Fos immunostaining (22) showed that the NTS, the dorsal motor nucleus of the vagus (DMNX), and the A1, A1/C1, and C1groups of catecholaminergic neurons of the brainstem were particularly responsive to this glucoprivicchallenge. In addition, whereas injections of 5-thioglucose in different nuclei of the hypothalamusfailed to induce a glucoregulatory response, strong responses were obtained by injections of thisantimetabolite into the NTS and the medullary regions containing the A1 and C1 catecholaminergicneurons (23). These catecholaminergic neurons project to different sites of the hypothalamus tocontrol counterregulation but also feeding (23–25). The NTS has also been demonstrated to be sensitive to small variations in blood glucose concentrations, a mechanism that requires the functionof the K

ATP

channel (26,27). Together, these data suggest that the glucose-sensing systems involved in controlling glucagonsecretion form a highly interactive network linked by nerve connections; in this network, thebrainstem may have a critical role for physiological hypoglycemia sensing.The cells and molecules involved in glucose sensing and counterregulation have not yet beenidentified. This is due to a lack of molecular markers that could be unambiguously associated with thephysiological response to hypoglycemia and that could be used to identify the responsive cells. TheK

ATP

channel is involved in central glucose sensing (18,19); however, the Kir6.2 subunit is expressed at a high level in all brain areas (28) and thus cannot provide precise markers for glucose-sensitivecells.In a previous study, we showed that ripglut1;glut2

–/–

mice, which have an inactivated glut2 gene butnormal glucose-regulated insulin secretion due to transgenic expression of GLUT1 in their β-cells (29),have abnormal regulation of glucagon plasma levels. This was characterized by fedhyperglucagonemia, which could be normalized by ganglionic blockade, indicating an increasedautonomic tone to the α cell, and by suppressed response to moderate hypoglycemic levels (~2.5mM). However, a strong response could still be induced by deep hypoglycemia (≤ 1 mM). These dataindicate that glucagon secretion is under the control of GLUT2-dependent and independenthypoglycemia detection systems that can be activated at different glycemic levels.Here, we extend these observations by providing evidence that GLUT2-dependent glucose sensors arelocated centrally, that they are involved in the activation of neurons of the NTS and DMNX, and thatGLUT2 needs to be expressed in glial cells for the gluco-detection system to function.

Function

Glucagon ball and stick model, with thecarboxylterminus above and theaminoterminus below