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Glucagon is a hormone which is secreted by the alpha cells of langerhans. In addition,
small intestine (duodenal mucosa) secretes small amounts of enteroglucagon.
Glucagon is a single - chain polypeptide having a molecular weight of 3485. It consists of
29 aminoacids.
NH2 - His - Ser - Gin - Gly - Thr - Phe - Thr - Ser - Asp - Tyr -Ser- Lys - Tyr - Leu - Asp -
Ser - Arg - Arg - Ala - Gin -Asp -Phe - Val - Gin - Trp - Leu - Met - Asn - Thr - COOH.
It is synthesized as much larger MW of about 9000 proglucagon precusor. Only 30-40% of
glucagon in plasma is pancreatic glucagon, the rest consists of biologically inactive larger molecules. Its plasma half-life is short, around 5 mins. It is inactivated by the liver, which has an enzyme, that removes the first 2 aminoacids from the N-terminal end by cleaving between Ser 2 and Gin 3.
The normal serum value of glucagon in fasting state is 20-100 Mg/1 (20-100pg/ml)
Regulation :
1. Blood Glucose : It is the most potent factor controlling glucagon secretion. A decrease
ins blood glucoge concentration increases glucagon secretion whereas on increase in
blood glucose decreases glucagon secretion.
2. Aminoacids : High concentrations of aminoacids stimulate the secretion of glucagon.
(Aminoacids also stimulate insulin secretion.)
3. Exercise : Exercise increases glucagon level. This might be due to increased circulating
levels of aminoacids during exercise or due to direct nervous stimulation of pancreatic
islets.
4. Somatostatin : One of the other hormones secreted by the pancreatic islets, it acts
locally to depress the secretion of glucagon.
Actions
The action of glucagon are generally opposite to those of insulin. It stimulates
glycogenolysis and lipolysis. It is the most potent gluconeogenic hormone, and it is ketogenic.
The liver is the primary target. Glucagon binds to specific receptors in fhe hepatic cell
plasme membrane, and this activates adenylate cyclase which causes the formation of cyclic AMP. The elevated cAMP can induces a number of enzymes. A low insulin ; glucagon ratio can, thus induce, and high ratio can thus suppress the following enzymes (1) :-
1. Glucose - 6- phosphatase
2. Phosphoenolpyruvate carboxykinase (PEPCK)
3. Fructose - 1, 6 - bisphosphatase.
On the other hand a low insulin : glucagon ratio suppress and a high ratio induces the
following enzymes
1. Glucokinase
2. Citrate cleavage enzyme
3. Acetyl - CoA carboxylase
4. HMG -toA reductase
5. Pyurvate kinase
6. 6 - Phosphofructo - 1 – kinase
7. 6 - Phosphofructo - 2 kinase / fructose - 2, 6 bisphosphatase
Glucagon causes breakdown of liver glycogen (glycogenolysis) and increased glue on eo
genesis in the liver (2).
Glycogenolysis :
i. Glucagon activates adenyl cycalse in the hepatic cell membrane.
ii. Which causes the formation of cAMP.
iii. Which activates protein kinase regulator protein.
iv. Which activates protein kinase.
v. Which activates phosphorylase b kinase.
vi. Which converts phosphorylase b into phosphorylase a.
vii. Which promotes the degradation of glycogen into glucose - 1 -phosphate.
viii. Which then is dephosphorylated and the glucose increased from the liver cells.
Gluconeogenesis :- It is believed that glucagon causes activation of the enzyme system
for converting pyruvate to phosphoenolpyruvate, a rate limiting step in gluconeogenesis. Glucagon also increases the extraction of aminoacids from the blood by the liver cells, thus making a greater quantity of these available to be converted into glucose.
Lipolysis :- Glucagon is a potent lipolytic agent. It increases, adipose cell CAMP levels
and this activates the hormone - sensitive lipase. The increased fatty acid can be metabolized for energy or converted to the ketone bodise acetoacetate and b- hydroxybutyrate
Other actions : In very large concentrations, it
a) Enhances the force and rate & cardiac contractions. This is not antagonized by the p-
blockers.
b) Enhances bile secretion.
c. Inhibits gastric acid secretion & has a relaxant action on the gut. Enteroglucagon :- Its
physiologic actions are unknown.
Role of glucagon in pathogenesis of Diabetes Mellitus :- In impaired glucose tolerance
(IGP), the suppression of glucagon release is impaired coupled with impaired early insulin release.
It has also been found that in type 2 NIDDM, beta cell mass is intact but the alpha cells
are increased resulting in an elevated alpha to beta cells ratio. This results in a high and resistant plasma glucagon.
In type 1 IDDM, beta cell mass is decreased, again resulting in an elevated alpha to beta
cell ratio. This results in a high but suppressible plasma glucagon.
Thus diabetes mellitus (both IDDM & NIDDM) may be viewed as a bihormonal disorder
characterized by both a lack of insulin and an excess of glucagon (4). This is further supported by the fact that the correction of hyperglucagonemia reduces or corrects diabetic abnormalities (5).
But the possible role of glucagon as an essential co-mediator is not universally accepted.
For example, DM can occur in the total absence of glucagon folliwing pancreatectomy (6). Moreover, it is pointed out that glucagon excess may be a consequence of low insulin levels rather than primary abnormality. A balance review of this controversy concludes that although excess glucagon contributes to the metabolic abnormalities in DM, there is no evidence that it is an essential co-mediater (7).
Diabetic Ketoacidosis :- Diabetic Ketoacidosis appears to require insulin deficiency
coupled with a relative or absolute increase in glucagon concentration. It may be caused by the cessation of insulin intake where the concentration of glucagon rises secondary to insulin withdrawal. It may also result from physical or emotional stress where the stimulus for glucagon release is probably epinephrine (8).
In DK, glucagon has two critical effects. First, it inhibits glycolysis & induces maximal
gluconeogenesis by the mechanism previously explained. The resultant hyperglycemia induces an osmotic diuresis that leads to the volume depletion and dehydration that characterize the ketogenic process and initiates development of metabolic acidosis. For ketosis to occur, not only free fatty acid release is enhanced but there should also be accelerated fatty acid oxidation in the liver. While the former is achieved by insulin deficiency, the latter is achieved by glucagon excess.
Glucagon does this via its action on the carnitine palmitoyl transferase system of enzymes
responsible for the transport of fatty acids into the mitochondria. Glucagon causes a fall in Malonyl-CoA, which is a competitive inhibitor of carnitine palmitoyl transferase I, and a fall in its concentration activates the enzyme. Glucagon also causes a rise in hepatic carnitine concentration, which then drives the reaction towards fatty acylcarnitine formation by mass action. At high plasma fatty acid concentrations, hepatic uptake of fatty acids is sufficient to saturate both oxidative and esterifying pathways, resulting in fatty liver, hypertriglyceridemia and ketoacidosis.
Glucagonoma :- It is a tumor of the alpha cells of the pancreatic islets- It secrets high
levels of glucagon and frequently secrete additional peptides, including pancreatic polypeptide, somatostatin, insulin and gastrin in small quantities. They are characteristically single, large and slow growing. More than 75% have metastasized at the time of diagnosis, most commonly to the liver and bones.
Its clinical features consist of diabetes, which is usually mild. Patients may have glossitis,
stomatitis, angular cheilitis, dystrophic nails and hair thinning. They may also have erythema necrolytica migrans, the skin rash of.glucagonoma. It is located primarily on the face, abdomen, perineum and distal extremities.
A fasting plasma glucagon of 1000 pg/ml establishes the diagnosis. It can be
distinguished from other hyperglucagonemic syndromes by the failure of glucoes to suppress and the failure of arginine to enhance serum glucagon concentrations.
Glucagonoma has been reported in association with Multiple Endocrine Neoplasia type 1
(MEN 1), which consists of neoplastic transformation of parathyroid, pituitary and pancreatic islet cells.
Other Diseases :- Increased secretion of glucagon is found in all forms of severe tissue
injury like trauma, surgery, burns, infections, sepsis, prolonged fasting & myocardial infarction. Modest elevations of glucagon may occur in renal failure and hepatic failure. It is also increased in gluten sensitive enteropathy Lung carcinoma, carcinoid & renal carcinoma may infrequently ectopically secrete glucagon. Glucagon deficiency is rare. If present, it can cause fasting hypoglycemia.
Therapeutic Uses :- Glucagon can be given s.c., i.m. or i.v.
1) It is used in the treatment of hypoglycemia.
2) It is also used for the Radiological examination of gut, biliary colic diverticulitis. It is also
used to inhibit duodenal motility and enhance cannulation during ERCP (9)
3) It can be given in cardiogenic shock.
4) In intractable allergic reactions, it appears to play a potentially lifesaving role as a
supplemental therapy (10).
5) It is used to treat calcium channel antagonist poisoning. It can also treat acute
intravenous diltiazem toxicity (11).
6) Its cardiac activity may prove useful in the treatment of symptomatic bradycardia,
particularly in the setting of beta-adrenergic blockade 20(12)
Glucagon Like Peptide -1 (GLP-1) : GLP-1 is a hormone that is released by intestinal cells
into the circulation in response to food intake. Like glucagon, its precursor is also proglucagon (13). It molulates insulin, glucagon & somatostatin secretion. It has a stimulating effect on insulin secretion which is glucose dependent and requires the presence of the suger (14). Thus, it may present a unique advantage over sulponylurea drugs in the treatment of NIDDM.
It can be given i.v. or s.c. A mucoadhesive buccal GLP-1 tablet has also been developed
(15). It has a marked glucose - lowering effect during the first two hours. Infact, various studies have concluded that GLP-1 is able to normalize plasma glucose in all type 2 diabetic patients (16).
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metabolic control of diabetes. N. Engg. J. Med. 1978; 299:1366.
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potential use for NIDDM. Isr J Med Sci.; 1997 oct.: 33(10): 690-5.
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the incertin hormone glucagon - like peptide 1. Pflugers Arch. 1998 Apr.: 435(5): 583-
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15. Gutnaik MK, Larsson H et.al. GLP-1 tablet in type 2 diabetes in fasting and
postprandial conditions. Diabetes care. 1997 Dec.; 20(12): 1874-9.
16. Nanck MA, Hoist JJ, Willims B. Glucagon - like peptide 1 and its potential in the
treatment of noninsuHn dependent diabetes mellitus. Horm Metab Res. 1997 Sep;
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