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Questions And Answer

• Discovery

  Glucagon was first described in 1923 as an additional substance with hyperglycemic properties from pancreatic extracts. The amino acid sequence of glucagon was determined in the 1950s. After the establishment of a specific radioimmunoassay in the 1970s, the role of glucagon in physiology and disease was rapidly elucidated. The entire coding sequence of the preproglucagon gene was initially characterized in anglerfish by using the recombinant DNA technique.;

• Structure

  Glucagon is a single-chain polypeptide that contains 29 aa residues in all vertebrate species except the paddlefish, in which glucagon is 31 aa long. The primary structure of glucagon is identical in most mammals, including humans. The N-terminal two aa residues are cleaved off by dipeptidyl peptidase 4 (DPP-4) and the truncated glucagon fragment, glucagon (3–29), is a partial agonist of the glucagon receptor but shows no glycemic effect in vivo. Human glucagon: Mr 3483, theoretical pI 6.75. Crystalline glucagon is a white to off-white powder. Glucagon is relatively insoluble in water, methanol, ethanol, and ether, but soluble at a pH<3 or>9. 
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• Clinical implications

  Hyperglucagonemia is usually caused by the excessive production of glucagon by a tumor of the pancreatic α cells (glucagonoma). Hyperglucagonemia can also occur in diverse conditions such as acute pancreatitis, severe stress, acromegaly, Cushing’s syndrome, hepatocirrhosis, chronic hepatitis, chronic renal insufficiency, diabetic ketoacidosis, prolonged starvation, hypercorticism, septicemia, and familial hyperglucagonemia. Manifestations of hyperglucagonemia include dermatitis, diabetes, diarrhea, weight loss, abdominal pain, anemia, and thromboembolic disease. Hypoglucagonemia is rare, and can occur in conditions such as chronic pancreatitis, anterior pituitary failure, Addison’s disease, and glucagon deficiency.;

• Polypeptide hormone with straight-chain

  Glucagon, also known as glucagon, is a straight-chain polypeptide hormone secreted by pancreatic islet α cells, containing 29 amino acids, with molecular formula and relative molecular mass of C153H225N43O49S = 3482.8. China has synthesize this hormone. It is a kind of white, odorless, and tasteless fine crystalline powder at room temperature. Glucagon is nearly insoluble in water and most organic solvents, while it is soluble in dilute acid and dilute alkali solution. Most of the preparation are hydrochloride which is dissolved in water. It is known that glucagon must retain its molecular integrity in order to exert its physiological activity. The glucagon structure of human and mammalian (rabbit, bovine, porcine, rat, etc.) may be consistent, while slightly different birds.
  It is an important hormone to maintain normal blood glucose. The main role of glucagon is to activate the myocardium phosphorylation enzymes, promote glycogen breakdown and have a similar role of catecholamines. Therefore, it has a cardiac effect, making heart rate, myocardial contractility and coronary blood flow increased. Cardiac function is not associated with increased excitability of the heart, while it will make more calcium into the myocardial cells and can activate the adenylate cyclase of the liver cell membrane, thus promoting intracellular cyclization-synthesis of adenosine phosphate. Glucagon has been reported to be effective in certain heart failure cases. In addition, in the state of diabetes, liver disease, kidney disease, glucagon and stress, etc., the plasma levels are also increased to varying degrees. Glucagon owns four major physiological roles of the promotion of liver glycogen breakdown, glycogen gluconeogenesis, lipolysis and ketone body formation. It can promote the uptake of amino acids in liver cells, accelerate the process of amino acid deaminization in the liver, reduce the concentration of plasma amino acids, reduce the synthesis of protein, and promote liver glycogen. In addition, it can activate the lipase capacity of fat cells in the liver, increase the release of free fatty acids, speed up the process of lipid oxidation of liver cells, and increase the liver gluconeogenesis and ketone body. At the same time glucagon can inhibit the tension and peristalsis of stomach, small intestine and colon; reduce gallbladder tension; inhibit the process of pancreatic exocrinosity and the absorption of intestinal mucosa of water and salt. Large doses of glucagon can also increase concentration of myocardial cAMP, the heart rate and myocardial contractility.;

• Pharmacological effects

  The main role of glucogon is to promote the decomposition of glycogen and the production of glucose to elevate blood sugar; secondly, it also can promote lipolysis by leaving cyclic AMP (cAMP) levels increased via adenylate cyclase, thereby activating protein kinase and tissue lipase; in addition, through the activation of cardiac adenylate cyclase system, and promoting myocardial phosphorylase activity, it can increase the accumulation of calcium in the myocardium, thereby enhance myocardial contractility, increase cardiac output and blood pressure; It can promote insulin, somatostatin, thyroxine and calcitonin secretion; moreover, promote sympathetic and pheochromocyte  catecholamines release. Through glucagon and insulin, somatostatin co-regulation, blood sugar maintained at the normal range. The secretion of glucagon is inversely proportional to the concentration of glucose in the blood, and the secretion of glucagon is also affected by the contents of amino acids, plasma free fatty acids, α-adrenergic receptor stimulator (norepinephrine), growth hormone releasing inhibiting hormone and other factors.
  Glucagon is a single chain polypeptide hormone synthesized and secreted by islet α2 cells and it is a physiological antagonist of insulin. The impact on metabolism is similar to epinephrine. It has the following effects:
  1. Blood glucose elevating effects: it can activate the phosphorylase in the liver, promote hepatic glycogen decomposition and gluconeogenesis, thus increasing blood sugar.
  2. Positive inotropic action: it can increase intracellular cAMP levels, enhance myocardial contractility, increase cardiac output and stroke volume. Its positive inotropic effect can still manifest when applied with sufficient cardiac glycoside, and it will not be blocked by propranolol. Although it can increase heart rate and blood pressure, but will not cause arrhythmia. The mechanism is as follows: ①the activation of adenylate cyclase turned adenosine triphosphate into cyclization of adenosine monophosphate, making the myocardial contractility increased;
  ② promoting liver glycogen breakdown and increasing blood glucose levels;
  ③ promoting insulin release, improving the use of myocardial glucose and promoting myocardial anaerobic glycolysis, thereby improving myocardial energy metabolism. When combined with digitalis cardiac glycosides, It can increase the efficacy.
  3. The role on the kidney: expanding renal blood vessels, improving renal blood flow, and promoting the excretion of sodium, potassium and calcium.
  4. The role on the digestive system: it can cause the smooth muscle relaxation of stomach and duodenum, small intestine and colon and inhibit stomach, small intestine and colon peristalsis, increase the secretion of bile and intestinal fluid.
  5. The role on the secretion system: exciting adrenal medulla, promoting the release of catecholamines. It can also promote insulin, thyroid hormone, calcitonin and growth hormone secretion.;

• Indications

  Oral administration of this product is invalid, injection treatment is frequently applied. The action time in vivo is short; it will work after  5 minutes of intravenous injection. Blood glucose can be increased by 50% in 30 minutes. It is sustainable about 1 hour. It mainly inactivated in the liver, kidney and plasma. Plasma half-life time is 3 to 6 minutes. In clinical practice, it is used for insulin-dependent diabetes patients with severe hypoglycemic coma and the disability to eat, but also for the determination of pancreatic function, diagnosis of pancreatic tumor and pheochromocytoma. It is mainly used for acute heart failure, digitalis ineffective heart failure, heart failure with cardiogenic shock for circulatory system use. The efficacy of glucagon on chronic heart failure is poor. The main indications are as follows:
  ① acute low-emission syndrome.
  ② coronary heart disease and cardiomyopathy caused by acute heart failure or cardiogenic shock.
  ③ arrhythmia caused by the combined treatment of propranolol to digitalis poisoning.;

• Usage and dosage

  3~5mg for the first administration; intravenous injection of glucose solution. If there are no adverse reactions after 2~5min , intravenous infusion rate of  2.5~10mg/h is available. It will work after 1~3min of intravenous injection, 10min arrives at the peak, 30min effect disappears. It can be applied 24h continuously depending on the medical necessity.
  Intramuscular, subcutaneous or intravenous: hypoglycemic coma, 0.5~1mg, if necessary, re-administration every 20 minutes. 5 to 20 minutes can be effective. If after 1 hour is still invalid, use of glucose as soon as possible. The dose for children is 5μg/kg.
  Vein dropping: diluted infusion of 5% glucose injection. Congestive heart failure, 2.5~7.5mg per hour. Cardiogenic shock; 1~12mg per hour as the medical necessity; sustainable 24 hours intravenous infusion.;

• Side effects

  Too large or too fast not only can cause nausea, vomiting, but also hypokalemia, high blood sugar and bleeding tendency.;

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