Glucagon

Glucagon, USP. The hyperglycemic-glycogenolytic hormone elaborated by the a-cells of the pancreas is known as glucagon. It contains 29 amino acid residues in the sequence shown. Glucagon has been isolated from the amorphous fraction of a commercial insulin sample (4% glucagon).

TABLE 27.8 Dosage and Source of Insulin Preparations

USP Insulin Type

Strengths and Sources

Usual Adult Dose3

Insulin injection (regular insulin, crystalline zinc insulin, Cispro)

Isophane insulin suspension (NPH insulin)

Isophane insulin suspension (70%)

and insulin injection (30%) Insulin zinc suspension (Lente insulin)

Extended insulin zinc suspension

(Ultralente insulin) Prompt insulin zinc suspension (Semilente insulin)

Protamine zinc insulin suspension (PZI Insulin)

U-40 mixed,

U-100 mixed: purified beef, pork; purified pork; biosynthetic human; semisynthetic human

U-500: purified pork

U-40 mixed,

U-400 mixed: beef; purified beef, pork; purified pork; biosynthetic human; semisynthetic human

U-100: purified pork; semisynthetic human

U-40 mixed,

U-100 mixed: beef; purified beef; purified pork; biosynthetic human; semisynthetic human

U-40 mixed,

U-100 mixed: beef; purified beef

U-40 mixed,

U-100 mixed: beef; purified pork

U-40 mixed,

U-100 mixed: purified pork

Diabetic hyperglycemia: SC, as directed by physician 15-30 minutes before meals up to t.i.d. or q.i.d.

SC, as directed by physician, q.d. 30-60 minutes before breakfast; an additional dose before breakfast may be necessary for some patients about 30 minutes before a meal or at bedtime SC, as directed by physician, q.d. 15-30 minutes before breakfast, or as directed SC, as directed by physician, q.d. 30-60 minutes before breakfast; an additional dose may be necessary for some patients about 30 minutes before a meal or at bedtime SC, as directed by physician, q.d. 30-60 minutes before breakfast SC, as directed by physician, q.d. 30-60 minutes before breakfast; an additional dose may be necessary for some patients about 30 minutes before a meal or at bedtime SC, as directed by physician, q.d. 30-60 minutes before breakfast aSee USP DI for complete dosage information. SC, subcutaneously.

Attention has been focused on glucagon as a factor in the pathology of human diabetes. According to Unger et al.,62 the following observations support this implication of glucagon: elevated glucagon blood levels (hyperglucagonemia) have been observed in association with every type of hyper-glycemia; when secretion of both glucagon and insulin is suppressed, hyperglycemia is not observed unless the glucagon levels are restored to normal by the administration of glucagon; the somatostatin-induced suppression of glucagon release in diabetic animals and humans restores blood sugar levels to normal and alleviates certain other symptoms of diabetes.

Unger et al.62 propose that although the major role of insulin is regulation of the transfer of glucose from the blood to storage in insulin-responsive tissues (e.g., liver, fat, and muscle), the role of glucagon is regulation of the liver-mediated mobilization of stored glucose. The principal consequence of high concentrations of glucagon is liver-mediated release into the blood of abnormally high concen trations of glucose, thereby causing persistent hyperglycemia. This indicates that a relative excess of glucagon is an essential factor in the development of diabetes.

Glucagon's solubility is 50 ^g/mL in most buffers between pH 3.5 and 8.5. It is soluble, 1 to 10 mg/mL, in the pH ranges 2.5 to 3.0 and 9.0 to 9.5. Solutions of 200 ^g/mL at pH 2.5 to 3.0 are stable for at least several months at 4°C if sterile. Loss of activity by fibril formation occurs readily at high concentrations of glucagon at room temperature, or above, at pH 2.5. The isoelectric point appears to be at pH 7.5 to 8.5. Because it has been isolated from commercial insulin, its stability properties should be comparable to those of insulin.

As with insulin and some of the other polypeptide hormones, glucagon-sensitive receptor sites in target cells bind glucagon. This hormone-receptor interaction leads to activation of membrane adenylate cyclase, which catalyzes cAMP formation. Thus, intracellular cAMP levels are elevated. The mode of action of glucagon in glycogenolysis is basically the same as the mechanism of epinephrine (i.e., stimulation of adenylate cyclase). Subsequently, the increase in cAMP activates the protein kinase that catalyzes phosphorylation of phosphorylase kinase to phosphophosphorylase kinase. The latter is necessary for the activation of phosphorylase to form phosphorylase a. Finally, phosphorylase a catalyzes glycogenolysis, which is the basis for the hyperglycemic action of glucagon. Although both glucagon and epinephrine exert hyperglycemic action through cAMP, glucagon affects liver cells and epinephrine affects both muscle and liver cells.

Fain63 reviewed the many phenomena associated with hormones, membranes, and cyclic nucleotides, including several factors that activate glycogen phosphorylase in rat liver. These factors involve not only glucagon but also vasopressin and the catecholamines. Glucagon and jS-cate-cholamines mediate their effects on glycogen phosphorylase through cAMP, but may involve other factors as well.

Glucagon exerts other biochemical effects. Gluconeogen-esis in the liver is stimulated by glucagon, and this is accompanied by enhanced urea formation. Glucagon inhibits the incorporation of amino acids into liver proteins. Fatty acid synthesis is decreased by glucagon. Cholesterol formation is also reduced. Glucagon activates liver lipases, however, and stimulates ketogenesis. Ultimately, the availability of fatty acids from liver triglycerides is elevated, fatty acid oxidation increases acetyl-CoA and other acyl-CoAs, and ketogenesis is promoted. As glucagon effects elevation of cAMP levels, release of glycerol and free fatty acids from adipose tissue also is increased.

Glucagon, whose regulatory effect on carbohydrate and fatty acid metabolism is well understood, is therapeutically important. It is recommended for the treatment of severe hy-poglycemic reactions caused by the administration of insulin to diabetic or psychiatric patients. Of course, this treatment is effective only when hepatic glycogen is available. Nausea and vomiting are the most frequently encountered reactions to glucagon.

Usual dose: parenteral, adults, 500 pg to 1 mg (0.5-1.0 U), repeated in 20 minutes if necessary; pediatric, 25 pg/kg of body weight, repeated in 20 minutes if necessary.

Gastrointestinal Hormones

There is a formidable array of polypeptide hormones of the gastrointestinal tract that includes secretin, pancreozymin-cholecystokinin, gastrin, motilin, neurotensin, vasoactive intestinal peptide, somatostatin, and others. The biosynthesis, chemistry, secretion, and actions of these hormones have been reviewed.64

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