Insulin Therapy

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Insulin is synthesized in the B- (or p-) cells of the pancreatic islets of Langerhans. It is a protein (MW 5800) consisting of two peptide chains linked by two disulfide bridges; the A chain has 21 and the B chain 30 amino acids. Insulin is the "blood-sugar lowering" hormone. Upon ingestion of dietary carbohydrates, it is released into the blood and acts to prevent a significant rise in blood glucose concentration by promoting uptake of glucose in specific organs, viz., the heart, adipose tissue, and skeletal muscle, or its conversion to glycogen in the liver. It also increases lipogenesis and protein synthesis, while inhibiting lipo-lysis and release of free fatty acids.

Insulin is used in the replacement therapy of diabetes mellitus to supplement a deficient secretion of endogenous hormone.

Sources of therapeutic insulin preparations (A). Insulin can be obtained from pancreatic tissue of slaughtered animals. Porcine insulin differs from human insulin merely by one B chain amino acid, bovine insulin by two amino acids in the A chain and one in the B chain. With these slight differences, animal and human hormone display similar biological activity. Compared with human hormone, porcine insulin is barely antigenic and bovine insulin has a little higher antigenicity. Human insulin is produced by two methods: biosyn-thetically, by substituting threonine for the C-terminal alanine in the B chain of porcine insulin; or by gene technology involving insertion of the appropriate human DNA into E. coli bacteria.

Types of preparations (B). As a peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal proteases) and thus needs to be given parenterally. Usually, insulin preparations are injected subcutane-ously. The duration of action depends on the rate of absorption from the injection site.

Short-acting insulin is dispensed as a clear neutral solution known as regular insulin. In emergencies, such as hyperglycemic coma, it can be given intravenously (mostly by infusion because i.v. injections have too brief an action; plasma ti/2 ~ 9 min). With the usual subcutaneous application, the effect is evident within 15 to 20 min, reaches a peak after approx. 3 h, and lasts for ap-prox. 6 h. Lispro insulin has a faster onset and slightly shorter duration of action.

Insulin suspensions. When the hormone is injected as a suspension of insulin-containing particles, its dissolution and release in subcutaneous tissue are retarded (rapid, intermediate, and slow insulins). Suitable particles can be obtained by precipitation of apolar, poorly water-soluble complexes consisting of anionic insulin and cationic partners, e.g., the polycationic protein protamine or the compound aminoqui-nuride (Surfen). In the presence of zinc and acetate ions, insulin crystallizes; crystal size determines the rate of dissolution. Intermediate insulin preparations (NPH or isophane, lente or zinc insulin) act for 18 to 26 h, slow preparations (protamine zinc insulin, ultralente or extended zinc insulin) for up to 36 h.

Combination preparations contain insulin mixtures in solution and in suspension (e.g., ultralente); the plasma concentration-time curve represents the sum of the two components.

Unwanted effects. Hypoglycemia results from absolute or relative over-dosage (see p. 260). Allergic reactions are rare—locally: redness at injection site, atrophy of adipose tissue (lipodystro-phy); systemically: urticaria, skin rash, anaphylaxis. Insulin resistance can result from binding to inactivating antibodies. A possible local lipohypertrophy can be avoided by alternating injection sites.

Insulin EffectsAdverse Effect

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