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Chapter: Basic & Clinical Pharmacology : Pancreatic Hormones & Antidiabetic Drugs


Insulin is a small protein with a molecular weight in humans of 5808.



Insulin is a small protein with a molecular weight in humans of 5808. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges; there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids (Figure 41–1).

Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues; a small quantity of unpro-cessed or partially hydrolyzed proinsulin is released as well. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the beta cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. Originally, the unit was defined on the basis of the hypogly-cemic activity of insulin in rabbits. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay purposes contain 28 units per milligram.

Insulin Secretion

Insulin is released from pancreatic beta cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose), amino acids (especially gluconeogenic amino acids, eg, leucine, arginine), hormones such as glucagon-like polypeptide-1 (GLP-1), glucose-dependent insulinotropic poly-peptide (GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and β-adrenergic sympathetic activity are recognized. Stimulatory drugs are sulfonylureas, meglitinide and nateglinide, isoproterenol, and acetylcholine. Inhibitory signals are hormones including insulin itself and leptin, α-adrenergic sympathetic activity, chronically elevated glucose, and low concentrations of fatty acids. Inhibitory drugs include diazoxide, phenytoin, vin-blastine, and colchicine.

One mechanism of stimulated insulin release is diagrammed in Figure 41–2. As shown in the figure, hyperglycemia results in increased intracellular ATP levels, which close the ATP-dependent potassium channels. Decreased outward potassium efflux results in depolarization of the beta cell and opening of voltage-gated calcium channels. The resulting increased intracellular calcium triggers secretion of the hormone. The insulin secretagogue drug group (sulfonylureas, meglitinides, and D-phenylalanine) exploits parts of this mechanism.

Insulin Degradation

The liver and kidney are the two main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35–40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30–40%. The half-life of circulating insu-lin is 3–5 minutes.

Circulating Insulin

Basal insulin values of 5–15 μU/mL (30–90 pmol/L) are found in normal humans, with a peak rise to 60–90 μU/mL (360–540 pmol/L) during meals.

The Insulin Receptor

After insulin has entered the circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the membranes of most tissues. The biologic responses promoted by these insulin-receptor complexes have been identified in the pri-mary target tissues, ie, liver, muscle, and adipose tissue. The recep-tors bind insulin with high specificity and affinity in the picomolar range. The full insulin receptor consists of two cova-lently linked heterodimers, each containing an α subunit, which is entirely extracellular and constitutes the recognition site, and a subunit that spans the membrane (Figure 41–3). The β subunit contains a tyrosine kinase. The binding of an insulin molecule to the α subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic β subunits into closer proximity. This facilitates mutual phosphorylation of tyrosine residues on the subunits and tyrosine kinase activity directed at cytoplasmic proteins.

The first proteins to be phosphorylated by the activated recep-tor tyrosine kinases are the docking proteins, insulin receptor substrates (IRS). After tyrosine phosphorylation at several critical sites, the IRS molecules bind to and activate other kinases—most significantly phosphatidylinositol-3-kinase—which produce fur-ther phosphorylations. Alternatively, they may bind to an adaptor protein such as growth factor receptor-binding protein 2, which translates the insulin signal to a guanine nucleotide-releasing fac-tor that ultimately activates the GTP binding protein, ras, and the mitogen-activated protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine kinases have binding specificity with downstream molecules based on their surrounding 4–5 amino acid sequences or motifs that recognize specific Src homology 2 (SH2) domains on the other protein. This network of phospho-rylations within the cell represents insulin’s second message and results in multiple effects, including translocation of glucose trans-porters (especially GLUT 4, Table 41–2) to the cell membrane with a resultant increase in glucose uptake; increased glycogen synthase activity and increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis; and activation of transcription factors that enhance DNA synthesis and cell growth and division. 

Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin; growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor β subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation. 

Effects of Insulin on Its Targets

Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells (Figure 41–4) and influ-ences cell growth and the metabolic functions of a wide variety of tissues (Table 41–3).

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