Page 762 - Basic _ Clinical Pharmacology ( PDFDrive )

748 SECTION VII Endocrine Drugs

TABLE 41–1 Pancreatic islet cells and their secretory somatostatin, and leptin; α-adrenergic sympathetic activity;
products. chronically elevated glucose; and low concentrations of fatty
acids. Inhibitory drugs include diazoxide, phenytoin, vinblas-
Approximate tine, and colchicine.
Cell Types 1 Percent of Islet Mass Secretory Products
One mechanism of stimulated insulin release is diagrammed
Alpha (A) cell 20 Glucagon, proglucagon in Figure 41–2. As shown in the figure, hyperglycemia results in
Beta (B) cell 75 Insulin, C-peptide, increased intracellular ATP levels, which close ATP-dependent
proinsulin, amylin potassium channels. Decreased outward potassium efflux results
Delta (D) cell 3–5 Somatostatin in depolarization of the beta cell and opening of voltage-gated
Epsilon cell <1 Ghrelin calcium channels. The resulting increased intracellular calcium
triggers secretion of the hormone. The insulin secretagogue drug
1 Within pancreatic polypeptide-rich lobules of adult islets, located only in the poste-
rior portion of the head of the human pancreas, glucagon cells are scarce (<0.5%) and group (sulfonylureas, meglitinides, and d-phenylalanine) exploits
F cells make up as much as 80% of the cells. parts of this mechanism.

unprocessed or partially hydrolyzed proinsulin is released as well. Insulin Degradation
Although proinsulin may have some mild hypoglycemic action, The liver and kidney are the two main organs that remove insu-
C-peptide has no known physiologic function. Granules within lin from the circulation. The liver normally clears the blood of
the beta cells store the insulin in the form of crystals consisting of approximately 60% of the insulin released from the pancreas by
two atoms of zinc and six molecules of insulin. The entire human virtue of its location as the terminal site of portal vein blood flow,
pancreas contains up to 8 mg of insulin, representing approxi- with the kidney removing 35–40% of the endogenous hormone.
mately 200 biologic units. Originally, the unit was defined on However, in insulin-treated diabetics receiving subcutaneous
the basis of the hypoglycemic activity of insulin in rabbits. With insulin injections, this ratio is reversed, with as much as 60%
improved purification techniques, the unit is presently defined on of exogenous insulin being cleared by the kidney and the liver
the basis of weight, and present insulin standards used for assay removing no more than 30–40%. The half-life of circulating
purposes contain 28 units per milligram. insulin is 3–5 minutes.

Insulin Secretion Circulating Insulin
Insulin is released from pancreatic beta cells at a low basal rate Basal serum insulin values of 5–15 μU/mL (30–90 pmol/L) are
and at a much higher stimulated rate in response to a variety of found in normal humans, with a peak rise to 60–90 μU/mL
stimuli, especially glucose. Other stimulants such as other sugars (360–540 pmol/L) during meals.
(eg, mannose), amino acids (especially gluconeogenic amino
acids, eg, leucine, arginine), hormones such as glucagon-like
polypeptide 1 (GLP-1), glucose-dependent insulinotropic poly- The Insulin Receptor
peptide (GIP), glucagon, cholecystokinin, high concentrations After insulin has entered the circulation, it diffuses into tissues,
of fatty acids, and β-adrenergic sympathetic activity are recog- where it is bound by specialized receptors that are found on the
nized. Stimulatory drugs include sulfonylureas, meglitinide and membranes of most tissues. The biologic responses promoted by
nateglinide, isoproterenol, and acetylcholine. Inhibitory signals these insulin-receptor complexes have been identified in the pri-
are hormones including insulin itself, islet amyloid polypeptide, mary target tissues regulating energy metabolism, ie, liver, muscle,

C-peptide

A chain S S

1 10 21
S S
B chain S S 32
31
1 3 10 20 28 29 30
FIGURE 41–1 Structure of human proinsulin (C-peptide plus A and B chains) and insulin. Insulin is shown as the shaded (orange color)
peptide chains, A and B. Differences in the A and B chains and amino acid modifications for the rapid-acting insulin analogs (aspart, lispro,
and glulisine) and long-acting insulin analogs (glargine and detemir) are discussed in the text. (Adapted, with permission, from Gardner DG, Shoback D
[editors]: Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011. Copyright © The McGraw-Hill Companies, Inc.)