Review of Medical Physiology - William F. Ganong 2002

Endocrine System, Metabolism, and Reproduction
Endocrine Functions of the Pancreas and Regulation of Carbohydrate Metabolism
Structure, Biosynthesis, and Secretion of Insulin

Structure and Species Specificity

Insulin is a polypeptide containing two amino acid chains linked by disulfide bridges (Table 19-1). While there are minor variations in the Amino Acid Composition across different species, these are generally not significant enough to alter the biological activity of a given insulin in heterologous species; however, they are sufficient to render insulin antigenic. When insulin from one species is administered to subjects of another species over an extended period, the resulting anti-insulin Antibodies will inhibit it. Nearly all individuals receiving commercial bovine insulin for more than two months develop antibodies against it, though titers are typically low. Porcine insulin differs from human insulin by only a single amino acid residue and exhibits low antigenicity. Furthermore, human insulin produced by Bacteria using Recombinant DNA technology is now widely used to avoid antibody-related complications.

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Fig. 19-2. Electron micrograph of two adjacent human pancreatic B-Cells. Type B granules appear as membrane-bound vesicles containing crystals that range in shape from rhombic to round (magnification 26,000x; courtesy of A. Like. Reprinted with permission from Fawcett DW: Bloom and Fawcett, A Textbook of Histology, 11th ed. Saunders, 1986).

Fig. 19-3. A and B cells showing their relationship to Blood Vessels; rER = rough Endoplasmic reticulum. Insulin from the B-Cell and Glucagon from the A-cell are secreted via exocytosis across The Cell basement membrane and capillary basement membrane before entering the lumen of fenestrated blood capillaries (reprinted with permission from Junqueira LC, Carneiro J, Kelley RO: Basic Histology, 9th ed. McGraw-Hill, 1998).

Biosynthesis and Secretion

Insulin is synthesized in the rough endoplasmic reticulum of B-cells (see Fig. 19-3). The hormone is then transported to the Golgi apparatus, where it is packaged into membrane-bound granules. These granules move toward The Plasma Membrane through a microtubule-dependent process, releasing their contents via exocytosis (see Chapter 1). Subsequently, to enter the bloodstream, insulin crosses the basement membranes of the B-cells and adjacent capillaries, as well as the fenestrated capillary endothelium. Fenestrated blood capillaries are discussed in detail in Chapter 30. Like other polypeptide Hormones and similar Proteins entering The endoplasmic reticulum, insulin is synthesized as part of a larger preprohormone (see Chapter 1). The insulin Gene is located on the short arm of human chromosome 11. It contains two introns and three exons (Fig. 19-4). Preproinsulin features a 23-amino-acid N-terminal signal peptide (leader sequence) that is cleaved upon entering the endoplasmic reticulum. The remaining molecule then folds, Disulfide Bonds form, and proinsulin is generated. The peptide segment connecting the A and B chains—the connecting peptide (C-peptide)—facilitates folding and is subsequently cleaved within the granules prior to secretion. Two proteases are involved in proinsulin Processing. No other physiological activity has been identified for the C-peptide. Typically, 90–97% of the products released from the B-cell consist of insulin along with an equimolar amount of C-peptide, with the remainder being proinsulin. Notably, C-peptide can be measured by radioimmunoassay, and its level serves as an index of B-cell secretory activity in patients receiving exogenous insulin.

Table 19-1. Structure of human insulin (molecular weight 5,808) and structural Variability in other mammalian species. Islet cells in rats secrete two slightly different insulins, and four distinct forms have been identified in certain fish