Biomedical Engineering Reference
In-Depth Information
11.2.2 The insulin molecule
Insulin was fi rst identifi ed as an anti-diabetic factor in 1921, and was introduced clinically the
following year. Its complete amino acid sequence was determined in 1951. Although mature in-
sulin is a dimeric structure, it is synthesized as a single polypeptide precursor, i.e. preproinsulin.
This 108 amino acid polypeptide contains a 23 amino acid signal sequence at its amino terminal
end. This guides it through the endoplasmic reticulum membrane, where the signal sequence is
removed by a specifi c peptidase.
Proinsulin-containing vesicles bud off from the endoplasmic reticulum and fuse with the golgi
apparatus. Subsequently, proinsulin-containing vesicles (clathrin-coated secretory vesicles), in
turn, bud off from the golgi. As they move away from the golgi, they lose their clathrin coat,
becoming non-coated secretory vesicles. These vesicles serve as a storage form of insulin in the
β
-cell. Elevated levels of blood glucose, or other appropriate signals, cause the vesicles to fuse
with the plasma membrane, thereby releasing their contents into the blood via the process of
e xocytosis.
Proinsulin is proteolytically processed in the coated secretory granules, yielding mature in-
sulin and a 34-amino acid connecting peptide (C peptide, Figure 11.1). The C peptide is further
proteolytically modifi ed by removal of a dipeptide from each of its ends. The secretory granules
thus contain low levels of proinsulin, C peptide and proteases, in addition to insulin itself. The
insulin is stored in the form of a characteristic zinc-insulin hexamer, consisting of six molecules
of insulin stabilized by two zinc atoms.
Mature insulin consists of two polypeptide chains connected by two interchain disulfi de link-
ages. The A-chain contains 21 amino acids, whereas the larger B-chain is composed of 30 resi-
dues. Insulins from various species conform to this basic structure, while varying slightly in their
amino acid sequence. Porcine insulin (5777 Da) varies from the human form (5807 Da) by a single
amino acid, whereas bovine insulin (5733 Da) differs by three residues.
Figure 11.1
Proteolytic processing of proinsulin, yielding mature insulin, as occurs within the coated secre-
tory granules
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