section 22.3
Endocrine Pancreas and Pancreatic Hormones
F I G U R E 2 2 - 6
Structures of human proinsulin and insulin. Insulin is derived from proinsulin by cleavage at the dipeptides Arg-Arg and
Lys-Arg to give A and B chains held together by disulfide bonds. In the pig, B30 is Ala. In the cow, A8 is Ala, A10 is
Val, and B30 is Ala. Bovine and porcine insulins are used extensively in clinical practice.
and has the same biological activity as normal
human insulin. However, unlike normal human insulin,
lispro insulin has a reduced capacity for self-association
and thus begins its biological activity within 15 minutes
of subcutaneous administration; it has become the insulin
of choice in many patients with diabetes (discussed later).
Insulin biosynthesis resembles that of other export pro-
teins: gene transcription, processing and maturation of
precursor mRNA, translation of mature RNA, translo-
cation of preproinsulin to cisternae of the endoplasmic
reticulum with removal of the N-terminal leader or signal
sequence of 23 amino acids, folding of proinsulin and for-
mation of the proper disulfide bridges, packaging of proin-
sulin into secretory granules, and conversion of proinsulin
to equimolar amounts of insulin and connecting peptide
(C-peptide) by site-specific enzymatic cleavages. The hu-
man insulin gene is located on the short arm of chromo-
some 11 and consists of a 5' untranslated region split by an
intron; an exon that codes for the leader peptide; a region
coding for the B chain; a region coding for C-peptide that
is split by an intron; a region coding for the A chain; and
a 3' untranslated region.
Conversion of proinsulin to insulin and C-peptide in
secretory granules involves site-specific cleavages at the
Arg-Arg and Lys-Arg sequences (Figure 22-6); these
serve as signals for proteolytic processing of many
other proteins. Cleavage occurs at the C-terminal end
of each pair by trypsin-like enzymes and is followed by
removal of the basic residues by a carboxypeptidase B-like
Insulin monomers undergo noncovalent dimerization by
formation of antiparallel /f-plcated sheet associations be-
tween monomers involving the C-terminal portion of the
B chain. As discussed earlier, lispro insulin, in which the
B28 and B29 is reversed from the normal prolyl and lysyl
sequence, does not dimerize. Three insulin dimers subse-
quently self-associate to form hexamers in the presence of
Zn2+. The Zn2+ hexameric array of insulin probably gives
the /
-cell granule its unusual morphologic characteristics.
Zn2+ is released when insulin is secreted. Conversion
of proinsulin to insulin in the secretory granule is not com-
plete and some proinsulin is also released upon secretion
of insulin. Proinsulin has less than
of the biological
activity of insulin. The C-peptide has no physiological
function but assay of C-peptide helps distinguish between
endogenous and exogenous sources of insulin.
Like genes for other proteins, the insulin gene may un-
dergo mutation and produce an abnormal product. This
process may be suspected in individuals who exhibit
without hypoglycemia or evidence of
insulin resistance. Three abnormal insulins have been doc-
umented: one in which Ser replaces Phe at B24, another
in which Leu replaces Phe at B25, and a third in which
the Lys-Arg basic amino acid pair is replaced by Lys-X
(X = nonbasic amino acid). The former two mutations oc-
cur in the nucleotide sequence that codes for an invariant
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