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VOL. 71 (4), 765-782, 2005 OLD HORMONES OF THE INSULIN...

transported to distant body parts through the bloodstream, modifying
body functions (38). In the following decades, the study of hormones
was thus parallel to the study of the so named endocrine glands,
thinking that they were fixed couples. With the speed of biological
discovery in the «omics» era (genomics, proteomics, metabolomics,
etc.), however, very few concepts have the label of dogma for very
long time.

Insulin, since it was discovered by Banting and Best in 1921 and
extracted from the dog pancreas (2), started a medical and
pharmaceutical revolution in the treatment of diabetics, and
remained known as an exclusive pancreatic hormone of vertebrates
for most of the 20th century. With the advance of molecular and
cellular techniques in recent years, it has become evident that insulin
and its precursor proinsulin are expressed prior to pancreatic
development and in organisms without a pancreas. In essence, all
multicellular organisms are thought to have ancestral or evolved
protein(s) of the insulin family (6) whereas the yeast genome does
not contain any similar protein (8). The protochordate Amphioxus
contains a single proinsulin-like gene (7) and more recent
acquisitions led to the appearance of insulin-like growth factor (IGF)
I and II in fish, amphibians and birds (6). In humans, there is
an extended insulin family of proteins including relaxin, placentin
and Leydig insulin-like peptide (21). These peptides signal the cells
binding to several types of membrane tyrosine kinase receptors,
from the ancestral single insulin receptor found in Amphioxus (30),
to the mammalian diversified forms. These include the two forms of
insulin receptor, containing or skiping exon 11 (4), the IGF-I receptor
(15) and the hybrid receptors generated by them (17,29).
Autophosphorylation of tyrosine residues in the ß-subunit of these
receptors leads to phosphorylation in insulin receptor substrates
(IRS) 1 to 4 and other transduction molecules (26,34), activating two
major intracellular pathways: the PI3-kinase/Akt and the Ras/MAPK
pathways (5,24). These signalling cascades and networks of activated
molecules influence multiple cellular processes, including proli-
feration, cell growth, differentiation, migration, metabolism, and
overall life span (16,20,33).

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