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Lawson Research Institute, St. Joseph’s Health Center, London, Ontario, Canada N6A 4V2; and the Departments of Physiology (J.P., D.J.H.), Medicine (E.A., D.J.H.), Biochemistry (T.J.M.), Pharmacology and Toxicology (T.J.M.), and Pediatrics (J.P., D.J.H.), University of Western Ontario, and London Health Sciences Center (T.J.M.), London, Ontario, Canada N6A 5A5
Address all correspondence and requests for reprints to: Dr. D. J. Hill, Lawson Research Institute, St. Joseph’s Health Center, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2. E-mail: dhill{at}lri.stjosephs.london.on.ca
Islet cell ontogeny will define adult ß-cell mass and will consist of
a balance of islet cell birth and death. We have investigated the
ontogeny of factors that may be related to developmental apoptosis in
the islets, insulin-like growth factor II (IGF-II) and inducible nitric
oxide synthase (iNOS), in pancreata of young Wistar rats. Pancreata
were collected from rats of 21 days gestation to 29 days postnatal age.
In situ hybridization and immunohistochemistry showed
that IGF-II was expressed and present in fetal and neonatal islet
cells, but declined rapidly 2 weeks after birth. Little IGF-I was
associated with fetal or postnatal islets. Apoptosis in islet cells was
visualized by molecular histochemistry for DNA breakage in tissue
sections. Apoptosis was low in the fetus, but increased in incidence
postnatally so that 13% of islet cells were undergoing apoptosis on
postnatal day 14, with the incidence declining thereafter.
Immunohistochemistry for iNOS showed that it was expressed within
ß-cells and was most abundant 12 days after birth. When islets were
isolated from rat pancreata 20–22 days after birth, islet cell
viability, DNA synthetic rate, and insulin release were reduced after
incubation with interleukin-1ß, tumor necrosis factor, or
interferon-
. An increased rate of islet cell survival was found
after simultaneous incubation with IGF-I or -II. Cytokine-mediated
islet cell death involved the induction of apoptosis. Islets isolated
from neonatal rats were not killed after exposure to these cytokines at
the same concentrations, but cytokine-induced cell death was seen when
neonatal islets were incubated with a neutralizing antibody against
IGF-II. These experiments show that a peak of islet cell apoptosis that
is maximal in the rat pancreas 14 days after birth is temporally
associated with a fall in the islet cell expression of IGF-II. IGF-II
was shown to function as an islet survival factor in
vitro. The induction of islet cell apoptosis in
vivo may involve an increased expression of iNOS within
ß-cells.
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