-cell
replication, neogenesis and apoptosis. A second wave of neogenesis occurs
during weaning.
The incretin hormone glucagon-like polypeptide-1 (GLP-1) stimulates
pancreatic neogenesis and increases
β-cell mass. Therefore its
administration to rat pups who have undergone 90% partial pancreatectomy
results in an increase in both
β-cell mass and improved glucose
homeostasis. Exendin-4 is a long-acting GLP-1 which in addition to the
aforementioned activities stimulates expression of Pancreatic Duodenal
Homeobox (PDX) protein in the pancreas. PDX is critical for the early
development of both the endocrine and exocrine pancreas and mediates
glucose responsive stimulation of transcription of the insulin gene.
Stoffers and colleagues treated IUGR rat pups with exendin-4 during the
early postnatal period to study its effects on the subsequent development
of type 2 diabetes. Four groups of rat pups were studied: (1) control pups
given vehicle injection, (2) control pups given exendin-4 injections, (3)
IUGR pups given vehicle injections, and (4) IUGR pups given exendin-4
injections. Injections were administered on postnatal days 1 through 6.
Glucose tolerance,
β-cell mass,
β-cell proliferation and PDX gene
expression were measured at 14 days and 3 months of age. Glucose tolerance
was also determined at 7 weeks and 8 months of age.
Exendin–4 decreased weights in both control and IUGR pups (Groups 2 and
4) at 2 weeks. This decrease persisted into adulthood (Table). At day 14,
glucose tolerance in the IUGR pups treated with exendin-4 was similar to
that in control animals. The treated animals remained euglycemic at 8
months. Vehicle–treated IUGR pups (Group 3) developed diabetes by 3 months
and died by 8 months of age. Exendin-4 treated IUGR pups (Group 4) had
normal
β-cell mass comparable to that in Group 1 as the result of
normalized replication rates. While Pdx-1 mRNA levels were reduced by 60%
in IUGR rats not receiving exendin-4 at 14 days, those treated with
exendin-4 had normal levels.
The authors state their major finding is that a short treatment with
exendin-4 during the early newborn period prevents the development of
diabetes in the IUGR rat. It is not clear whether this effect is through
the stimulation of Pdx-1. However, the effect is independent of
β-cell
mass, since its effects were observed prior to any reduction in the IUGR
pancreatic mass. They suggest that the permanent improvement in
maintenance of
β-cell mass by exendin-4 may mean that similar drugs could
be effective in reducing the risk or preventing type 2 diabetes mellitus
in individuals born with IUGR. The negative part of the study was the
growth inhibiting effect of exendin-4.
Stoffers DA, et al. Diabetes 2003;52:734-740.
Editor’s Comment: These fascinating data suggest that possibly
there may be a treatment available in the future for the prevention of
type 2 diabetes mellitus in IUGR individuals, if treated early in the
neonatal period. Stoffers and colleagues have shown using an IUGR rat
model that exendin-4 given for a short period of time postnatally can
prevent glucose intolerance by restoring Pdx-1 function and normalizing
β-cell proliferation rates. One cannot read this study without thinking
about other morbidity associated with IUGR and how other treatments
administered in the neonatal period might someday become available to
treat those as well. The obvious example would be treatment given early to
restore normal growth velocity. These authors have presented data that
opens up a whole new world of possibilities.
William L. Clarke, MD
