Hussain, Ainy Hussain
Description
NODk mice are congenic for the protective MHC H2k (Idd 1 locus)
and unlike NOD
mice do not develop autoimmune diabetes. The aim of the study was
to determine if
NODk β-cells have a non-immune islet beta-cell defect that may
be revealed by stressing
the islets with high fat diet (HFD). B10k (B10.Br mice with H2k
haplotype) and Balb/c mice were used as comparator groups.
Male NODk, B10k and Balb/c mice were fed chow or HF diets from 4
weeks of age...[Show more] for
10 weeks (short-term study) and 20 weeks (long-term study). Body
weight and 9 AM
fed-state blood glucose levels were measured fortnightly. At 13
and 23 weeks of age
intraperitoneal glucose tolerance tests (ipGTT) were performed
for both studies. NODk
mice were refreshed by backcrossing on to NOD mice (NODk-REF) and
preliminary
experiments were performed to determine the effects of
HF-feeding. NODk-REF mice
were also fed chow or HF-diet from weaning, with fortnightly body
weight and fedstate
blood glucose measurements, and ipGTTs were performed after 9 and
20 weeks on
diets. At sacrifice, the pancreases were harvested for
histological assessment, including;
islet morphology, islet inflammation, beta-cell apoptosis,
insulin immunohistochemistry
and beta-cell mass measurement.
Despite excellent glucose tolerance at all ages on chow diet,
HF-fed NODk mice
developed diet-induced obesity, profound hyperinsulinemia and
diabetes by 13 weeks of
age. Severe hyperglycaemia caused several NODk mice to be
euthanased prior to
completing the long-term study. B10k mice had poor glucose
tolerance on chow diet
only, but despite some HF-diet induced excessive weight gain,
they did not develop
severe hyperinsulinemia or progress onto diabetes. Balb/c mice
maintained excellent
glucose tolerance on both diets. Analyses of the pancreas
histology does not indicate
that diabetes in the HF-fed NODk mice is due to insulitis. Islet
beta-cell mass initially
increased in HF-fed NODk mice, but finally began to decrease in
the long-term cohort,
accompanied by the presence of occasional apoptosis in endocrine
cells in the islets of
these mice.
The pancreas histological features of the B10k and Balb/c mice
did not indicate failure
of beta-cell mass compensatory effects with HF-feeding.
Many of the effects of HF-feeding of NODk mice were seen in the
HF-fed NODk-REF
mice, except for the development of diabetes. This suggests that
the NODk mice have an
additional islet beta-cell susceptibility to failure compared to
the NODk-REF mice.
These preliminary results indicate that a major diabetes
susceptibility factor present in
the NODk mice, important for type 2 diabetes (T2D) development,
is not necessary for
the development of type 1 diabetes (T1D).
In conclusion, NODk mice are prone to a severe type 2 diabetes
(T2D) phenotype when
fed a HF-diet. Underlying non-immune islet susceptibility factors
may contribute to the
propensity of NOD mice to develop T1D and the NODk mice to
develop T2D. These
results are also consistent with the beta-cell overwork
hypothesis in diabetes pathogenesis
as seen in NODk mice. In addition, these results show that
beta-cell underwork or “lazy” beta-
cells in B10k mice may protect them from more severe failure.
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