<p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p> <p>Albert Renold strived to gain insight into the abnormalities
of human diabetes by defining the pathophysiology
of the disease peculiar to a given animal.
He investigated the Israeli desert-derived spiny mice
(Acomys cahirinus), which became obese on fat-rich
seed diet. After a few months hyperplasia and hypertrophy
of <italic>β</italic>-cells occurred leading to a sudden rupture,
insulin loss and ketosis. Spiny mice were low
insulin responders, which is probably a characteristic
of certain desert animals, protecting against insulin
oversecretion when placed on an abundant
diet. We have compared the response to overstimulation
of several mutant diabetic species and nutritionally
induced nonmutant animals when placed on
affluent diet. Some endowed with resilient <italic>β</italic>-cells
sustain long-lasting oversecretion, compensating for
the insulin resistance, without lapsing into overt diabetes.
Some with labile beta cells exhibit apoptosis
and lose their capacity of coping with insulin resistance
after a relatively short period. The wide
spectrum of response to insulin resistance among
different diabetes prone species seems to represent
the varying response of human beta cells among the
populations. In search for the molecular background
of insulin resistance resulting from overnutrition we
have studied the Israeli desert gerbil Psammomys
obesus (sand rat), which progresses through hyperinsulinemia,
followed by hyperglycemia and irreversible
beta cell loss. Insulin resistance was found
to be the outcome of reduced activation of muscle insulin
receptor tyrosine kinase by insulin, in association
with diminished GLUT4 protein and DNA
content and overexpression of PKC isoenzymes, notably
of PKC<italic>ε</italic>. This overexpression and translocation
to the membrane was discernible even prior to hyperinsulinemia
and may reflect the propensity to diabetes
in nondiabetic species and represent a marker
for preventive action. By promoting the phosphorylation
of serine/threonine residues on certain proteins
of the insulin signaling pathway, PKC<italic>ε</italic> exerts a
negative feedback on insulin action. PKC<italic>ε</italic> was also
found to attenuate the activity of PKB and to promote
the degradation of insulin receptor, as determined
by co-incubation in HEK 293 cells. PKC<italic>ε</italic>
overexpression was related to the rise in muscle diacylglycerol
and lipid content, which are prevalent
on lascivious nutrition especially if fat-rich. Thus,
Psammomys illustrates the probable antecedents of
the development of worldwide diabetes epidemic in
human populations emerging from food scarcity to
nutritional affluence, inappriopriate to their metabolic
capacity.</p>
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Int J Exp Diabetes Res. 2001; 2(4):299-319