18 research outputs found
Albert Renold Memorial Lecture: Molecular Background of Nutritionally Induced Insulin Resistance Leading to Type 2 Diabetes – From Animal Models to Humans
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 β-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 β-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 PKCε. 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, PKCε exerts a
negative feedback on insulin action. PKCε 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. PKCε
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
Protein Tyrosine Phosphatase Activity in Insulin-Resistant Rodent Psammomys Obesus
Phosphotyrosine phosphatase (PTPase) activity and its regulation
by overnight food deprivation were studied in Psammomys
obesus (sand rat), a gerbil model of insulin resistance and nutritionally
induced diabetes mellitus. PTPase activity was measured
using a phosphopeptide substrate containing a sequence identical
to that of the major site of insulin receptor (IR) β-subunit autophosphorylation.
The PTPase activity in membrane fractions was 3.5-,
8.3-, and 5.9-fold lower in liver, fat, and skeletal muscle, respectively,
compared with corresponding tissues of albino rat.Western
blotting of tissue membrane fractions in Psammomys showed lower
PTPase and IR than in albino rats. The density of PTPase transmembrane
protein band was 5.5-fold lower in liver and 12-fold
lower in adipose tissue. Leukocyte antigen receptor (LAR) and IR
were determined by specific immunoblotting and protein bands
densitometry and were also found to be 6.3-fold lower in the liver
and 22-fold lower in the adipose tissue in the hepatic membrane
fractions. Liver cytosolic PTPase activity after an overnight food
deprivation in the nondiabetic Psammomys rose 3.7-fold compared
with postprandial PTPase activity, but it did not change significantly
in diabetic fasted animals. Similar fasting-related changes
were detected in the activity of PTPase derived from membrane
fraction. In conclusion, the above data demonstrate that despite
the insulin resistance, Psammomys is characterized by low level of
PTPase activities in membrane and cytosolic fractions in all 3 major insulin responsive tissues, as well as in liver. PTPase activity does
not rise in activity as a result of insulin resistance and nutritionally
induced diabetes
Contribution of animal models to the research of the causes of diabetes
In most publications, animal models of diabetes have mainly been investigated for their multiple etiologies as well as for changes leading to diabetes and their genetic derivation. Aspects which seem important and need a special research endeavor are the mechanism of the causes of diabetes and the lapse into complications in different species, their molecular basis and possible arrest and prevention. A concise list and and short discussion of the intensively studied rodents is presented of spontaneous or nutritional background causing Type 2 diabetes but omitting diabetes evoked by transgenic manipulations or gene knockout techniques