nitial Stages of the Insulin Signaling System

Initial Stages of the Insulin Signaling System in the Brain
of Rats with Experimental Diabetes Mellitus
O. V. Chistyakova, I. B. Sukhov, M. L. Loshkareva, V. N. Shipilov,
V. M. Bondareva, and A. O. Shpakov
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 153, No. 1, pp. 31-24, January, 2012
Original article submitted September 23, 2010
We studied reactivity of insulin signal pathway elements, insulin receptor and insulin receptor
substrate protein-2 (IRS2 protein), in rat brain in response to insulin insuffi ciency and insulin
resistance during the development of experimental type 1 or type 2 diabetes mellitus. In type
1 diabetes mellitus characterized by acute insulin insuffi ciency, specifi c binding of insulin
in rat brain increased 2-fold in comparison with the control and IRS2-gene expression in rat
hypothalamus and cortex 2-4 fold surpassed the normal values. In type 2 diabetes mellitus
(110 and 190 days of development), changes in the test parameters in rat brain were less
pronounced. These fi ndings attest to involvement of the brain insulin signal pathway into the
response to systemic insulin defi ciency in type 1 diabetes mellitus.
Key Words: insulin; insulin receptor; IRS protein; brain; diabetes mellitus
Laboratory of Molecular Endocrinology, I. M. Sechenov Institute of
Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia. Address for correspondence: [email protected] O. V. Chistyakova
According to current views, insulin in CNS acts as
a neurohormone that regulates a wide spectrum of
physiological and biological parameters and processes, including glucose level, energy balance, reproductive function control, and memory processes
[1,5,11]. Insulin signal pathway in the brain is similar to that in peripheral tissues [11]. Insulin receptor
consists of two supermembrane hormone-binding
α-subunits and two transmembrane β-subunits with
tyrosine kinase activity. Insulin receptors were found
in all brain regions, with highest concentration in
the olfactory bulbs and hypothalamus arcuate nuclei
[9]. Coupling of activated receptors with intracellular signaling pathways involves endogenous insulin receptor substrate proteins (IRS1-4 proteins)
[11,14]. Substantial accumulation of IRS2 protein
was observed in the brain, particularly in hypothalamus arcuate nuclei. Interaction of IRS protein with a
variety of intracellular effector and adaptive proteins
determines insulin regulation of mitogen-activated
protein kinases, phospholipid pathway coupled with
phosphatidyl inositol-3-kinase enzyme, and signal
pathways dependent on protein tyrosine phosphatase
activity [14].
Recent studies showed that dysfunction of the
insulin signaling system in CNS leads to numerous
metabolic disturbances and neurodegenerative diseases. Specifi c knockout of insulin receptor gene in
mouse neurons results in the development of insulin
resistance, diabetes mellitus (DM), and obesity [2].
IRS-2 protein gene homozygotic mice are phenotypically similar to knockout animals and have almost
3-fold lower brain weight in comparison with controls
[12]. Despite substantial progress in understanding
of the role of insulin in CNS functioning, molecular mechanisms of hormone action under normal and
pathological conditions, particularly in DM of various
etiology, remain poorly studied [7].
Here we studied the response of initial stages of
insulin signal pathway in rat brain, insulin receptor
and IRS2 protein, to systemic insulin defi ciency and
insulin resistance in the models of experimental type
1 and type 2 DM (DM1 and DM2).


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