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Growth Factor Receptor‐Bound Protein 10‐Mediated Negative Regulation of the Insulin‐Like Growth Factor‐1 Receptor‐Activated Signalling Pathway Results in Cognitive Disorder in Diabetic Rats
Author(s) -
Ma L.,
Wei Q.,
Deng H.,
Zhang Q.,
Li G.,
Tang N.,
Xie J.,
Chen Y.
Publication year - 2013
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12040
Subject(s) - endocrinology , medicine , insulin like growth factor , insulin receptor , insulin like growth factor 1 receptor , biology , receptor , insulin , growth factor , insulin resistance
Growth factor receptor‐bound protein 10 (Grb10) is a S rc homology 2 domain‐containing protein and one of the binding partners for several transmembrane tyrosine kinase receptors, including insulin receptor ( IR ) and insulin‐like growth factor‐1 receptor ( IGF 1‐R). The hippocampus, which is critical for cognitive functions, is one of the main distribution areas of G rb10 in the central nervous system. In recent years, diabetic encephalopathy has been defined as a third type of diabetes and the IGF 1‐ IR pathway was shown to be critical for the neuropathogenic process of cognitive disorder in diabetes. However, the role of endogenous Grb10 in regulating the IGF 1‐ IR pathway and neurobehavioural changes is not explicit. The present study aimed to determine the in vivo function of endogenous G rb10 in diabetic encephalopathy and the underlying mechanisms. Using stereotaxic surgical techniques and lentiviral vectors expressing specific short hairpin RNA , we could steadily knockdown G rb10 expression in the hippocampus. More importantly, we demonstrated that hippocampus‐specific modulation of G rb10 protein levels led to a prominent remission of cognitive disorder, including improvements in both ultrastructural pathology and abnormal neurobehavioural changes. Our findings indicate that endogenous overexpression of G rb10 functions as a suppressor of the IGF 1‐ IR pathway, which may represent an important mechanism for regulating cognitive disorder in diabetes.