Glutamate-induced over-expression of GAD is down-regulated by acetyl-L-carnitine in rat islet cells.
Glutamic acid decarboxylase (GAD65 and GAD67) in pancreatic beta cells is the target of autoantibodies and autoreactive T cells in insulin-dependent diabetes mellitus (IDDM). Regulating expression of GAD perhaps is a practical approach to treat IDDM. In this study, we established an in vitro system, in which GAD was expressed and glutamate treatment produced over-expression of GAD67 and GAD65 in rat islet cells. By using the system we were able to demonstrate basal level of expression of GAD and effects of glutamate and the antioxidant, acetyl-L-carnitine (ALC) on expression of GAD. We found that GAD67 expressed in 10% of islets cells, whereas GAD65 was localized in only 4% of the cells. Glutamate treatment resulted in significant over-expression of GAD67, but not GAD65. Such glutamate-induced overexpression of GAD67 was attenuated by pretreatment with ALC (100 microM). These findings suggest that the over-expression of GAD67 induced by glutamate in islet cells of rat may act as a suitable cellular model to study GAD autoreactivity during the development of IDDM. Meanwhile, it indicates that ALC, an ester of the trimethylated amino acid, can block glutamate-induced over-expression of GAD67, a key beta-cell autoantigen, suggesting a therapeutic potential of ALC in IDDM.
Hao
Yanlei
Y
Laboratory of Molecular Pathophysiology, NIMH, NIH, Bethesda, Maryland 20892, USA.
Basile
A S
AS
Chen
Guang
G
Zhang
Lei
L
D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D005968:Glutamate Decarboxylase / Q000096:biosynthesis*; D018698:Glutamic Acid / Q000494:pharmacology; D007515:Islets of Langerhans / Q000201:enzymology*; D007527:Isoenzymes / Q000096:biosynthesis*; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D018697:Nootropic Agents; D018698:Glutamic Acid; D000108:Acetylcarnitine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2