Hypoglycemia is the major problem to blood glucose homeostasis in treatment of diabetes and is associated with severe irreversible consequences including seizures, coma and death. GABAergic inhibitory function in the cerebral cortex plays an important role in controlling the excitability and responsiveness of cortical neurons. Present study analysed effects of insulin induced hypoglycemia and streptozotocin induced diabetes on the cortical GABA receptor binding, GABA(Aά1), GABA(B) receptor subtype expression, GAD and GLUT3 expression. Diabetic rats showed decreased [(3)H] GABA binding in the cerebral cortex compared to control while hypoglycemia exacerbated the decrease. GABA receptor subunits; GABA(Aά1), GABA(B) and GAD expression significantly decreased in diabetic rats whereas hypoglycemia significanly decreased the expression compared to diabetic. GLUT3 expression significantly up regulated during both hypo and hyperglycemia. Our results showed that hypoglycemia and hyperglycemia decreased GABAergic neuroprotective function in the cerebral cortex, which account for the increased vulnerability of cerebral cortex to subsequent neuronal damage during hypo/hyperglycemia.
"Recently, it was shown that insulin-induced hypoglycemic and streptozotocin-induced diabetic rats exhibit significantly decreased expression of GABRA1 with reduced cortical GABA binding (Antony et al. 2010; Sherin et al. 2010, 2012), indicating that Network 2 shown in Figure 3B also represents the effects of insulin signaling impairment owing to the decreased expression of PCSK1 and PCSK2. Moreover, silencing of the CPLX1 gene, which is also part of Network 2 and which was also downregulated in AD brains (Fig. 3B), has been reported to cause strong impairment of insulin secretion in response to glucose (Abderrahmani et al. 2004). "
[Show abstract][Hide abstract] ABSTRACT: Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular
mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated
for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus
was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression
changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified
by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western
blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in
noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related
to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent
of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains
is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.
"Much of the accumulated data from Type-1 animal models has come from the discovery of a novel diabetogenic compound Streptozotocin (STZ). The influence of STZ on the modulation of GAD expression has been shown earlier on GAD67 in MIN cells and also the INS cells treated with STZ show increased release of GABA in the culture medium that indirectly measures the rate of GAD expression [34,48]. Several key transcriptional factors like NFκB and p53 have been shown to regulate the expression of GAD. "
[Show abstract][Hide abstract] ABSTRACT: GAD65 (Glutamic acid decarboxylase 65 KDa isoform) is one of the most important auto-antigens involved in Type 1 diabetes induction. Although it serves as one of the first injury markers of β-islets, the mechanisms governing GAD65 expression remain poorly understood. Since the regulation of GAD65 is crucial for the proper functioning of insulin secreting cells, we investigated the stress induced regulation of GAD65 transcription.
The present study shows that SMAR1 regulates GAD65 expression at the transcription level. Using a novel protein-DNA pull-down assay, we show that SMAR1 binding is very specific to GAD65 promoter but not to the other isoform, GAD67. We show that Streptozotocin (STZ) mediated DNA damage leads to upregulation of SMAR1 and p53 expression, resulting in elevated levels of GAD65, in both cell lines as well as mouse β-islets. SMAR1 and p53 act synergistically to up-regulate GAD65 expression upon STZ treatment.
We propose a novel mechanism of GAD65 regulation by synergistic activities of SMAR1 and p53.
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