Deregulation of CREB Signaling Pathway Induced by Chronic Hyperglycemia Downregulates NeuroD Transcription

Abstract

CREB mediates the transcriptional effects of glucose and incretin hormones in insulin-target cells and insulin-producing β-cells. Although the inhibition of CREB activity is known to decrease the β-cell mass, it is still unknown what factors inversely alter the CREB signaling pathway in β-cells. Here, we show that β-cell dysfunctions occurring in chronic hyperglycemia are not caused by simple inhibition of CREB activity but rather by the persistent activation of CREB due to decreases in protein phophatase PP2A. When freshly isolated rat pancreatic islets were chronically exposed to 25 mM (high) glucose, the PP2A activity was reduced with a concomitant increase in active pCREB. Brief challenges with 15 mM glucose or 30 µM forskolin after 2 hour fasting further increased the level of pCREB and consequently induced the persistent expression of ICER. The excessively produced ICER was sufficient to repress the transcription of NeuroD, insulin, and SUR1 genes. In contrast, when islets were grown in 5 mM (low) glucose, CREB was transiently activated in response to glucose or forskolin stimuli. Thus, ICER expression was transient and insufficient to repress those target genes. Importantly, overexpression of PP2A reversed the adverse effects of chronic hyperglycemia and successfully restored the transient activation of CREB and ICER. Conversely, depletion of PP2A with siRNA was sufficient to disrupt the negative feedback regulation of CREB and induce hyperglycemic phenotypes even under low glucose conditions. Our findings suggest that the failure of the negative feedback regulation of CREB is the primary cause for β-cell dysfunctions under conditions of pathogenic hyperglycemia, and PP2A can be a novel target for future therapies aiming to protect β-cells mass in the late transitional phase of non-insulin dependent type 2 diabetes (NIDDM).

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan

“…Alternatively, the FMD may increase survival of newly-differentiated neurons, as observed in the dentate gyrus of alternate day-fed rodents (Lee et al, 2002; Mattson et al, 2001). The observed improvements in cognitive performance in the FMD cohort might be affected by an the increase in neurogenesis mediated by PKA/CREB-dependent regulation of NeuroD1 (Cho et al, 2012; Sharma et al, 1999), which is known to increase neuronal survival and differentiation of hippocampal progenitors (Roybon et al, 2009), enhance functional integration of new neurons, and alleviate memory deficits in a mouse model of Alzheimer’s disease (Richetin et al, 2015). …”

The Fractalkine/CX3CR1 System Regulates β Cell Function and Insulin Secretion

“…7 days of chronic in vitro treatment of islets with FKN led to increased expression of PDX1, NeuroD, HIF-1α and insulin (Figure 6L), and these genes were all down regulated in the CX3CR1 KO islets (Figure 3H). Recently, it has been shown that beta cell dysfunction induced by HFD or free fatty acid treatment, is, at least partially, mediated by the induction of inducible cyclic AMP early repressor (ICER-1) (Cho et al, 2012; Favre et al, 2011; Hussain et al, 2000; Zhou et al, 2003). Interestingly, ICER-1 expression was highly induced in the CX3CR1 KO islets (Figure 6M) and FKN treatment abolished palmitate-induced induction of ICER-1 mRNA in Min6 cells (Figure 6N).…”

CREM/ICERs up-regulation suppresses sponge endothelial CRE-HIF-1α-VEGF-dependent signaling and impairs angiogenesis in type 2 diabetes

“…Indeed, the current data demonstrating that ICER mRNA and protein expression were elevated in diabetic SIECs in connection with a reduction in a number of CRE target genes, such as NURR1 , IRS2 and VEGF , give credence to the aforementioned proposition. These findings are not unique to the diabetic SIECs as a persistent elevation of CREM/ICER and the concomitant suppression of gene transcription was also evident in other pathological conditions and cell types, such as hypercortisolemia ( Shepard et al, 2005 ), hypercatecholemia ( Lewin et al, 2009 ; Leopold et al, 2007 ) and hyperglycemia ( Cho et al, 2012 ), in addition to angiotensin-II-treated cardiomyocytes ( Ding et al, 2005 ) or oxidized LDL-treated insulin-secreting cells ( Favre et al, 2011 ).…”