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Deregulation of CREB signaling pathway induced by chronic hyperglycemia downregulates NeuroD transcription
In-Su Cho1, Miyoung Jung, Ki-Sun Kwon
1Department of Anatomy, Ajou University, Suwon, South Korea.
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).
Insights
Chronic hyperglycemia causes persistent CREB activation in beta-cells due to reduced PP2A, leading to dysfunction. Restoring PP2A activity protects beta-cell mass in type 2 diabetes.
Area of Science:
- Cellular and Molecular Biology
- Endocrinology
- Diabetes Research
Background:
- CREB (cAMP response element-binding protein) regulates gene transcription in response to glucose and hormones.
- While CREB inhibition reduces beta-cell mass, factors causing inverse alterations in the CREB pathway in beta-cells remain unclear.
- Understanding CREB regulation is crucial for addressing beta-cell dysfunction in diabetes.
Purpose of the Study:
- To investigate the mechanisms underlying CREB signaling pathway alterations in beta-cells during chronic hyperglycemia.
- To identify the role of protein phosphatase 2A (PP2A) in regulating CREB activity in pancreatic beta-cells.
- To explore PP2A as a potential therapeutic target for preserving beta-cell function and mass.
Main Methods:
- Primary rat pancreatic islets were cultured under varying glucose concentrations (high 25 mM vs. low 5 mM).
- Chronic hyperglycemia exposure effects on PP2A activity, CREB phosphorylation (pCREB), and ICER expression were analyzed.
- Gene expression of NeuroD, insulin, and SUR1 was quantified.
- PP2A overexpression and siRNA-mediated depletion were used to assess its functional role.
- Forskolin and glucose were used as stimuli to evaluate CREB activation dynamics.
Main Results:
- Chronic high glucose reduced PP2A activity, leading to persistent CREB activation (pCREB increase) and ICER overexpression in beta-cells.
- Excessive ICER repressed the transcription of key beta-cell genes (NeuroD, insulin, SUR1).
- In contrast, low glucose resulted in transient CREB activation and minimal ICER expression.
- PP2A overexpression reversed hyperglycemia-induced CREB dysregulation and restored normal gene expression.
- PP2A depletion induced hyperglycemic phenotypes even under low glucose conditions, disrupting CREB negative feedback.
Conclusions:
- Failure of CREB negative feedback regulation, driven by decreased PP2A activity, is a primary cause of beta-cell dysfunction in pathogenic hyperglycemia.
- PP2A plays a critical role in maintaining CREB signaling homeostasis in beta-cells.
- PP2A represents a promising therapeutic target for protecting beta-cell mass in type 2 diabetes, particularly during transitional phases.
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