Objective: In type 2 diabetes, chronic hyperglycemia is detrimental to beta-cells, causing apoptosis and impaired insulin secretion. The transcription factor cAMP-responsive element-binding protein (CREB) is crucial for beta-cell survival and function. We investigated whether prolonged exposure of beta-cells to high glucose affects the functional integrity of CREB.
Research Design And Methods: INS-1E cells and rat and human islets were used. Gene expression was analyzed by RT-PCR and Western blotting. Apoptosis was detected by cleaved caspase-3 emergence, DNA fragmentation, and electron microscopy.
Results: Chronic exposure of INS-1E cells and rat and human islets to high glucose resulted in decreased CREB protein expression, phosphorylation, and transcriptional activity associated with apoptosis and impaired beta-cell function. High-glucose treatment increased CREB polyubiquitination, while treatment of INS-1E cells with the proteasome inhibitor MG-132 prevented the decrease in CREB content. The emergence of apoptosis in INS-1E cells with decreased CREB protein expression knocked down by small interfering RNA suggested that loss of CREB protein content induced by high glucose contributes to beta-cell apoptosis. Loading INS-1E cells or human islets with a cell-permeable peptide mimicking the proteasomal targeting sequence of CREB blocked CREB degradation and protected INS-1E cells and human islets from apoptosis induced by high glucose. The insulin secretion in response to glucose and the insulin content were preserved in human islets exposed to high glucose and loaded with the peptide.
Conclusions: These studies demonstrate that the CREB degradation by the ubiquitin-proteasome pathway contributes to beta-cell dysfunction and death upon glucotoxicity and provide new insight into the cellular mechanisms of glucotoxicity.
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http://dx.doi.org/10.2337/db08-0926 | DOI Listing |
Life Sci
January 2025
Immuno-Endocrinology, Diabetes & Metabolism Laboratory, Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET - Universidad Austral, Pilar, Argentina; Facultad de Ciencias Biomédicas, , Universidad Austral, Pilar, Argentina. Electronic address:
Aims: Type 2 diabetes (T2D) is a prevalent metabolic disease linked to obesity and metabolic syndrome (MS). The glucolipotoxic environment (GLT) impacts tissues causing low-grade inflammation, insulin resistance and the gradual loss of pancreatic β-cell function, leading to hyperglycemia. We have previously shown that Compound A (CpdA), a plant-derived dissociative glucocorticoid receptor-modulator with inflammation-suppressive activity, displays protective effects on β-cells in type 1 diabetes murine models.
View Article and Find Full Text PDFJ Gastroenterol
January 2025
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
Cells
November 2024
Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of Sciences, 841 04 Bratislava, Slovakia.
Sarco/endoplasmic reticulum Ca-ATPase (SERCA) is an important regulatory protein responsible for maintaining calcium homeostasis within cells. Impairment of SERCA associated with activity/expression decrease has been implicated in multiple chronic conditions, including cardiovascular diseases, diabetes, cancer, neurodegenerative diseases, and skeletal muscle pathologies. Natural polyphenols have been recognized to interact with several target proteins involving SERCA.
View Article and Find Full Text PDFFEBS J
January 2025
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Type 1 diabetes (T1D) is characterized by immune cell infiltration in the islets of Langerhans, leading to the destruction of insulin-producing beta cells. This destruction is driven by secreted cytokines and cytotoxic T cells inducing apoptosis in beta cells. Butyrate, a metabolite produced by the gut microbiota, has been shown to have various health benefits, including anti-inflammatory and anti-diabetic effects.
View Article and Find Full Text PDFPLoS One
November 2024
Department of Experimental Medical Sciences, Unit of Medical Protein Science, Lund University, Lund, Sweden.
Apolipoprotein A-I (ApoA-I), the primary component of high-density lipoprotein (HDL) cholesterol primes β-cells to increase insulin secretion, however, the mechanisms involved are not fully defined. Here, we aimed to confirm ApoA-I receptors in β-cells and delineate ApoA-I-receptor pathways in β-cell insulin output. An LRC-TriCEPS experiment was performed using the INS-1E rat β-cell model and ApoA-I for unbiased identification of ApoA-I receptors.
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