Antiapoptotic Actions of Exendin-4 against Hypoxia and Cytokines Are Augmented by CREB
Abstract
Islets isolated from cadaveric donor pancreas are functionally viable and can be transplanted in diabetic patients to reduce insulin requirements. This therapeutic approach is less efficient because a significant portion of functional islets is lost due to oxidative stress, inflammation, and hypoxia. Exendin-4, a glucagon-like peptide-1 receptor agonist, is known to improve islet survival through activation of the transcription factor, cAMP response element binding protein (CREB). However, isolated human islets are exposed to several stresses known to down-regulate CREB. The objective of the present study was to determine whether the cytoprotective actions of exendin-4 in human islets can be augmented by increasing the levels of CREB. Simulation of ischemia/reperfusion injury and exposure to hypoxic conditions in cultured human islets resulted in decreased CREB activation and induction of apoptosis. Islets were transduced with adenoviral CREB followed by exposure to exendin-4 as a strategy for improving their survival. This combination increased the levels of several proteins needed for β-cell survival and function, including insulin receptor substrate-2, Bcl-2, and baculoviral IAP repeat-containing 3, and suppressed the expression of proapoptotic and inflammatory genes. A combination of CREB and exendin-4 exerted enhanced antiapoptotic action in cultured islets against hypoxia and cytokines. More significantly, transplantation of human islets transduced with adenoviral CREB and treated with exendin-4 showed improved glycemic control over a 30-d period in diabetic athymic nude mice. These observations have significant implications in the therapeutic potential of exendin-4 and CREB in the islet transplantation setting as well as in preserving β-cell mass of diabetic patients.
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Exendin-4 (50 nM) suppressed the expression of inflammatory genes such as NFκB1(p105), NFκB2(p100), RelA (p65), TNF receptor superfamily member 1A, and receptor-interacting serine/threonine kinase 2 in cultured human islets.
“Treatment of cultured human islets with exendin-4 (50 nM), a GLP-1 receptor agonist, suppressed the expression of inflammatory genes such as NFκB1(p105), NFκB2(p100), RelA (also termed p65), TNF receptor superfamily member 1A, and receptor-interacting serine/threonine kinase 2.”
From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [44]
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- Authors
- Velmurugan, K., Balamurugan, A. N., Loganathan, G., Ahmad, A., Hering, B. J., & Pugazhenthi, S.
- Affiliations
- Denver VA Medical Center (US)
- University of Minnesota (US)
- National Jewish Health (US)
- Corresponding author
- Pugazhenthi, Subbiah
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-03-01
- Volume
- 153
- Issue
- 3
- Pages
- 1116-1128
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2122768933
- Cited by
- 53
- References
- 62
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 9 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 4 · 2013: 9 · 2012: 3
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001837)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- exendin-4, CREB, islet transplantation, islet survival, hypoxia, cytokines, apoptosis, beta-cell survival, ischemia-reperfusion injury, adenoviral gene transfer, GLP-1 receptor agonists, Bcl-2, cIAP2, insulin receptor substrate 2, inflammation, type 1 diabetes, glycemic control
- MeSH terms
- Exenatide, Animals, Hypoxia, Cell Line, Cells, Cultured, Computer Simulation, Humans, Islets of Langerhans, Male, Mice, Nude, Pancreas, Peptides, Venoms, Signal Transduction, Reperfusion Injury, Cytokines, Apoptosis, Cyclic AMP Response Element-Binding Protein, Insulin-Secreting Cells, Mice, Insulin Receptor Substrate Proteins
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