Antiapoptotic Actions of Exendin-4 against Hypoxia and Cytokines Are Augmented by CREB

• Published in: Endocrinology (Philadelphia) Vol. 153; no. 3; pp. 1116 - 1128
• Main Authors: Velmurugan, Kalpana, Balamurugan, A. N, Loganathan, Gopalakrishnan, Ahmad, Aftab, Hering, Bernhard J, Pugazhenthi, Subbiah
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01-03-2012; Oxford University Press
• Subjects: Allografts; Animals; Apoptosis; Bcl-2 protein; Beta cells; Biological and medical sciences; Cadavers; Cell Line; Cell survival; Cells, Cultured; Computer Simulation; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cytokines; Cytokines - metabolism; Diabetes; Diabetes mellitus; Donors; Exenatide; Exposure; Fundamental and applied biological sciences. Psychology; Glucagon; Glucagon-like peptide 1; Humans; Hypoxia; IAP protein; Inflammation; Injuries; Insulin; Insulin Receptor Substrate Proteins - metabolism; Insulin receptors; Insulin-Secreting Cells - cytology; Ischemia; Islet cells; Islets of Langerhans; Islets of Langerhans - cytology; Male; Mice; Mice, Nude; Oxidative stress; Pancreas; Pancreas - metabolism; Pancreas transplantation; Pancreatic islet transplantation; Peptides - pharmacology; Proteins; Receptors; Regulatory sequences; Reperfusion; Reperfusion Injury - pathology; Signal Transduction; Survival; Transcription activation; Transcription factors; Transplantation; Venoms - pharmacology; Vertebrates: endocrinology; Oxygen; Gastrointestinal hormone; Analog; Cytokine; Environmental factor; Hypoxia; Exenatide; Transcription factor CREB; Glucagon like peptide 1
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2011-1895

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.