Journal
BIOCHEMICAL PHARMACOLOGY
Volume 132, Issue -, Pages 9-17Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2017.02.007
Keywords
Islet beta-cell; Glucotoxicity; G proteins; Racl; Tiaml; Vav2
Categories
Funding
- Department of Veterans Affairs [1I0113X002801, 13S-RCS-006]
- National Institutes of Health [DK74921, EY022230]
- Juvenile Diabetes Research Foundation [52012-257]
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Glucose-stimulated insulin secretion [GSIS] from the islet 3-cell involves a well-orchestrated interplay between metabolic and cationic events. It is well established that intracellular generation of adenine and guanine nucleotide triphosphates [e.g., ATP and GTP] represents one of the requisite signaling steps in GSIS. The small molecular mass GTP-binding proteins [G-proteins; e.g., Racl and Cdc42] have been shown to regulate islet 8-cell function including actin cytoskeletal remodeling and fusion of insulin granules with the plasma membrane for GSIS to occur. In this context, several regulatory factors for these G-proteins have been identified in the pancreatic 8-cell; these include guanine nucleotide exchange factors [GEFs] and guanine nucleotide dissociation inhibitors [GDI]. Recent pharmacological and molecular biological evidence identified Tiam1 and Vav2 as GEFs for Racl in promoting physiological insulin secretion. Paradoxically, emerging evidence in multiple cell types, including the islet 3-cell, suggests key roles for Racl in the onset of cellular dysfunction under conditions of metabolic stress and diabetes. Furthermore, functional inactivation of either Tiam1 or Vav2 appears to attenuate sustained activation of Rac1 and its downstream signaling events [activation of stress kinases] under conditions of metabolic stress. Together, these findings suggest both friendly and non-friendly roles for Tiaml/Vav2-Racl signaling axis in islet 8-cell in health and diabetes. Our current understanding of the field and the knowledge gaps that exist in this area of islet biology are heighted herein. Furthermore, potential caveats in the specificity and selectivity of pharmacological inhibitors that are available currently are discussed in this Commentary. Published by Elsevier Inc.
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