Abstract
The GTPases Rab3a and Rab27a and their effectors Granuphilin/Slp4 and Noc2 are essential regulators of neuroendocrine secretion. Chronic exposure of pancreatic beta-cells to supraphysiological glucose levels decreased selectively the expression of these proteins. This glucotoxic effect was mimicked by cAMP-raising agents and blocked by PKA inhibitors. We demonstrate that the transcriptional repressor ICER, which is induced in a PKA-dependent manner by chronic hyperglycemia and cAMP-raising agents, is responsible for the decline of the four genes. ICER overexpression diminished the level of Granuphilin, Noc2, Rab3a and Rab27a by binding to cAMP responsive elements located in the promoters of these genes and inhibited exocytosis of beta-cells in response to secretagogues. Moreover, the loss in the expression of the genes of the secretory machinery caused by glucose and cAMP-raising agents was prevented by an antisense construct that reduces ICER levels. We propose that induction of inappropriate ICER levels lead to defects in the secretory process of pancreatic beta-cells possibly contributing, in conjunction with other known deleterious effects of hyperglycemia, to defective insulin release in type 2 diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cyclic AMP / metabolism
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Cyclic AMP Response Element Modulator / metabolism*
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DNA, Antisense / pharmacology
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Electrophoretic Mobility Shift Assay
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Exocytosis / physiology*
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Gene Expression Regulation / physiology*
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Glucose / metabolism
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Humans
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Hyperglycemia / metabolism*
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Insulin / metabolism*
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Insulin Secretion
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Intracellular Signaling Peptides and Proteins
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Islets of Langerhans / metabolism
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Male
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Promoter Regions, Genetic
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Proteins / genetics
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Proteins / metabolism
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Rats
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Rats, Sprague-Dawley
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Repressor Proteins / metabolism*
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Response Elements / genetics
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / metabolism
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rab GTP-Binding Proteins / genetics
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rab GTP-Binding Proteins / metabolism
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rab27 GTP-Binding Proteins
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rab3 GTP-Binding Proteins / genetics
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rab3 GTP-Binding Proteins / metabolism
Substances
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DNA, Antisense
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Insulin
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Intracellular Signaling Peptides and Proteins
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Proteins
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Repressor Proteins
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Rph3al protein, rat
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SYTL4 protein, human
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Sytl4 protein, rat
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Vesicular Transport Proteins
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rab27 GTP-Binding Proteins
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Cyclic AMP Response Element Modulator
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Cyclic AMP
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RAB27A protein, human
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Rab27a protein, mouse
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Rab27a protein, rat
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rab GTP-Binding Proteins
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rab3 GTP-Binding Proteins
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Glucose