Elevated SNAP-25 is associated with fatty acid-induced impairment of mouse islet function.
ABSTRACT The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in insulin secretion following chronic exposure to non-esterified fatty acids (NEFAs) has not been extensively investigated. Here, we show that synaptosome-associated protein of 25 kDa (SNAP-25) levels were predominantly elevated in the soluble fraction of mouse islets exposed to palmitate. This coincided with an impairment of insulin secretion to glucose and non-glucose secretagogues, consistent with a defect at a distal regulatory step in exocytosis. Removal of palmitate from the media restored both SNAP-25 protein levels and insulin secretion to control levels. We conclude that increased expression of SNAP-25 is associated with NEFA-induced impairment of insulin secretion in mouse islets.
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ABSTRACT: Regulated exocytosis is a fundamental and common feature of all secretory cells specialized in the release of essential bioactive substances. This process is tightly controlled to adapt the amount of released products in response to the variable physiological cues. However it occurs that inadequate, excessive and/or prolonged exposure to environmental demands become stressful and desensitizes or irreversibly damage the cell secretory competence. The insulin-releasing β-cells of the islets of Langerhans represent a well characterized model of adaptation of the secretory response. In this system, while physiological elevation of glucose or lipids concentration can acutely stimulate insulin release, prolonged exposure to these secretagogues can have deleterious effects on the cells contributing to severe insulin secretion defects in diabetic patients. New emerging data provide evidence that prolonged exposure to elevated glucose concentration is associated with a reduction in the expression of a set ofgenes essential for exocytosis. This chapter discusses this phenomenon, which occurs at transcriptional levels and leads to a decline in the secretory function. These glucose effects appear to be mediated by a sustained rise in cAMP levels, which in turn induces expression of the inducible cAMP early repressor (ICER), a transcription factor known to be activated in response to stress. Based on these findings, this chapter highlights the role of ICER in the control of the exocytotic apparatus challenged with a stressful environment.12/2008: pages 161-173;
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ABSTRACT: Neprilysin contributes to free fatty acid (FFA)-induced cellular dysfunction in nonislet tissues in type 2 diabetes. Here, we show for the first time that with prolonged FFA exposure, islet neprilysin is upregulated and this is associated with reduced insulin pre-mRNA and ATP levels, oxidative/nitrative stress, impaired potassium and calcium channel activities, and decreased glucose-stimulated insulin secretion (GSIS). Genetic ablation of neprilysin specifically protects against FFA-induced impairment of calcium influx and GSIS in vitro and in vivo but does not ameliorate other FFA-induced defects. Importantly, adenoviral overexpression of neprilysin in islets cultured without FFA reproduces the defects in both calcium influx and GSIS, suggesting that upregulation of neprilysin per se mediates insulin secretory dysfunction and that the mechanism for protection conferred by neprilysin deletion involves prevention of reduced calcium influx. Our findings highlight the critical nature of calcium signaling for normal insulin secretion and suggest that interventions to inhibit neprilysin may improve β-cell function in obese humans with type 2 diabetes.Diabetes 01/2013; · 7.90 Impact Factor