Zusammenfassung
Objective: Free fatty acids (FFAs) deplete the intracellular insulin stores of pancreatic P-cells. It has been suggested that this results from a lipotoxic dysregulation of both insulin secretion and insulin synthesis. In the present study, this hypothesis was tested within a 12-h time-course by directly relating the FFA-induced loss of intracellular insulin to corresponding parameters of insulin ...
Zusammenfassung
Objective: Free fatty acids (FFAs) deplete the intracellular insulin stores of pancreatic P-cells. It has been suggested that this results from a lipotoxic dysregulation of both insulin secretion and insulin synthesis. In the present study, this hypothesis was tested within a 12-h time-course by directly relating the FFA-induced loss of intracellular insulin to corresponding parameters of insulin secretion and de novo biosynthesis. Palmitate, cis-monoenic oleate and the trans-monoenic claidate were employed as model FFAs to elucidate potentially different effects due to chain length and configuration. Methods: INS-1 cells were incubated for 1, 4 or 12 h with 11.2 mmol/l glucose with 200 mumol/l palmitate, oleate or elaidate and compared with non-FFA-exposed controls with respect to content and secretion of immunoreactive insulin (IRI). Biosynthesis of insulin was monitored by pulse-labeling experiments and by Northern blot analysis. Results: IRI content dropped by 50-60% after a short-term exposure with all FFAs employed (P less than or equal to 0.001). It tended to recover after 12 h of treatment with oleate and elaidate but not with palmitate. FFA treatment increased insulin secretion by 25% (P less than or equal to 0.05) which could not account quantitatively for the intracellular loss. FFA-induced changes in insulin biosynthesis did not correlate clearly with the FFA-induced intracellular loss. Conclusions: The FFA-induced loss of IRI is an acute effect independent of the FFA employed. It cannot be sufficiently explained by FFA-induced perturbances of IRI secretion and biosynthesis. We therefore postulate an additional FFA-triggered mechanism, e.g. intracellular IRI degradation.
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