Glucose refractoriness of β-cells from fed fa/fa rats is ameliorated by nonesterified fatty acids

Abstract

The aim of this study was to characterize the glucose responsiveness of individual β-cells from fa/fa rats under ad libitum feeding conditions. Enlarged intact islets from fed fa/fa rats had a compressed insulin response curve to glucose compared with smaller islets. Size-sorted islets from obese rats yielded β-cells whose glucose responsiveness was assessed by reverse hemolytic plaque assay to determine whether glucose refractoriness was caused by a decreased number of responsive cells or output per cell. In addition, the effects of palmitic acid on glucose-stimulated insulin secretion were assessed because of evidence that nonesterified fatty acids have acute beneficial effects. Two- to three-fold more β-cells from >250 µm diameter (large) islets than <125 µm diameter (small) or lean islets responded to low glucose. Increasing the glucose (8.3-16.5 mM) induced a >10-fold increase in recruitment of active cells from small islets, compared with only a 2.6-fold increase in large islets. This refractoriness was partially reversed by preincubation of the cells in low glucose for 2 h. In addition, secretion per cell of the large islet β-cell population was significantly reduced compared with lean β-cells, so that the overall response capacity of large but not small islet β-cells was significantly reduced at high glucose. Therefore, continued near-normal function of the β-cells from small islets of fa/fa rats seems crucial for glucose responsiveness. Incubation of β-cells from large islets with palmitic acid normalized the secretory capacity to glucose mainly by increasing recruitment and secondarily by increasing secretion per cell. In conclusion, these studies demonstrate refractoriness to glucose of β-cells from large islets of fa/fa rats under ad libitum feeding conditions. When acutely exposed to nonesterified fatty acids, islets from fa/fa rats have a potentiated insulin response despite chronic elevation of plasma lipids in vivo.Key words: Zucker rat, insulin secretion, palmitic acid, glucose, β-cells.