Distinct Effects of Saturated and Monounsaturated Fatty Acids on β-Cell Turnover and Function

Abstract

Glucotoxicity and lipotoxicity contribute to the impaired ␤-cell function observed in type 2 diabetes. Here we examine the effect of saturated and unsaturated fatty acids at different glucose concentrations on ␤-cell proliferation and apoptosis. Adult rat pancreatic islets were cultured onto plates coated with extracellular matrix derived from bovine corneal endothelial cells. Exposure of islets to saturated fatty acid (0.5 mmol/l palmitic acid) in medium containing 5.5, 11.1, or 33.3 mmol/l glucose for 4 days resulted in a five-to ninefold increase of ␤-cell DNA fragmentation. In contrast, monounsaturated palmitoleic acid alone (0.5 mmol/l) or in combination with palmitic acid (0.25 or 0.5 mmol/l each) did not affect DNA fragmentation. Increasing concentrations of glucose promoted ␤-cell proliferation that was dramatically reduced by palmitic acid. Palmitoleic acid enhanced the proliferation activity in medium containing 5.5 mmol/l glucose but had no additional effect at higher glucose concentrations (11.1 and 33.3 mmol/l). The cell-permeable ceramide analog C 2 -ceramide mimicked both the palmitic acid-induced ␤-cell apoptosis and decrease in proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on ␤-cell viability. Additionally, palmitic acid but not palmitoleic acid decreased the expression of the mitochondrial adenine nucleotide translocator and induced release of cytochrome c from the mitochondria into the cytosol. Finally, palmitoleic acid improved ␤-cell-secretory function that was reduced by palmitic acid. Taken together, these results suggest that the lipotoxic effect of the saturated palmitic acid involves an increased apoptosis rate coupled with reduced proliferation capacity of ␤-cells and impaired insulin secretion. The deleterious effect of palmitate on ␤-cell turnover is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid does not affect ␤-cell apoptosis, yet it promotes ␤-cell proliferation at low glucose concentrations, counteracting the negative effects of palmitic acid as well as improving ␤-cell function. Diabetes 50:69-76, 2001

Soybean oil treatment impairs glucose-stimulated insulin secretion and changes fatty acid composition of normal and diabetic islets

“…Fatty acids are key components of cellular membrane phospholipids and are involved in intracellular mechanisms, as previously described [12,13]. Previous studies reported the stimulatory effect of the monounsaturated palmitoleic acid (C16:1) on KATP channel activity [16] and promotion of β-cell function and proliferation at low glucose concentrations [27]. Although we observed a significant increase in palmitoleic acid (C16:1) in untreated diabetic islets (Fig.…”

“…3c). Previous studies reported that the increase of the monounsaturated palmitoleic acid (C16:1) is associated with β-cell proliferation at low glucose concentrations [27] and β-cell function improvement [12,17]. Accordingly, the failure of SO-treated GK islet insulin response observed in our study could be related to a decrease in islet palmitoleic acid.…”

“…It has been shown that palmitic acid (C16:0) is toxic to β-cells, even at moderate levels [19,25]. This fatty acid affects glucose-induced insulin gene expression, ceramide synthesis and activates mitochondrial apoptotic pathways [13,15,[26][27][28]. In contrast, the monounsaturated palmitoleic acid (C16:1) promotes β-cell proliferation at low glucose concentrations, improves β-cell function and counteracts the negative effects of palmitic acid [27].…”

“…This fatty acid affects glucose-induced insulin gene expression, ceramide synthesis and activates mitochondrial apoptotic pathways [13,15,[26][27][28]. In contrast, the monounsaturated palmitoleic acid (C16:1) promotes β-cell proliferation at low glucose concentrations, improves β-cell function and counteracts the negative effects of palmitic acid [27]. Along the same line, it has been shown that the saturated stearic acid (C18:0) has proapoptotic properties unlike equivalent concentrations of the polyunsaturated linoleic acid (C18:2n6c) [15,29].…”

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

“…Mouse islets were isolated by bile duct perfusion and collagenase digestion, as described elsewhere [16]. The islets were cultured on matrix-coated plates derived from bovine corneal endothelial cells (Novamed, Jerusalem, Israel), allowing the cells to attach to the dishes and spread [17].…”