Maedler K, Spinas G A, Dyntar D, Moritz W, Kaiser N, Donath M Y
Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland.
Diabetes. 2001 Jan;50(1):69-76. doi: 10.2337/diabetes.50.1.69.
Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function observed in type 2 diabetes. Here we examine the effect of saturated and unsaturated fatty acids at different glucose concentrations on beta-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 beta-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 beta-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 C2-ceramide mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on beta-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 beta-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 beta-cells and impaired insulin secretion. The deleterious effect of palmitate on beta-cell turnover is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid does not affect beta-cell apoptosis, yet it promotes beta-cell proliferation at low glucose concentrations, counteracting the negative effects of palmitic acid as well as improving beta-cell function.
糖毒性和脂毒性导致了2型糖尿病中观察到的β细胞功能受损。在此，我们研究了在不同葡萄糖浓度下饱和脂肪酸和不饱和脂肪酸对β细胞增殖和凋亡的影响。将成年大鼠胰岛培养在涂有源自牛角膜内皮细胞的细胞外基质的平板上。在含有5.5、11.1或33.3 mmol/L葡萄糖的培养基中，将胰岛暴露于饱和脂肪酸（0.5 mmol/L棕榈酸）4天，导致β细胞DNA片段化增加了5至9倍。相比之下，单独的单不饱和棕榈油酸（0.5 mmol/L）或与棕榈酸联合使用（各0.25或0.5 mmol/L）均不影响DNA片段化。葡萄糖浓度的增加促进了β细胞增殖，但棕榈酸使其显著降低。棕榈油酸增强了含有5.5 mmol/L葡萄糖的培养基中的增殖活性，但在较高葡萄糖浓度（11.1和33.3 mmol/L）下没有额外作用。可渗透细胞的神经酰胺类似物C2-神经酰胺模拟了棕榈酸诱导的β细胞凋亡和增殖减少。此外，神经酰胺合成酶抑制剂伏马菌素B1阻断了棕榈酸对β细胞活力的有害影响。此外，棕榈酸而非棕榈油酸降低了线粒体腺嘌呤核苷酸转运体的表达，并诱导细胞色素c从线粒体释放到细胞质中。最后，棕榈油酸改善了被棕榈酸降低的β细胞分泌功能。综上所述，这些结果表明饱和棕榈酸的脂毒性作用涉及β细胞凋亡率增加、增殖能力降低以及胰岛素分泌受损。棕榈酸盐对β细胞更新的有害作用是通过神经酰胺的形成和凋亡线粒体途径的激活介导的。相比之下，单不饱和棕榈油酸不影响β细胞凋亡，但在低葡萄糖浓度下促进β细胞增殖，抵消棕榈酸 的负面影响并改善β细胞功能。
