Haber Esther P, Procópio Joaquim, Carvalho Carla R O, Carpinelli Angelo R, Newsholme Philip, Curi Rui
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Int Rev Cytol. 2006;248:1-41. doi: 10.1016/S0074-7696(06)48001-3.
Insulin resistance states as found in type 2 diabetes and obesity are frequently associated with hyperlipidemia. Both stimulatory and detrimental effects of free fatty acids (FFA) on pancreatic beta cells have long been recognized. Acute exposure of the pancreatic beta cell to both high glucose concentrations and saturated FFA results in a substantial increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release but palmitate can augment insulin release in the presence of nonstimulatory concentrations of glucose. These results imply that changes in physiological plasma levels of FFA are important for regulation of beta-cell function. Although it is widely accepted that fatty acid (FA) metabolism (notably FA synthesis and/or formation of LC-acyl-CoA) is necessary for stimulation of insulin secretion, the key regulatory molecular mechanisms controlling the interplay between glucose and fatty acid metabolism and thus insulin secretion are not well understood but are now described in detail in this review. Indeed the correct control of switching between FA synthesis or oxidation may have critical implications for beta-cell function and integrity both in vivo and in vitro. LC-acyl-CoA (formed from either endogenously synthesized or exogenous FA) controls several aspects of beta-cell function including activation of certain types of PKC, modulation of ion channels, protein acylation, ceramide- and/or NO-mediated apoptosis, and binding to and activating nuclear transcriptional factors. The present review also describes the possible effects of FAs on insulin signaling. We have previously reported that acute exposure of islets to palmitate up-regulates some key components of the intracellular insulin signaling pathway in pancreatic islets. Another aspect considered in this review is the potential source of fatty acids for pancreatic islets in addition to supply in the blood. Lipids can be transferred from leukocytes (macrophages) to pancreatic islets in coculture. This latter process may provide an additional source of FAs that may play a significant role in the regulation of insulin secretion.
2型糖尿病和肥胖症中出现的胰岛素抵抗状态常与高脂血症相关。游离脂肪酸（FFA）对胰腺β细胞的刺激作用和有害作用早已为人所知。胰腺β细胞急性暴露于高葡萄糖浓度和饱和FFA会导致胰岛素释放大幅增加，而长期暴露则会导致脱敏和分泌抑制。禁食大鼠或人类血浆FFA水平降低会严重损害葡萄糖诱导的胰岛素释放，但在非刺激浓度的葡萄糖存在下，棕榈酸酯可增强胰岛素释放。这些结果表明，生理血浆FFA水平的变化对β细胞功能的调节很重要。尽管人们普遍认为脂肪酸（FA）代谢（特别是FA合成和/或LC-酰基辅酶A的形成）是刺激胰岛素分泌所必需的，但控制葡萄糖和脂肪酸代谢之间相互作用从而调节胰岛素分泌的关键调节分子机制尚未完全了解，本文将对此进行详细描述。事实上，正确控制FA合成或氧化之间的转换可能对体内和体外β细胞的功能和完整性具有关键意义。LC-酰基辅酶A（由内源性合成或外源性FA形成）控制β细胞功能的多个方面，包括某些类型PKC的激活、离子通道的调节、蛋白质酰化、神经酰胺和/或NO介导的细胞凋亡，以及与核转录因子的结合和激活。本文还描述了FA对胰岛素信号传导的可能影响。我们之前报道过，胰岛急性暴露于棕榈酸酯会上调胰腺胰岛细胞内胰岛素信号通路的一些关键成分。本文考虑的另一个方面是除血液供应外，胰腺胰岛脂肪酸的潜在来源。在共培养中，脂质可以从白细胞（巨噬细胞）转移到胰腺胰岛。后一过程可能提供了FA的额外来源，这可能在胰岛素分泌的调节中发挥重要作用。
