PDF(Pubmed)
Abstract：
A detailed study of palmitate metabolism in pancreatic islets subject to different experimental conditions, like varying concentrations of glucose, as well as fed or starved conditions, has allowed us to explore the interaction between the two main plasma nutrients and its consequences on hormone secretion. Palmitate potentiates glucose-induced insulin secretion in a concentration-dependent manner, in a physiological range of both palmitate (0-2 mM) and glucose (6-20 mM) concentrations; at glucose concentrations lower than 6 mM, no metabolic interaction with palmitate was apparent. Starvation (48 h) increased islet palmitate oxidation two-fold, and the effect was resistant to its inhibition by glucose (6-20 mM). Consequently, labelled palmitate and glucose incorporation into complex lipids were strongly suppressed, as well as glucose-induced insulin secretion and its potentiation by palmitate. 2-bromostearate, a palmitate oxidation inhibitor, fully recovered the synthesis of complex lipids and insulin secretion. We concluded that palmitate potentiation of the insulin response to glucose is not attributable to its catabolic mitochondrial oxidation but to its anabolism to complex lipids: islet lipid biosynthesis is dependent on the uptake of plasma fatty acids and the supply of α-glycerol phosphate from glycolysis. Islet secretion of glucagon and somatostatin showed a similar dependence on palmitate anabolism as insulin. The possible mechanisms implicated in the metabolic coupling between glucose and palmitate were commented on. Moreover, possible mechanisms responsible for islet gluco- or lipotoxicity after a long-term stimulation of insulin secretion were also discussed. Our own data on the simultaneous stimulation of insulin, glucagon, and somatostatin by glucose, as well as their modification by 2-bromostearate in perifused rat islets, give support to the conclusion that increased FFA anabolism, rather than its mitochondrial oxidation, results in a potentiation of their stimulated release. Starvation, besides suppressing glucose stimulation of insulin secretion, also blocks the inhibitory effect of glucose on glucagon secretion: this suggests that glucagon inhibition might be an indirect or direct effect of insulin, but not of glucose. In summary, there seems to exist three mechanisms of glucagon secretion stimulation: 1. glucagon stimulation through the same secretion coupling mechanism as insulin, but in a different range of glucose concentrations (0 to 5 mM). 2. Direct or indirect inhibition by secreted insulin in response to glucose (5-20 mM). 3. Stimulation by increased FFA anabolism in glucose intolerance or diabetes in the context of hyperlipidemia, hyperglycemia, and hypo-insulinemia. These conclusions were discussed and compared with previous published data in the literature. Specially, we discussed the mechanism for inhibition of glucagon release by glucose, which was apparently contradictory with the secretion coupling mechanism of its stimulation.
摘要：
在不同实验条件下胰岛中棕榈酸代谢的详细研究，比如不同浓度的葡萄糖，以及进食或饥饿的条件，使我们能够探索两种主要血浆营养素之间的相互作用及其对激素分泌的影响。棕榈酸盐以浓度依赖性方式增强葡萄糖诱导的胰岛素分泌，在棕榈酸盐（0-2mM）和葡萄糖（6-20mM）浓度的生理范围内；在葡萄糖浓度低于6mM时，与棕榈酸盐没有明显的代谢相互作用。饥饿（48小时）使胰岛棕榈酸酯氧化增加两倍，并且效果对葡萄糖（6-20mM）的抑制作用具有抵抗力。因此,标记的棕榈酸和葡萄糖掺入复合脂质受到强烈抑制，以及葡萄糖诱导的胰岛素分泌及其棕榈酸酯的增强作用。2-溴硬脂酸酯，一种棕榈酸氧化抑制剂,完全恢复了复杂脂质的合成和胰岛素的分泌。我们得出的结论是，胰岛素对葡萄糖的反应的棕榈酸增强作用不是归因于其分解代谢的线粒体氧化，而是归因于其对复杂脂质的合成代谢：胰岛脂质的生物合成取决于血浆脂肪酸的摄取和来自糖酵解的α-甘油磷酸的供应。胰高血糖素和生长抑素的胰岛分泌对棕榈酸合成代谢的依赖性与胰岛素相似。评论了葡萄糖和棕榈酸之间代谢偶联的可能机制。此外，还讨论了长期刺激胰岛素分泌后导致胰岛葡萄糖或脂毒性的可能机制。我们自己的同时刺激胰岛素的数据，胰高血糖素,和葡萄糖的生长抑素，以及在融合的大鼠胰岛中通过2-溴硬脂酸酯修饰，支持FFA合成代谢增加的结论，而不是它的线粒体氧化，导致其刺激释放的增强。饥饿,除了抑制胰岛素分泌的葡萄糖刺激，也阻断了葡萄糖对胰高血糖素分泌的抑制作用：这表明胰高血糖素抑制可能是胰岛素的间接或直接作用，但不是葡萄糖。总之,胰高血糖素分泌刺激的机制有三种:1.通过与胰岛素相同的分泌偶联机制刺激胰高血糖素，但在不同范围的葡萄糖浓度（0至5mM）。2.分泌的胰岛素对葡萄糖(5-20mM)的直接或间接抑制。3.在高脂血症的情况下，糖耐量不耐受或糖尿病中FFA合成代谢增加的刺激，高血糖症,和低胰岛素血症.对这些结论进行了讨论，并与文献中先前发表的数据进行了比较。特别是,我们讨论了葡萄糖抑制胰高血糖素释放的机制，这显然与其刺激的分泌偶联机制相矛盾。
