Biohemistry Department, Medical School, Complutense University, 28040 Madrid, Spain.
Int J Mol Sci. 2024 May 31;25(11):6052. doi: 10.3390/ijms25116052.
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.
对不同实验条件下（如葡萄糖浓度变化、喂食或饥饿状态）胰岛中棕榈酸代谢的详细研究，使我们能够探讨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。棕榈酸以浓度依赖的方式增强葡萄糖诱导的胰岛素分泌，在棕榈酸（0-2 mM）和葡萄糖（6-20 mM）浓度的生理范围内；在葡萄糖浓度低于 6 mM 时，与棕榈酸没有明显的代谢相互作用。饥饿（48 小时）使胰岛棕榈酸氧化增加两倍，并且这种作用不受葡萄糖（6-20 mM）的抑制。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被棕榈酸增强。2-溴硬脂酸，一种棕榈酸氧化抑制剂，完全恢复了复合脂质的合成和胰岛素的分泌。我们得出结论，棕榈酸增强胰岛素对葡萄糖的反应不是归因于其代谢的线粒体氧化，而是归因于其合成复合脂质：胰岛脂质生物合成依赖于血浆脂肪酸的摄取和糖酵解中α-甘油磷酸的供应。胰岛胰高血糖素和生长抑素的分泌也表现出类似于胰岛素的对棕榈酸合成的依赖。对葡萄糖和棕榈酸之间代谢偶联所涉及的可能机制进行了评论。此外，还讨论了长期刺激胰岛素分泌后胰岛发生葡萄糖或脂毒性的可能机制。我们自己关于葡萄糖同时刺激胰岛素、胰高血糖素和生长抑素以及 2-溴硬脂酸在离体大鼠胰岛中的作用的数据，支持了这样的结论，即增加的 FFA 合成代谢而不是其线粒体氧化导致其刺激释放的增强。饥饿除了抑制葡萄糖刺激的胰岛素分泌外，还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，而不是葡萄糖的作用。总之，似乎存在三种胰高血糖素分泌刺激机制：1. 通过与胰岛素相同的分泌偶联机制刺激胰高血糖素分泌，但在不同的葡萄糖浓度范围（0 至 5 mM）。2. 葡萄糖刺激时，由于分泌的胰岛素而直接或间接抑制（5-20 mM）。3. 在高血糖、高血脂和低胰岛素血症的情况下，葡萄糖不耐受或糖尿病中 FFA 合成代谢增加的刺激。这些结论进行了讨论，并与文献中的先前发表数据进行了比较。特别是，我们讨论了葡萄糖抑制胰高血糖素释放的机制，这显然与胰高血糖素刺激的分泌偶联机制相矛盾。
