Role of endogenous lipids in the regulation of biphasic insulin secretion.

内源性脂质在双相胰岛素分泌调节中的作用。

• 批准号: RGPIN-2016-04145
• 负责人: Joseph, Jamie
• 金额: $ 2.4万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614869
• 关键词: Role; endogenous; lipids; regulation; biphasic

There are three sources of free fatty acids (FFA) 1) exogenously-derived FFAs, 2) endogenously-synthesized FFAs (de novo lipogenesis (DNL)) and 3) release from internal triglyceride stores. DNL occurs primarily in liver cells, however, many tissue types are able to produce limited amounts of lipid. The role of this small amount of DNL in these cell types is not completely understood. For example, insulin secreting cells of the pancreas express enzymes that lead to DNL in proportion to the amount of glucose exposure. This glucose driven DNL has been proposed to be important in generating metabolic signaling molecules important for regulating insulin exocytosis. It has also been suggested that glycerolipid (GL)/ FFA cycling from internal triglyceride stores may also play a role in the regulation of insulin release. Inhibition of this cycling suppresses FFA augmentation of glucose-stimulated insulin release. We have published results showing that the effects of manipulating four key enzymes (PC, CL, ACC and FAS) and three metabolic carriers (pyruvate carrier, citrate carrier and dicarboxylate carrier) that are involved in DNL lead to conflicting results for and against a role of DNL in regulating insulin exocytosis. We will continue to investigate the role of DNL in the regulation of glucose-stimulated insulin release using newly developed tools in the lab. We have also identified several glucose derived endogenous lipid species that may be critical for regulating biphasic insulin secretion using a metabolomics approach. A number of questions arise from these metabolomics studies for example what is the source of these glucose derived endogenous lipids (e.g. release from triglyceride (TG) stores or from DNL) and how might these lipids be involved in regulating biphasic insulin release. We will expand on these studies to further investigate the role of endogenous lipids in the regulation of biphasic insulin release. Hypothesis: Endogenous lipids generate signaling molecules that are critical to the metabolic regulation of biphasic insulin secretion. Experimental approach: We have identified several endogenous lipid species that may be critical for regulating biphasic insulin secretion using a metabolomics approach. We will use molecule cloning techniques, siRNAs and siRNA adenoviruses, metabolic assays, enzymatic assays, secretion assays, fluorescent imaging and metabolomics to measure metabolite profiles and metabolic fluxes in key endocrine models of fuel regulated secretion. The combination of these approaches will allow us to study all aspects of the metabolic regulation of biphasic insulin secretion by DNL. Novelty and significance: It is well known that exogenous lipids regulate insulin secretion but the role of endogenous is less well defined. These studies will provide invaluable insights towards understanding the unique role of lipids play in the regulation of exocytosis.

游离脂肪酸（FFA）有三种来源：1)外源性来源的FFA， 2)内源性合成的FFA（从头脂肪生成（DNL））和3)体内甘油三酯储存释放的FFA。DNL主要发生在肝细胞中，然而，许多组织类型能够产生有限数量的脂质。这少量的DNL在这些细胞类型中的作用尚不完全清楚。例如，胰腺的胰岛素分泌细胞表达导致DNL的酶与葡萄糖暴露量成正比。这种葡萄糖驱动的DNL在产生代谢信号分子中起重要作用，这些信号分子对调节胰岛素胞吐作用很重要。也有人认为甘油脂(GL)/ FFA循环从内部甘油三酯储存也可能发挥调节胰岛素释放的作用。这种循环的抑制抑制了FFA对葡萄糖刺激的胰岛素释放的增强。我们发表的研究结果表明，操纵DNL中涉及的四种关键酶（PC、CL、ACC和FAS）和三种代谢载体（丙酮酸载体、柠檬酸载体和二羧酸载体）的影响导致DNL在调节胰岛素胞吐作用中的作用相互矛盾。我们将在实验室中使用新开发的工具继续研究DNL在葡萄糖刺激胰岛素释放调节中的作用。我们还利用代谢组学方法确定了几种葡萄糖来源的内源性脂质，它们可能对调节双相胰岛素分泌至关重要。这些代谢组学研究产生了许多问题，例如，这些葡萄糖来源的内源性脂质是什么（例如，从甘油三酯（TG）储存或DNL释放）以及这些脂质如何参与调节双相胰岛素释放。我们将在这些研究的基础上进一步研究内源性脂质在调节双相胰岛素释放中的作用。