The role of sphingolipids in insulin signal transduction

多肽激素胰岛素刺激骨骼肌对葡萄糖的摄取和储存，同时抑制葡萄糖从肝脏流出。在某些病理情况下，最明显的是II型糖尿病，这些组织会对胰岛素的作用产生抵抗力，导致葡萄糖稳态的异常。确定将胰岛素到达细胞表面与其众多生理反应联系起来的信号转导事件对于全面了解胰岛素抵抗的发展至关重要。膜脂已成为激素作用的重要调节因子。例如，PI3-激酶的磷脂酰肌醇产物对胰岛素的合成代谢作用至关重要。相反，在糖尿病组织中升高的神经鞘磷脂衍生物神经酰胺，通过阻止PI3-激酶激活下游信号分子来对抗胰岛素刺激的葡萄糖摄取。此外，与糖尿病发病有关的循环因素，如游离脂肪酸或肿瘤坏死因子-α，促进神经酰胺的生物合成，表明神经酰胺的异常积聚可能有助于胰岛素抵抗的发展。有趣的是，我们实验室获得的初步数据表明，另一种鞘氨醇1-磷酸可能阻止神经酰胺对胰岛素信号的影响。该项目将评估神经酰胺和1-磷酸鞘氨醇调节胰岛素作用的分子机制。首先，我们将测试神经酰胺调节PI3-激酶依赖信号的几种假想机制。其次，我们将评估1-磷酸鞘氨醇作为神经酰胺信号的拮抗剂和正常胰岛素作用的正向调节剂的有效性。所获得的结果，除了提供对鞘磷脂对基础激素信号转导的贡献的洞察外，还可能对我们对II型糖尿病的理解和治疗具有重要的意义。

The peptide hormone insulin stimulates glucose uptake and storage in skeletal muscle while simultaneously inhibiting glucose efflux from the liver. In certain pathological conditions, most notably type II diabetes mellitus, these tissues become resistant to insulin's effects, leading to abnormalities in glucose homeostasis. Determining the signal transduction events that link insulin's arrival at the cell surface to its numerous physiological responses is critical for a complete understanding of the development of insulin resistance. Membrane lipids have emerged as important regulators of hormone action. For example, phosphoinositide products of PI3-kinase are critical for the anabolic effects of insulin. Conversely, the sphingomyelin derivative ceramide, which is elevated in diabetic tissues, antagonizes insulin-stimulation of glucose uptake by preventing PI3-kinase from activating downstream signaling molecules. Moreover, circulating factors implicated in diabetic onset, such as free fatty acids or tumor necrosis factor-alpha, promote ceramide biosynthesis, suggesting that aberrant ceramide accumulation might contribute to the development of insulin resistance. Interestingly, preliminary data obtained in our laboratory indicate that another sphingolipid, sphingosine 1- phosphate, may prevent the ceramide effect on insulin signaling. The project proposed herein will evaluate the molecular mechanisms underlying ceramide and sphingosine 1-phosphate regulation of insulin action. First, we will test several hypothetical mechanisms by which ceramide regulates PI3-kinase dependent signaling. Second, we will evaluate the effectiveness of sphingosine 1-phosphate as both an antagonist of ceramide signaling and a positive regulator of normal insulin action. Results obtained, in addition to providing insight into the contribution of sphingolipids to basic hormonal signal transduction, could have significant implications on our understanding and treatment of type II diabetes mellitus.