The role of sphingolipids in insulin signal transduction

肽激素胰岛素刺激骨骼肌中的葡萄糖摄取和储存，同时抑制葡萄糖从肝脏流出。 在某些病理条件下，最明显的是II型糖尿病，这些组织变得对胰岛素的作用有抗性，导致葡萄糖稳态异常。 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完整理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剂。 例如，PI 3-激酶的磷酸肌醇产物对于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鞘磷脂衍生物神经酰胺通过阻止PI 3-激酶激活下游信号分子来拮抗葡萄糖摄取的胰岛素刺激。 此外，与糖尿病发病有关的循环因子，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，这表明异常的神经酰胺积累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，另一种鞘脂，鞘氨醇1-磷酸，可能会阻止神经酰胺对胰岛素信号的影响。本文提出的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PI 3激酶依赖性信号传导的几种假设机制。 其次，我们将评估1-磷酸鞘氨醇作为神经酰胺信号传导拮抗剂和正常胰岛素作用正调节剂的有效性。所获得的结果，除了提供洞察的贡献鞘脂的基本激素信号转导，可能有显着的影响，我们的理解和治疗II型糖尿病。

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.