The role of sphingolipids in insulin signal transduction

描述（由申请人提供）：肽激素胰岛素刺激葡萄糖和其他营养物质的摄取和储存进入脂肪组织和骨骼肌，同时抑制葡萄糖从肝脏流出。当正常剂量的激素不能引起这些合成代谢反应时，就会发生胰岛素抵抗，并且这种情况是2型糖尿病发病机制的主要因素。大量研究表明，这些外周组织的脂质过量供应有助于胰岛素抵抗的发展，可能是通过促进能够抑制胰岛素作用的脂肪衍生代谢物的积累。已显示鞘脂神经酰胺在胰岛素抵抗组织中蓄积并抑制分离细胞中的胰岛素信号传导。此外，我们最近发现，内源性神经酰胺是一个足够的和必要的中间连接饱和游离脂肪酸抑制胰岛素信号在培养的肌管。本文描述的研究将调查神经酰胺对啮齿动物胰岛素抵抗发展的贡献。首先，使用各种策略来调节啮齿动物中的神经酰胺水平，包括药理学抑制剂和一种无法在大多数组织中产生神经酰胺的新型敲除小鼠，我们将确定鞘脂在胰岛素抵抗发展中的定量影响。其次，我们将研究神经酰胺对胰岛素作用的拮抗作用的分子机制。第三，我们将研究控制神经酰胺积累的调节机制。从这些实验中获得的信息可以提出治疗胰岛素抵抗和2型糖尿病的新治疗策略。

DESCRIPTION (provided by applicant): The peptide hormone insulin stimulates the uptake and storage of glucose and other nutrients into adipose tissue and skeletal muscle while simultaneously repressing glucose efflux from the liver. Insulin resistance occurs when a normal dose of the hormone is incapable of eliciting these anabolic responses, and the condition is a major contributor to the pathogenesis of type 2 diabetes. Numerous studies suggest that lipid oversupply to these peripheral tissues contributes to the development of insulin resistance, perhaps by promoting the accumulation of fat-derived metabolites capable of inhibiting insulin action. The sphingolipid ceramide has been shown to accumulate in insulin resistant tissues and to inhibit insulin signaling in isolated cells. Moreover, we recently found that endogenous ceramide is both a sufficient and necessary intermediate linking saturated free fatty acids to the inhibition of insulin signaling in cultured myotubes. The studies desribed herein will investigate the contribution of ceramides to the development of insulin resistance in rodents. First, using various strategies to regulate ceramide levels in rodents, including pharmacological inhibitors and a novel knockout mouse that is incapable of making ceramide in most tissues, we will determine the quantitative impact of the sphingolipid in the development of insulin resistance. Second, we will investigate the molecular mechanisms accounting for the antagonistic effects of ceramide on insulin action. And third, we will investigate the regulatory mechanisms controlling ceramide accrual. Information garnered from these experiments could suggest novel therapeutic strategies in the treatment of insulin resistance and type 2 diabetes.