The Role of Ceramides in the Pancreatic Beta Cell

总结 该提案探讨了神经酰胺等鞘脂作为常见的细胞自主 2型糖尿病是一种常见的糖尿病类型，也是2型糖尿病的一种常见类型。这个想法 是基于本文提供的数据预测的，这些数据显示， 神经酰胺生物合成到啮齿类动物保存β细胞，并防止两种形式的发育， 疾病（即在Zucker糖尿病肥胖大鼠以及非肥胖糖尿病小鼠中）。该理论得到进一步支持 通过对人类和小鼠胰岛的研究，发现神经酰胺是连接饱和脂肪酸和 炎症细胞因子对胰岛素分泌、线粒体功能和β细胞存活的损害。我们 我将通过以下方式评估神经酰胺及其代谢物在胰岛中的假设作用 目的： ·首先，我们将研究允许有条件的β细胞特异性基因调节的新小鼠模型。 参与神经酰胺的合成或降解，使我们能够确定脂质是否是（a） 必要或（B）足以导致β细胞衰竭和明显高血糖症的发作。 ·第二，我们将测试一类新的神经酰胺合成抑制剂的疗效， 去饱和酶-1作为改善胰岛素分泌和预防1型或2型糖尿病治疗剂， 啮齿动物 ·第三，我们将确定神经酰胺损害小鼠功能的机制， 人类的小岛我们将测试神经酰胺作为代谢重编程驱动因素的假设作用， 最先进的代谢追踪、线粒体表型分析和细胞功能测定。 从这些研究中获得的发现可以揭示新的营养感应和/或炎症机制， 调节胰岛功能、存活和生长。此外，这项工作的翻译部分可能导致 开发用于预防或治疗糖尿病的新的治疗替代品。

SUMMARY This proposal explores the hypothesis that sphingolipids such as ceramides serve as common, cell-autonomous signals that impair beta cell function and contribute to the development of type 1 and type 2 diabetes. The idea is predicated upon data presented herein showing that the administration of a pharmacological inhibitor of ceramide biosynthesis to rodents preserves the beta cell and prevents the development of both forms of the disease (i.e. in Zucker Diabetic Fatty rats as well as Non-Obese Diabetic mice). The theory is further supported by studies in human and mouse islets implicating ceramides as intermediates linking saturated fatty acids and inflammatory cytokines to the impairment of insulin secretion, mitochondrial function, and beta cell survival. We will evaluate this hypothesized role for ceramides and its metabolites in the pancreatic islet through the following aims: · First, we will study new mouse models allowing for the conditional, beta cell-specific modulation of genes involved in ceramide synthesis or degradation, allowing us to determine whether the lipids are either (a) necessary or (b) sufficient for beta cell failure and the onset of frank hyperglycemia. · Second, we will test the efficacy of a new class of ceramide synthesis inhibitors targeting dihydroceramide desaturase-1 as therapeutics that improve insulin secretion and prevent type 1 or type 2 diabetes in rodents. · Third, we will determine the mechanisms through which ceramides impair the function of mouse and human islets. We will test a hypothesized role for ceramides as drivers of metabolic reprogramming using state-of-the-art metabolic tracing, mitochondrial phenotyping, and cell function assays. Findings obtained from these studies could uncover new nutrient-sensing and/or inflammatory mechanisms that modulate islet function, survival and growth. Moreover, the translational component of this work could lead to the development of new therapeutic alternatives for preventing or treating diabetes.