Effects of Fractalkine on Beta Cell Function

描述（由申请人提供）：在过去的几十年里，2型糖尿病的患病率在美国和全球范围内急剧上升，现在已经达到流行病的程度。这种疾病的病因涉及胰岛素抵抗和细胞功能下降，并且通常需要这两种缺陷（2击假说）才能发展为完全的高血糖糖尿病状态。目前的抗糖尿病疗法是可用的，但 不足以控制大多数患者的疾病，并且对于治疗糖尿病以预防发病率和死亡率的更好方法存在大量未满足的医疗需求。我们最近的研究发现，Fractalkine（FKN）（CX 3CL 1）仅通过其同源受体CX 3CR 1在细胞中的信号传导起作用，导致葡萄糖，精氨酸和GLP-1刺激胰岛素分泌增强，并显着改善肥胖和糖尿病小鼠模型的葡萄糖耐量。因此，CX 3CR 1 KO小鼠由于胰岛素分泌减少而葡萄糖不耐受。此外，在WT小鼠中，通过施用抗FKN抗体中和循环FKN导致胰岛素分泌突然减少，伴有葡萄糖耐受不良。此外，体内FKN给药导致WT小鼠胰岛素分泌增加，葡萄糖耐量改善，但在CX 3CR 1 KO动物中完全没有影响。在体外，FKN给药直接导致B细胞系、分离的胰岛和胰岛细胞中胰岛素分泌增加。 CX 3CR 1基因缺失对胰岛细胞的增殖无明显影响。这导致了FKN是一种新型的细胞胰岛素分泌增强剂的结论。本研究试图建立在新发现的FKN/CX 3CR 1 B细胞调节系统的基础上，以确定FKN诱导胰岛素分泌的细胞和分子机制。我们还将在一系列高血糖小鼠模型中检验长期FKN治疗对葡萄糖代谢和胰岛素分泌有益的假设。此外，我们将测试的总体假设，即FKN将有有益的影响B细胞的“健康”。这是基于我们目前的发现，FKN抑制细胞凋亡和刺激B细胞分化基因程序。 最后，我们将检验另外的假设，即体内给予FKN将抑制LDLR KO小鼠模型中动脉粥样硬化的发展。如果结合到本申请中的想法得到所提出的实验的支持，那么这将强烈支持FKN-的概念在人体内给予基于生物素的胰岛素可增强葡萄糖刺激的胰岛素分泌。这种治疗策略可用于治疗2型糖尿病患者，以增强他们响应营养素和其他刺激而分泌胰岛素的能力，并预防糖尿病的发生。这种疾病的特征是细胞质量的下降。这将导致改善血糖控制，在我们的治疗设备中添加一个新的组件来治疗这种广泛的疾病。

DESCRIPTION (provided by applicant): The prevalence of Type 2 diabetes has risen dramatically in the United States and globally for the past few decades and has now reached epidemic proportions. The etiology of this disease involves both insulin resistance and decreased �ell function, and one typically needs both defects (2 hit hypothesis) in order to develop the full hyperglycemic diabetic state. Current anti-diabetic therapeutics is available, but is inadequate to control the disease in most patients and there is a large unmet medical need for better methods of treating diabetes to prevent morbidity and mortality. Our recent work has led to the discovery that Fractalkine (FKN) (CX3CL1) working exclusively by signaling through its cognate receptor CX3CR1 in �ells, leads to enhanced glucose, arginine, and GLP-1 stimulated insulin secretion with markedly improved glucose tolerance in obese and diabetic mouse models. Thus, CX3CR1 KO mice are glucose intolerant due to decreased insulin secretion. Furthermore, neutralization of circulating FKN by administration of anti-FKN antibodies leads to an abrupt decrease in insulin secretion with glucose intolerance in WT mice. Furthermore, in vivo FKN administration leads to increased insulin secretion with improved glucose tolerance in WT mice, but is completely without effect in CX3CR1 KO animals. In vitro, FKN administration directly causes increased insulin secretion in b cell lines, isolated islets and perfused islets, but it is without any effect when CX3CR1 is deleted from the �ells. This led to the conclusion that FKN is a novel potentiator of �ell insulin secretion. This proposal seeks to build on this newly identified FKN/CX3CR1 b cell regulatory system to identify the underlying cellular and molecular mechanisms of FKN-induced insulin secretion. We will also test the hypothesis that long-term FKN treatment will have beneficial effects on glucose metabolism and insulin secretion in a series of hyperglycemic mouse models. In addition, we will test the overall hypothesis that FKN will have beneficial effects on b cell "health". This is based on our current findings that FKN inhibits �ell apoptosis and stimulates the b cell differentiation gene program. Finally, we will test the additional hypothesis that FKN administration in vivo will inhibit the development of atherosclerosis in the LDLR KO mouse model. If the ideas incorporated into this application are supported by the proposed experiments, then this would strongly support the concept that a FKN-based biotherapeutic could be administered in vivo to potentiate glucose stimulated insulin secretion in man. This therapeutic strategy could be used for the treatment of patients with Type 2 diabetes mellitus to augment their ability to secrete insulin in response to nutrients and other stimuli and to prevent the decline in �ell mass which characterizes this disease. This would lead to improved glycemic control adding a new component in our therapeutic armamentarium for the treatment of this widespread disease.