Effects of Fractalkine on Beta Cell Function

描述(由申请人提供)：在过去的几十年里，2型糖尿病在美国和全球的患病率急剧上升，现在已经达到流行的程度。这种疾病的病因涉及胰岛素抵抗和�细胞功能降低，通常需要这两种缺陷(两次击打假说)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 在大多数患者中，糖尿病的治疗不足以控制疾病，而且有大量未得到满足的医疗需求，需要更好的治疗糖尿病的方法，以防止发病率和死亡率。我们最近的工作发现，Fractalkine(FKN)(CX3CL1)仅通过其同源受体CX3CR1在�细胞中发挥作用，导致肥胖和糖尿病小鼠模型中葡萄糖、精氨酸和GLP-1刺激的胰岛素分泌增加，并显著改善糖耐量。因此，CX3CR1 KO小鼠由于胰岛素分泌减少而出现糖耐量异常。此外，通过注射抗FKN抗体中和循环FKN会导致WT小鼠出现葡萄糖耐量异常时胰岛素分泌突然减少。此外，体内注射FKN可导致WT小鼠胰岛素分泌增加并改善糖耐量，但对CX3CR1 KO动物则完全无效。在体外，FKN直接导致b细胞系、分离的胰岛和 灌流胰岛，但当CX3CR1从�细胞中删除时不起任何作用。由此得出结论，FKN是一种新的�细胞胰岛素分泌增强剂。这项建议试图建立在这个新发现的FKN/CX3CR1 b细胞调控系统的基础上，以确定FKN诱导胰岛素分泌的潜在细胞和分子机制。我们还将在一系列高血糖小鼠模型中测试长期服用FKN将对葡萄糖代谢和胰岛素分泌产生有益影响的假设。此外，我们还将检验FKN对b细胞健康有益的总体假设。这是基于我们目前的发现，即fkn抑制�细胞的凋亡并刺激b细胞分化基因程序。 最后，我们将检验额外的假设，即体内给药FKN将抑制LDLR KO小鼠模型的动脉粥样硬化的发展。如果结合到这项申请中的想法得到了拟议实验的支持，那么这将有力地支持基于FKN的生物疗法可以在体内实施以增强葡萄糖刺激的人类胰岛素分泌的概念。这一治疗策略可用于2型糖尿病患者的治疗，以增强他们对营养物质和其他刺激的反应而分泌胰岛素的能力，并防止本病特征的�细胞质量下降。这将导致改善血糖控制，在我们的治疗设备中增加一个新的成分，用于治疗这种广泛传播的疾病。

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.