Effects of Fractalkine on Beta Cell Function

Fractalkine 对 β 细胞功能的影响

基本信息

批准号：
9109627
负责人：
jerrold Michael OLEFSKY
金额：
$ 38.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109627
关键词：
Acute Affect Amino Acids Animals Antibodies Apoptosis Arginine Atherosclerosis Beta Cell Binding Biochemical Biological Response Modifier Therapy CX3CL1 gene Calcium Channel Cell Differentiation process Cell Line Cell physiology Cells ChIP-seq Chimeric Proteins Chronic Couples Coupling Defect Development Diabetes Mellitus Diabetic mouse Disease Epidemic Etiology Fractalkine Genes Glucose Glucose Intolerance Half-Life Health High Fat Diet Human Hyperglycemia Hyperglycemic Mice In Vitro Insulin Insulin Resistance Knockout Mice Lead MEKs Mediating Medical Methods Modality Molecular Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity Palmitates Palmitic Acids Pathway interactions Patients Physiological Potassium Prevalence Process Reagent Research Design Rodent Model Series Signal Transduction Specificity Stimulus System Testing Therapeutic United States Widespread Disease Work arrestin 1 base beta-arrestin diabetic disorder control feeding glucagon-like peptide 1 glucose metabolism glucose tolerance glycemic control improved in vivo insulin secretagogues insulin secretion insulin sensitivity islet man mortality mouse model novel novel strategies novel therapeutics prevent programs receptor research study response transcriptome sequencing

项目摘要

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.

描述（由申请人提供）：过去几十年来，2 型糖尿病的患病率在美国和全球急剧上升，目前已达到流行病的程度。这种疾病的病因涉及胰岛素抵抗和细胞功能下降。一个人通常需要两种缺陷（2击假说）才能形成完全的高血糖糖尿病状态，但目前的抗糖尿病疗法是可用的。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，我们最近的工作发现 Fractalkine (FKN) (CX3CL1) 仅通过信号传导发挥作用。其细胞中的同源受体 CX3CR1 会导致葡萄糖、精氨酸和 GLP-1 刺激胰岛素分泌增加，从而显着改善肥胖和糖尿病小鼠模型的葡萄糖耐量。 CX3CR1 KO 小鼠由于胰岛素分泌减少而出现葡萄糖不耐受。此外，通过施用抗 FKN 抗体中和循环 FKN 会导致 WT 小鼠胰岛素分泌突然减少，并伴有葡萄糖不耐受。此外，体内施用 FKN 会导致胰岛素增加在 WT 小鼠中，FKN 的分泌会改善葡萄糖耐量，但在 CX3CR1 KO 动物中完全没有影响。在体外，FKN 给药直接导致 b 细胞系、分离的胰岛和胰岛的胰岛素分泌增加。灌注胰岛，但当 CX3CR1 从细胞中删除时，它没有任何影响。这得出 FKN 是细胞胰岛素分泌的新型增强剂的结论。该提案旨在建立在这种新发现的 FKN/CX3CR1 b 细胞调节的基础上。我们还将测试长期 FKN 治疗将对葡萄糖代谢和胰岛素分泌产生有益影响的假设。此外，我们将测试 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 抑制细胞凋亡并刺激 b 细胞分化基因程序。最后，我们将测试另一个假设，即体内施用 FKN 将强烈抑制 LDLR KO 小鼠模型中动脉粥样硬化的发展，如果纳入本申请的想法得到所提出的实验的支持，那么这将支持 FKN 的概念。可以在体内施用基于葡萄糖的生物治疗剂以增强人体中葡萄糖刺激的胰岛素分泌，这种治疗策略可以用于治疗2型糖尿病患者以增强他们响应营养物质分泌胰岛素的能力。和其他刺激，并防止这种疾病所特有的体重下降，这将改善血糖控制，为我们治疗这种广泛疾病的治疗装备添加新的成分。