Effects of Fractalkine on Beta Cell Function

Fractalkine 对 β 细胞功能的影响

基本信息

批准号：
8813806
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/8813806
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 ChIP-seq Chimeric Proteins Chronic Couples Coupling Defect Development Diabetes Mellitus Diabetic mouse Diet Disease Epidemic Etiology Fatty acid glycerol esters Fractalkine Genes Glucose Glucose Intolerance Half-Life Health Human Hyperglycemia Hyperglycemic Mice In Vitro Insulin Insulin Resistance 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 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 β cell 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 β cells, 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 β cell lines, isolated islets and perfused islets, but it is without any effect when CX3CR1 is deleted from the β cells. This led to the conclusion that FKN is a novel potentiator of β cell insulin secretion. This proposal seeks to build on this newly identified FKN/CX3CR1 β 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 β cell "health". This is based on our current findings that FKN inhibits β cell apoptosis and stimulates the β 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 β cell 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（由适用提供）：在过去的几十年中，2型糖尿病的患病率在美国和全球范围内急剧上升，现在已经达到了流行比例。该疾病的病因既涉及胰岛素抵抗和β细胞功能的增加，并且通常需要两个缺陷（2个命中假设）才能发展出完整的高血糖糖尿病状态。当前的抗糖尿病治疗可用，但我们最近的工作导致了这样的发现，即通过通过其同源受体CX3CR1发出信号传导的β细胞中的分子碱（FKN）（CX3CL1），从而导致葡萄糖，精氨酸和GLP-1刺激胰岛素分泌增强，并在肥胖症和糖尿病小鼠模型中促进了胰岛素的分泌，并显着改善了葡萄糖。这是由于胰岛素分泌减少，CX3CR1 KO小鼠是葡萄糖不耐受的。此外，通过抗FKN抗体的给药中和循环FKN的中和导致WT小鼠中葡萄糖intlerance的胰岛素分泌突然降低。此外，体内FKN的给药会导致胰岛素分泌增加，并提高WT小鼠的葡萄糖耐量，但在CX3CR1 KO动物中完全没有影响。体外，FKN给药直接导致β细胞系，分离的胰岛和灌注胰岛，但是当从β细胞中删除CX3CR1时，它没有任何影响。这导致了一个结论，即FKN是β细胞胰岛素分泌的新型潜力。该建议旨在基于这种新确定的FKN/CX3CR1β细胞调节系统，以鉴定FKN诱导的胰岛素分泌的潜在细胞和分子机制。我们还将检验以下假设：在一系列高血糖小鼠模型中，长期FKN治疗将对葡萄糖代谢和胰岛素分泌具有有益作用。此外，我们将检验总体假设，即FKN将对β细胞“健康”产生有益的影响。这是基于我们目前的发现，即FKN抑制β细胞凋亡并刺激β细胞分化基因程序。最后，我们将测试以下假设：在LDLR KO小鼠模型中，体内施用FKN将抑制动脉粥样硬化的发展。如果拟议的实验支持将其纳入本应用的想法，那么这将强烈支持以下概念：基于FKN的生物疗法可以在体内给药，以在人类中潜在的葡萄糖刺激的胰岛素分泌。该理论策略可用于治疗2型糖尿病患者，以增强其对养分和其他刺激的秘密胰岛素的能力，并防止表征这种疾病的β细胞肿块下降。这将导致血糖控制的改善，从而在我们的治疗性武器库中增加一个新成分，以治疗这种宽度疾病。