Therapeutic ultrasound for stimulation of insulin release

刺激胰岛素释放的治疗性超声

基本信息

批准号：
10404062
负责人：
Vesna Zderic
金额：
$ 49.11万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404062
关键词：
Acinar Cell Acute Amputation Animals Apoptotic Beta Cell Biological Biological Assay Blindness Blood Glucose CASP3 gene Calcium Calcium Channel Cell Survival Cell physiology Cells Cessation of life Chelating Agents Chronic Clinical Trials Complex Defect Development Diabetes Mellitus Diabetic mouse Disease Dose Dyes Effectiveness Egtazic Acid End stage renal failure Endocrine Endocrine System Diseases Epidemic Exclusion Exocrine pancreas Exposure to Failure Fluorescence Formulation Frequencies Functional disorder Future Gastrointestinal Hormones Gene Activation Gene Expression Genes Genetic Genetic Transcription Glucagon Glucose Hormones Human Hyperglycemia Hypoglycemia Image In Situ In Vitro Injections Insulin Islet Cell Islets of Langerhans Longitudinal Studies Mediating Medication Management Metabolic Metabolic Diseases Methods Microscopy Modeling Non-Insulin-Dependent Diabetes Mellitus Oral Pancreas Pancreatic Hormones Patients Peripheral Permeability Persons Pharmaceutical Preparations Pharmacology Physiological Prediabetes syndrome Prevalence Property Publishing Rattus Research Methodology Risk Rodent Rodent Model Safety Sampling Severities Slice Source Structure of beta Cell of islet System Testing Therapeutic Therapeutic Effect Therapeutic Uses Time Tissues Transgenic Mice Trypan Blue Ultrasonic Therapy United States Visual impairment Weight Gain Western Blotting Work channel blockers clinical application clinically relevant combat cytotoxic diabetic effectiveness evaluation effectiveness study experimental study gastrointestinal hormone analog improved in vivo in vivo Model in vivo evaluation insulin secretagogues insulin secretion insulin sensitivity insulin sensitizing drugs interest islet islet amyloid polypeptide novel premature process repeatability promoter protein expression release of sequestered calcium ion into cytoplasm safety testing side effect ultrasound voltage

项目摘要

Abstract Type 2 diabetes mellitus is a complex metabolic disease that has reached epidemic proportions in the United States and around the world. The prevalence of type 2 diabetes in the United States is approximately 9.3%; worldwide, there are about 422 million cases, a number expected to increase by at least 50% in the next 20 years. Diabetes increases the risk of development of chronic complications resulting in premature death, vision impairment and blindness, end stage kidney disease and amputation. Type 2 diabetes results from the interplay of multiple metabolic abnormalities including decreased insulin sensitivity of peripheral tissues and insufficient insulin secretion from pancreatic beta cells. Controlling type 2 diabetes is often difficult as pharmacological management routinely requires complex therapy with multiple medications, and loses its effectiveness over time. Many classes of pharmacologic agents are now employed to control hyperglycemia in patients with type 2 diabetes including insulin sensitizers, insulin secretagogues, and gastrointestinal hormone analogues and modulators. However, pharmacological management is often associated with increased risks of hypoglycemia, weight gain, gastrointestinal side effects and other risks. Also, treatment with oral agents may become less effective over time as beta cell failure progresses. Therefore, many patients ultimately require insulin therapy. However, intensive therapy with insulin may require injections of multiple doses of different insulin formulations and is also associated with side effects including weight gain and hypoglycemia. Thus, there is a growing interest in finding alternative methods for the treatment of this disease. The objective of this proposal is to explore a novel, non-pharmacological approach that utilizes the application of ultrasound energy to improve insulin release from the pancreas. Our in vitro results have indicated that ultrasound can be used to achieve a significant increase in insulin release from pancreatic beta cells without loss in cell viability, and in a controllable and repeatable manner. Our recent preliminary in vivo results in a diabetic rodent model also confirm these findings. This ultrasound-induced insulin increase is within physiological range and similar to what would be achieved when pancreatic beta cells are exposed to glucose in a healthy person. We are now proposing to work on elucidation of mechanisms of ultrasound action in stimulation of insulin release, and determination of effectiveness and safety of this method in excised pancreas, human islets, and diabetic rodent models in vivo. Studies in Specific Aim 1 will study effectiveness and safety of ultrasound stimulation on transcription and expression of beta cell specific genes and release of islet hormones in an ex vivo rat pancreas slice model. In Specific Aim 2, we will continue to study impact of ultrasound stimulation on endocrine genes activation and hormones turnover in acute human pancreatic islets. In Specific Aim 3, we will test the safety and effectiveness of ultrasound application in animal diabetic models in long-term longitudinal studies. If shown successful, our approach may open new strategies to combat type 2 diabetes.

抽象的 2 型糖尿病是一种复杂的代谢性疾病，在美国已达到流行病的程度各国和世界各地。在美国，2 型糖尿病的患病率约为 9.3%；全球范围内约有 4.22 亿例病例，预计未来 20 年这一数字将增加至少 50% 年。糖尿病会增加出现慢性并发症的风险，导致过早死亡、视力下降损伤和失明、终末期肾病和截肢。 2 型糖尿病是相互作用的结果多种代谢异常，包括外周组织胰岛素敏感性降低和胰岛素不足胰腺β细胞分泌胰岛素。控制 2 型糖尿病通常很困难，因为药物管理通常需要使用多种药物进行复杂的治疗，并且随着时间的推移而失去其有效性。现在使用多种药物来控制 2 型患者的高血糖糖尿病，包括胰岛素增敏剂、胰岛素促分泌剂和胃肠激素类似物，以及调制器。然而，药物管理通常与低血糖风险增加相关，体重增加、胃肠道副作用和其他风险。此外，口服药物治疗可能会减少随着 β 细胞衰竭的进展，它会随着时间的推移而有效。因此，许多患者最终需要胰岛素治疗。然而，胰岛素强化治疗可能需要注射多剂量的不同胰岛素制剂并且还与体重增加和低血糖等副作用有关。因此，人们的兴趣越来越浓厚寻找治疗这种疾病的替代方法。该提案的目的是探索一种新颖的非药物方法，利用超声波能量的应用来改善胰岛素从胰腺释放。我们的体外结果表明超声波可用于实现胰腺β细胞释放的胰岛素显着增加，且不损失细胞活力，且可控和可重复的方式。我们最近在糖尿病啮齿动物模型中的初步体内结果也证实了这些发现。这种超声波引起的胰岛素增加在生理范围内，类似于当健康人的胰腺β细胞暴露于葡萄糖时即可实现。我们现在提议致力于阐明超声波刺激胰岛素释放的作用机制，并确定该方法在离体胰腺、人类胰岛和糖尿病啮齿动物体内模型中的有效性和安全性。具体目标 1 的研究将研究超声刺激对转录和转录的有效性和安全性。在离体大鼠胰腺切片模型中β细胞特异性基因的表达和胰岛激素的释放。在具体目标2，我们将继续研究超声刺激对内分泌基因激活的影响和急性人类胰岛中的激素更新。在具体目标3中，我们将测试安全性和有效性长期纵向研究中超声在动物糖尿病模型中的应用。如果显示成功，我们的这种方法可能会开辟对抗 2 型糖尿病的新策略。