Therapeutic ultrasound for stimulation of insulin release

摘要 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比例。 国家和世界各地。美国2型糖尿病的患病率约为9.3%; 全世界约有4.22亿例，预计在未来20年内，这一数字将至少增加50%。 年糖尿病增加了慢性并发症的风险，导致过早死亡，视力 损伤和失明、终末期肾病和截肢。2型糖尿病是由 多种代谢异常，包括外周组织胰岛素敏感性降低和 胰腺β细胞分泌胰岛素。控制2型糖尿病通常很难， 管理常规地需要使用多种药物的复杂治疗，并且随着时间的推移而失去其有效性。 许多类型的药物现在被用来控制2型糖尿病患者的高血糖症 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， 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不同的胰岛素制剂 并且还与包括体重增加和低血糖的副作用有关。因此，越来越多的人 寻找治疗这种疾病的替代方法。本建议的目的是探讨一个 一种新的非药物方法，利用超声能量的应用， 胰岛素从胰腺中释放出来。我们的体外实验结果表明，超声波可以用来实现 胰腺β细胞的胰岛素释放显著增加，而细胞活力没有损失，并且在可控制的 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 调查结果。这种超声波诱导的胰岛素增加在生理范围内，并且类似于 当胰腺β细胞暴露于健康人的葡萄糖时，我们现时建议 致力于阐明超声波刺激胰岛素释放的作用机制，并测定 该方法在体内切除的胰腺、人胰岛和糖尿病啮齿动物模型中的有效性和安全性。 特定目标1中的研究将研究超声刺激对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， 急性人胰岛激素周转。在具体目标3中，我们将测试安全性和有效性 超声在糖尿病动物模型中的长期纵向研究。如果成功，我们 这种方法可能会开辟新的战略，以打击2型糖尿病。

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.