Therapeutic ultrasound for stimulation of insulin release

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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.