Department of Biomedical Engineering Posters and Presentations

Title

Low-Frequency, Low-Intensity Ultrasound as a Potential Treatment for Type 2 Diabetes

Document Type

Poster

Publication Date

4-2017

Abstract

OBJECTIVE: The objective of this study was to explore the safety and efficacy of a potential new treatment method that utilizes a non-invasive application of ultrasound energy to induce exocytosis of insulin from pancreatic beta cells. Amperometric measurements offer confirmation of secretion as well as data that could lead to optimization in controlling the release via ultrasound application. Finite-element modeling studies provide information regarding the thermal and mechanical effects of therapeutic ultrasound in the human abdomen.


METHODS: Initial experiments focused on detecting exocytotic secretions from pancreatic beta cells in response to ultrasound stimulation using carbon fiber amperometry. Neurotransmitters, specifically dopamine and its precursor L-DOPA, were loaded into secretory vesicles in beta cells and co-released with insulin. Cells were stimulated at 800 kHz and an intensity of 0.5 W/cm2 for 5 s, 10 s, and 15 s at various time intervals. Secretion of insulin was detected by proxy through the oxidation of these neurotransmitters using commercially available carbon fiber electrodes. A negative control group was included in which cells were not loaded with the dopamine and L-DOPA, however still exposed to ultrasound. Calcium dependence was evaluated by stimulating cells in the presence of an extracellular calcium chelator, EGTA. In parallel with these experiments, a finite-element modeling study to determine the safety of therapeutic levels of ultrasound to the human pancreas in vivo without adverse mechanical or thermal effects in the surrounding tissues.


RESULTS: Immediate secretory amperometric readings were recorded after application of ultrasound at the parameters described above. With the application of consecutive ultrasound pulses, a prolonged response was recorded for a prolonged stimulation. In experiments where Ca2+ dependence was explored, a statistically significant lower response was observed (p < 0.01). Consequently, the negative control group with unloaded cells did not produce an amperometric response. Ongoing work is focusing on finding the optimal acoustic windows for ultrasound applications in patients through simulations.


CONCLUSIONS: These results confirm that ultrasound stimulation induces secretory events in beta cells, and points towards a Ca2+ dependent process. Ongoing work is looking at the elucidation of mechanisms of ultrasound in the stimulation of insulin release and determining safety and effectiveness of this method in clinically relevant models including human pancreatic islets and in vivo diabetic rat model. Our proposed technology would directly target beta cell dysfunction, one of the underlying causes of insulin deficiency in Type 2 Diabetes, potentially resulting in a new therapeutic approach for the treatment of Type 2 Diabetes.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Open Access

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To be presented at GW Annual Research Days 2017.

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Low-Frequency, Low-Intensity Ultrasound as a Potential Treatment for Type 2 Diabetes

OBJECTIVE: The objective of this study was to explore the safety and efficacy of a potential new treatment method that utilizes a non-invasive application of ultrasound energy to induce exocytosis of insulin from pancreatic beta cells. Amperometric measurements offer confirmation of secretion as well as data that could lead to optimization in controlling the release via ultrasound application. Finite-element modeling studies provide information regarding the thermal and mechanical effects of therapeutic ultrasound in the human abdomen.


METHODS: Initial experiments focused on detecting exocytotic secretions from pancreatic beta cells in response to ultrasound stimulation using carbon fiber amperometry. Neurotransmitters, specifically dopamine and its precursor L-DOPA, were loaded into secretory vesicles in beta cells and co-released with insulin. Cells were stimulated at 800 kHz and an intensity of 0.5 W/cm2 for 5 s, 10 s, and 15 s at various time intervals. Secretion of insulin was detected by proxy through the oxidation of these neurotransmitters using commercially available carbon fiber electrodes. A negative control group was included in which cells were not loaded with the dopamine and L-DOPA, however still exposed to ultrasound. Calcium dependence was evaluated by stimulating cells in the presence of an extracellular calcium chelator, EGTA. In parallel with these experiments, a finite-element modeling study to determine the safety of therapeutic levels of ultrasound to the human pancreas in vivo without adverse mechanical or thermal effects in the surrounding tissues.


RESULTS: Immediate secretory amperometric readings were recorded after application of ultrasound at the parameters described above. With the application of consecutive ultrasound pulses, a prolonged response was recorded for a prolonged stimulation. In experiments where Ca2+ dependence was explored, a statistically significant lower response was observed (p < 0.01). Consequently, the negative control group with unloaded cells did not produce an amperometric response. Ongoing work is focusing on finding the optimal acoustic windows for ultrasound applications in patients through simulations.


CONCLUSIONS: These results confirm that ultrasound stimulation induces secretory events in beta cells, and points towards a Ca2+ dependent process. Ongoing work is looking at the elucidation of mechanisms of ultrasound in the stimulation of insulin release and determining safety and effectiveness of this method in clinically relevant models including human pancreatic islets and in vivo diabetic rat model. Our proposed technology would directly target beta cell dysfunction, one of the underlying causes of insulin deficiency in Type 2 Diabetes, potentially resulting in a new therapeutic approach for the treatment of Type 2 Diabetes.