Abstract
This study demonstrates that pulsed focused ultrasound (pFUS) therapy can non-invasively enhance the function and engraftment of pancreatic islets following transplantation. In vitro, we show that islets treated with pFUS at low (peak negative pressure (PNP): 106kPa, spatial peak temporal peak intensity (Isptp): 0.71 W/cm2), medium (PNP: 150kPa, Isptp: 1.43 W/cm2) or high (PNP: 212kPa, Isptp: 2.86 W/cm2) acoustic intensities were stimulated resulting in an increase in their function (i.e. insulin secretion at low-intensity: 1.15 ± 0.17, medium-intensity: 2.02 ± 0.25, and high-intensity: 2.54 ± 0.38 fold increase when compared to control untreated islets; P < 0.05). Furthermore, we have shown that this improvement in islet function is a result of pFUS increasing the intracellular concentration of calcium (Ca2+) within islets which was also linked to pFUS increasing the resting membrane potential (Vm) of islets. Following syngeneic renal sub-capsule islet transplantation in C57/B6 mice, pFUS (PNP: 2.9 MPa, Isptp: 895 W/cm2) improved the function of transplanted islets with diabetic animals rapidly re-establishing glycemic control. In addition, pFUS was able to enhance the engraftment by facilitating islet revascularization and reducing inflammation. Given a significant number of islets are lost immediately following transplantation, pFUS has the potential to be used in humans as a novel non-invasive therapy to facilitate islet function and engraftment, thereby improving the outcome of diabetic patients undergoing islet transplantation.
Highlights
Reaction (IBMIR) towards islets[6]
Following stimulation of islets at both low and high glucose concentrations, the concentration of insulin secreted by islets significantly increased when Pulsed focused ultrasound (pFUS) was applied to islets, in an acoustic intensity-dependent manner:
We found that pFUS can (i) safely stimulate insulin secretion from islets via a voltage dependent mechanism which stimulated calcium influx into cells that was acoustic intensity dependent and (ii) be used in vivo to facilitate the function, engraftment and survival of transplanted islets by promoting islet revascularization as well as reducing inflammation
Summary
Reaction (IBMIR) towards islets[6]. Together, this reduces the number of viable islets which jeopardizes the long-term success of any islet transplant. Once islets engraft following their transplantation, they need to be able to function to release insulin from β cells. In response to elevated blood glucose levels, adenosine triphosphate (ATP)-sensitive potassium channels in β cells close, causing membrane depolarization thereby increasing intracellular free Ca2+ ([Ca2+]i). This triggers the exocytosis of insulin granules from β cells[7] (Fig. 1). A significant proportion of transplanted islets become “glucose-blind”, wherein β cells still contain insulin granules but cannot effectively release them in response to elevated glucose levels[10]. We will examine in vivo whether applying pFUS to the site of islet transplantation can improve the function, viability and engraftment of transplanted islets within recipient diabetic animals. We will induce diabetes in mice using streptozocin (STZ) and transplant islets under the renal capsule, which is a well-established technique for islet transplantation in small animal models[17]
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