Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes

• Published in: Nature communications Vol. 11; no. 1; p. 2238
• Main Authors: Ramirez, David G., Abenojar, Eric, Hernandez, Christopher, Lorberbaum, David S., Papazian, Lucine A., Passman, Samantha, Pham, Vinh, Exner, Agata A., Benninger, Richard K. P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 14/34; 639/925/352/2734; 692/699/249/1313/1418; Accumulation; Animal models; Animals; Backscattering; Beta cells; Contrast agents; Contrast Media; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - diagnostic imaging; Diabetes Mellitus, Type 1 - pathology; Female; Humanities and Social Sciences; Humans; Immune system; Insulin; Insulin-Secreting Cells - pathology; Insulitis; Islets of Langerhans; Islets of Langerhans - diagnostic imaging; Islets of Langerhans - pathology; Lymphocytes T; Mice; Microvasculature; multidisciplinary; Nanoparticles; Pancreas; Pancreas - diagnostic imaging; Pancreas - pathology; Permeability; Science; Science (multidisciplinary); Signs and symptoms; Ultrasonic imaging; Ultrasonic methods; Ultrasonic testing; Ultrasonography; Ultrasound
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15957-8

In type1 diabetes (T1D) autoreactive T-cells infiltrate the islets of Langerhans, depleting insulin-secreting β-cells (insulitis). Insulitis arises during an asymptomatic phase, prior to clinical diagnosis of T1D. Methods to diagnose insulitis and β-cell mass changes during this asymptomatic phase are limited, precluding early therapeutic intervention. During T1D the islet microvasculature increases permeability, allowing nanoparticles to access the microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide acoustic backscatter in vasculature. Here, we report that sub-micron sized ‘nanobubble’ ultrasound contrast agents can be used to measure increased islet microvasculature permeability and indicate asymptomatic T1D. Through CEUS and histological analysis, pre-clinical models of T1D show accumulation of nanobubbles specifically within pancreatic islets, correlating with insulitis. Importantly, accumulation is detected early in disease progression and decreases with successful therapeutic intervention. Thus, sub-micron sized nanobubble ultrasound contrast agents provide a predicative marker for disease progression and therapeutic reversal early in asymptomatic T1D. Infiltration of immune cells to the pancreatic islets precedes clinical symptoms of type 1 diabetes, and lack of methods to detect this insulitis impedes early interventions. Here the authors report a contrast enhanced ultrasound method that can detect early insulitis in mouse models of type 1 diabetes, based on increased microvascular permeability.