Detecting insulitis in type 1 diabetes with ultrasound phase-change contrast agents – pnas.org

Significance

Methods to detect type 1 diabetes (T1D) progression prior to clinical diagnosis are needed. T1D results from autoreactive T cells infiltrating the islets of Langerhans, destroying insulin-producing -cells. Overt disease takes years to present, and at diagnosis, there is substantial -cell loss. Therapeutic intervention to preserve -cell mass is hampered by an inability to follow presymptomatic T1D progression. Several immunotherapies can delay T1D development. However, identifying at-risk individuals and tracking whether therapeutic interventions are impacting disease progression, are lacking. We present ultrasound imaging of nanodroplet (ND) contrast-agent accumulation within the islet. ND accumulation is dependent on immune infiltration; therefore, it tracks presymptomatic T1D development and progression to diabetes. This provides an opportunity to guide therapeutic treatments to prevent T1D.

Type 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing cells within the pancreatic islets of Langerhans (insulitis). Early diagnosis during presymptomatic T1D would allow for therapeutic intervention prior to substantial -cell loss at onset. There are limited methods to track the progression of insulitis and -cell mass decline. During insulitis, the islet microvasculature increases permeability, such that submicron-sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Submicron nanodroplet (ND) phase-change agents can be vaporized into micron-sized bubbles, serving as a microbubble precursor. We tested whether NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in nonobese diabetic (NOD) mice and NOD;Rag1ko controls and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10-wk-old NOD mice following ND infusion and vaporization but was absent in both the noninfiltrated kidney of NOD mice and the pancreas of Rag1ko controls. High-contrast elevation also correlated with rapid diabetes onset. Elevated contrast was also observed as early as 4 wk, prior to mouse insulin autoantibody detection. In the pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression, to guide and assess preventative therapeutic interventions for T1D.

Author contributions: M.A.B. and R.K.P.B. designed research; D.G.R., M.C., A.K.U., V.T.P., and R.K.P.B. performed research; D.G.R. and M.C. analyzed data; and D.G.R. and R.K.P.B. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission. M.V.H. is a guest editor invited by the Editorial Board.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2022523118/-/DCSupplemental.

All data and analysis are available to be shared upon request. Raw data, including czi microscopy files (for histology), Vevo ultrasound data files (for ultrasound images), and glucose and mIAA data have been deposited at https://www.ebi.ac.uk/biostudies/studies/S-BIAD189.

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Detecting insulitis in type 1 diabetes with ultrasound phase-change contrast agents - pnas.org