Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients

Abstract

Type 1A diabetes (T1D) is an autoimmune disease characterized by leukocyte infiltration of the pancreatic islets of Langerhans. A major impediment to advances in understanding, preventing, and curing T1D has been the inability to "see" the disease initiate, progress, or regress, especially during the occult phase. Here, we report the development of a noninvasive method to visualize T1D at the target organ level in patients with active insulitis. Specifically, we visualized islet inflammation, manifest by microvascular changes and monocyte/macrophage recruitment and activation, using magnetic resonance imaging of magnetic nanoparticles (MNPs). As a proof of principle for this approach, imaging of infused ferumoxtran-10 nanoparticles permitted effective visualization of the pancreas and distinction of recent-onset diabetes patients from nondiabetic controls. The observation that MNPs accumulate in the pancreas of T1D patients opens the door to exploiting this noninvasive imaging method to follow T1D progression and monitoring the ability of immunomodulatory agents to clear insulitis.

Figure 1. Pancreas volume index (PVI) of recently diagnosed diabetes patients is less than that of controls.

(A) PVI, calculated by dividing pancreas volume by body-surface area, of patients with recent onset T1D (n = 10, circles) is less than that of nondiabetic controls (n = 11, squares). The bars indicate mean values (T1D 24.1 ± 5.7 ml/m², controls 35.0 ± 11.5 ml/m²; Mann-Whitney U test, P = 0.007). (B) Representative single MR-VIBE slices at the level of the body/tail of the pancreas are shown with the pancreas outlined in green. The control subject (upper panel) and the individual with recent onset T1D (lower panel) have total estimated pancreas volumes of 119 ml and 50 ml respectively.

Figure 2. Insulitis may be visualized by MRI.

Shown are T2-pseudocolor reconstructions of the pancreas overlaid on 3D-VIBE images, measured before and 48 hours after MNP infusion. T2 values in the pancreas are similar between the patient and control subjects before infusion but different after infusion.

Figure 3. MRI-MNP may be used for the noninvasive quantification of pancreatic changes associated with the development of diabetes.

(A) ΔT2 was measured inside matching ROIs before and 48 hours after infusion of MNPs, reflecting local accumulation of MNPs. Comparing recent-onset T1D patients (n = 9) and controls (n = 11), there was a significant difference in ΔT2 within the pancreas (T1D 14.1 ± 4.7 msec, controls 7.1 ± 4.9 msec) but not within paraspinous muscle (T1D 1.28 ± 0.78 msec, controls 1.23 ± 0.90 msec). (B) A composite index was computed using the formula 100 × (ΔT2_pancreas/PVI); (T1D 59.7 ± 20.1, controls 22.5 ± 17.5).