Non-invasive Magnetic Resonance Imaging of Microvascular Changes in Type 1 Diabetes

Abstract

Objective: The pathogenesis of type 1 diabetes (T1D) involves autoimmune lymphocytic destruction of insulin-producing beta-cells and metabolic dysregulation. An early biomarker of pancreatic islet damage is islet microvascular dysfunction. Alterations in vascular volume, flow, and permeability have been reported in numerous models of T1D. Consequently, the ability to non-invasively monitor the dynamics of pancreatic microvasculature would aid in early diagnosis and permit the assessment, design, and optimization of individualized therapeutic intervention strategies.

Research Design and Methods: Here, we employed the long-circulating paramagnetic contrast agent, PGC-GdDTPA-F (protected graft copolymer covalently linked to gadolinium-diethylenetriaminepentaacetic acid residues and labeled with fluorescein), for the noninvasive semi-quantitative evaluation of vascular changes in a streptozotocin (STZ)-induced mouse model of T1D. Diabetic animals and non-diabetic controls were monitored by magnetic resonance imaging (MRI) after injection of PGC-GdDTPA-F.

Results: Our findings demonstrated a significantly greater accumulation of PGC-GdDTPA-F in the pancreata of diabetic animals, as compared to controls. MRI permitted the in vivo semi-quantitative assessment and direct visualization of the differential distribution of PGC-GdDTPA-F in diabetic and control pancreata. Ex vivo histology revealed extensive distribution of PGC-GdDTPA-F within the vascular compartment of the pancreas, as well as considerable leakage of the probe into the islet interstitium. By, contrast, in non-diabetic controls, PGC-GdDTPA-F was largely restricted to the pancreatic vasculature at the islet periphery.

Conclusions: Based on these observations we conclude that in the STZ model of T1D, changes in vascular volume and permeability associated with early stages of the disease, can be monitored non-invasively and semi-quantitatively by MRI.