Noninvasive Magnetic Resonance Imaging of Microvascular Changes in Type 1 Diabetes

Abstract

The pathogenesis of type 1 diabetes involves autoimmune lymphocytic destruction of insulin-producing beta-cells and metabolic dysregulation. An early biomarker of pancreatic islet damage is islet microvascular dysfunction, and alterations in vascular volume, flow, and permeability have been reported in numerous models of type 1 diabetes. Consequently, the ability to noninvasively monitor the dynamics of the pancreatic microvasculature would aid in early diagnosis and permit the assessment, design, and optimization of individualized therapeutic intervention strategies. Here, we used the long circulating paramagnetic contrast agent, protected graft copolymer (PGC) covalently linked to gadolinium-diethylenetriaminepentaacetic acid residues (GdDTPAs) labeled with fluorescein isothiocyanate (PGC-GdDTPA-F), for the noninvasive semiquantitative evaluation of vascular changes in a streptozotocin (STZ)-induced mouse model of type 1 diabetes. Diabetic animals and nondiabetic controls were monitored by magnetic resonance imaging (MRI) after injection of PGC-GdDTPA-F. Our findings demonstrated a significantly greater accumulation of PGC-GdDTPA-F in the pancreata of diabetic animals compared with controls. MRI permitted the in vivo semiquantitative 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 nondiabetic controls, PGC-GdDTPA-F was largely restricted to the pancreatic vasculature at the islet periphery. Based on these observations, we conclude that in the STZ model of type 1 diabetes, changes in vascular volume and permeability associated with early stages of the disease can be monitored noninvasively and semiquantitatively by MRI.