Functional MRI characterization of isolated human islet activation

Abstract

The noninvasive assessment of pancreatic islets would be an invaluable tool in advancing the treatment of type I diabetes and in understanding its pathophysiology. As shown previously in rodents, manganese-enhanced MRI (MEMRI) can be successfully used to quantify β-cell function. In this study, we successfully applied this technique to isolated human pancreatic islets in both a static and, more significantly, MRI-compatible perfusion set-up. Unlike rodent islets, which produced a significant increase in the signal-to-noise ratio (SNR) when treated with 25 µM MnCl(2) or less, human islets demonstrated significant manganese uptake when exposed to an extracellular concentration of 50 µM MnCl(2). Nonspecific passive manganese uptake was present and quantified in a 15% SNR increase over the control group. However, glucose-induced manganese uptake caused an SNR increase equal to 45% over nonactivated islets. This corresponds to a statistically significant decrease in the T(1) relaxation time from 1501 ms for untreated islets to 1362 ms following passive uptake, and to 861 ms following glucose stimulation. As expected, no manganese cytotoxicity was measured, as shown by normal insulin secretion profiles. These data confirm the viability of MEMRI to assess isolated human islet functionality in vitro, and this technique shows promise for the monitoring of their performance in vivo following transplantation.

Translational Molecular Imaging of Diabetes

“…It has been demonstrated that in the presence of MnCl2, glucoseactivated pancreatic islets yield significant signal enhancement in T1-weigheted MR images in vitro and in animal models of diabetes [16][17][18][19][20][21][22][23]. This approach has also been tested in preliminary studies in patients with T2D.…”

MEMRI Characterization and Quantification Maps of Human Pancreatic Islets

“…Using this technique, functional β-cells take-up Mn ions through the calcium channels and enhance their MR signal intensity compared to non-functional cells [10,12,16,17,18,24,28]. Manganese is a mineral element that is both nutritionally essential, useful in a number of physiologic processes and potentially toxic.…”

“…Mn has an ionic radius close to that of Calcium and is believed to be handled similarly in many biological systems. Divalent Manganese ions (Mn +2 ) ions are paramagnetic and can enter cells through voltage gated calcium channels [11,12,17]. Mn +2 accumulations in β-cells due to Glucose Stimulation should alter T1 relaxation times offering an approach to sensitize MRI to calcium influx in the pancreas (Figure 1).…”

“…The increase in signal enhancement is proportional to the concentration of the contrast agent. We have shown previously methods to obtain high resolution imaging of islets [11,12,14,17,18,23]. This study focuses on assessing human pancreatic islets and characterizing their MR properties.…”

Manganese-Mediated MRI Signals Correlate With Functional β-Cell Mass During Diabetes Progression

“…Similar to Ca 2+ , Mn 2+ is taken up by glucose-activated b-cells, resulting in a robust signal increase in glucose-stimulated rodent b-cell lines and in islets (16,17). The uptake of Mn 2+ is controlled by voltage-gated Ca 2+ channels (18), and Mn…”