Noninvasive assessment of pancreatic β-cell function in vivo with manganese-enhanced magnetic resonance imaging

Abstract

Loss of beta-cell function in type 1 and type 2 diabetes leads to metabolic dysregulation and inability to maintain normoglycemia. Noninvasive imaging of beta-cell function in vivo would therefore provide a valuable diagnostic and research tool for quantifying progression to diabetes and response to therapeutic intervention. Because manganese (Mn(2+)) is a longitudinal relaxation time (T1)-shortening magnetic resonance imaging (MRI) contrast agent that enters cells such as pancreatic beta-cells through voltage-gated calcium channels, we hypothesized that Mn(2+)-enhanced MRI of the pancreas after glucose infusion would allow for noninvasive detection of beta-cell function in vivo. To test this hypothesis, we administered glucose and saline challenges intravenously to normal mice and mice given high or low doses of streptozotocin (STZ) to induce diabetes. Serial inversion recovery MRI was subsequently performed after Mn(2+) injection to probe Mn(2+) accumulation in the pancreas. Time-intensity curves of the pancreas (normalized to the liver) fit to a sigmoid function showed a 51% increase in signal plateau height after glucose stimulation relative to saline (P < 0.01) in normal mice. In diabetic mice given a high dose of STZ, only a 9% increase in plateau signal intensity was observed after glucose challenge (P = not significant); in mice given a low dose of STZ, a 20% increase in plateau signal intensity was seen after glucose challenge (P = 0.02). Consistent with these imaging findings, the pancreatic insulin content of high- and low-dose STZ diabetic mice was reduced about 20-fold and 10-fold, respectively, compared with normal mice. We conclude that Mn(2+)-enhanced MRI demonstrates excellent potential as a means for noninvasively monitoring beta-cell function in vivo and may have the sensitivity to detect progressive decreases in function that occur in the diabetic disease process.

Noninvasive MRI of β-cell function using a Zn 2+ -responsive contrast agent

“…A MRI sensor with these properties may allow whole-body detection of Zn 2+ only in those tissues where the extracellular concentration is high and physiologically important. Antkowiak et al (19) recently reported the first example of imaging β-cell function by showing that Mn 2+ -enhanced MRI may be used to detect temporal differences in T 1 enhancement of the pancreas between normal and streptozotocin (STZ)-treated mice after a bolus injection of glucose. MRI enhancement of the pancreas in that study was thought to reflect influx of Mn 2+ into islet β-cells through voltage-gated Ca 2+ channels because those cells respond to high glucose.…”

Unique sphingomyelin patches are targets of a beta-cell-specific antibody

“…Recent years have seen exponential progress in applying various imaging modalities (MRI, positron emission tomography, optical) for noninvasive detection and monitoring of pancreatic ␤ -cell mass (2)(3)(4)(5)(6). A crucial prerequisite for clinical application of these techniques is the availability of a contrast agent with high affi nity and high specifi city toward ␤ -cell surface markers.…”

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

“…Mn 2+ behaves like calcium and will therefore enter metabolically active b-cells (16). MnCl 2 -enhanced signals also reflect functional b-cells in vivo; pancreatic MRI signals of mice with streptozotocin (STZ)-induced diabetes were decreased in the case of both high-and low-dose STZ compared with nondiabetic control animals (20) and in BDC2.5 T-cell receptor transgenic nonobese diabetic mice even before the diabetes onset could be measured in the blood (21). Individual islets can be detected by MRI in MnCl 2 -injected exteriorized pancreases, exactly correlating with immunohistochemistry performed in parallel (22).…”

“…Chronic exposure to high concentrations of Mn 2+ lead to extrapyramidal dysfunction resembling the dystonic movements associated with Parkinson disease, called manganism (26)(27)(28). Based on previous studies in mice, 20-35 mg/kg doses MnCl 2 were used for pancreas MRI in rodents (20,22). Although LD 50 levels of 38 mg/kg i.v.…”