Empirical mathematical model for dynamic manganese-enhanced MRI of the murine pancreas for assessment of β-cell function

Abstract

Autoimmune ablation of pancreatic β-cells and alteration of its microvasculature may be a predictor of Type I diabetes development. A dynamic manganese-enhanced MRI (MEMRI) approach and empirical mathematical model was developed to monitor whole pancreatic β-cell function and vasculature modifications in mice. Normal and streptozotocin-induced diabetic FVB/N mice were imaged on a 9.4T MRI system using a 3D magnetization prepared rapid acquisition gradient echo pulse sequence to characterize low dose manganese kinetics in the pancreas head, body and tail. Average signal enhancement in the pancreas (head, body, and tail) as a function of time was fit by a novel empirical mathematical model characterizing contrast uptake/washout rates and yielding parameters describing peak signal, initial slope, and initial area under the curve. Signal enhancement from glucose-induced manganese uptake was fit by a linear function. The results demonstrated that the diabetic pancreatic tail had a significantly lower contrast uptake rate, smaller initial slope/initial area under the curve, and a smaller rate of Mn uptake following glucose activation (p < 0.05) compared to the normal pancreatic tail. These observations parallel known patterns of β-cell loss and alteration in supportive vasculature associated with diabetes. Dynamic MEMRI is a promising technique for assessing β-cell functionality and vascular perfusion with potential applications for monitoring diabetes progression and/or therapy.

Direct Measurement of the Mn(II) Hydration State in Metal Complexes and Metalloproteins through 17O NMR Line Widths

“…For example, this strategy has been used to track changes in β-cell mass in studies pertaining to the onset and progression of type diabetes. 52 Mn(II) uptake in hepatocytes has also been used to visualize hepatic lesions. 53,54 However the molecular forms of Mn(II) in the brain, pancreas, or liver are unknown, e.g.…”

Dynamic Electron Paramagnetic Resonance Imaging: Modern Technique for Biodistribution and Pharmacokinetic Imaging

“…As this was the preliminary experiment, using model-based analysis, for example, the two-compartment model (TCM), may not be the correct choice. However, based on the shape of the pharmacokinetic profiles and its similarity to dynamic contrast-enhanced imaging, ,− the application of a curve analysis using the empirical mathematical model seems to be a proper approach, which can provide reliable and reproducible results. Therefore, in this work, we adapted the empirical mathematical model (EMM) ,,, and applied it to determine the rates of uptake and washout coefficients, as well as the pharmacokinetic parameters, according to eq below where A is the upper limit of the EPR signal amplitude, α is the rate of spin probe uptake (1/min), β is the overall rate of spin probe washout (1/min), γ is the initial rate of spin probe washout (1/min), and q is the radius of curvature of C ( t ) at the transition from the first-pass uptake to the initial washout.…”

“…However, based on the shape of the pharmacokinetic profiles and its similarity to dynamic contrast-enhanced imaging, 4,33−35 the application of a curve analysis using the empirical mathematical model seems to be a proper approach, which can provide reliable and reproducible results. Therefore, in this work, we adapted the empirical mathematical model (EMM) 4,33,36,37 and applied it to determine the rates of uptake and washout coefficients, as well as the pharmacokinetic parameters, according to eq 1 below…”

PET/MRI enables simultaneous in vivo quantification of β-cell mass and function

“…Previous imaging studies validated in vivo the specificity of Mn for the pancreatic β-cells using VDCC blockers or streptozotocin (STZ)-treated mice 18-20. However, controversial results showed that changes in the vascularity of the pancreas, rather than β-cell destruction, might lead to a decrease in perfusion and wash-out of Mn in STZ-mice 19. Thus, the specificity of the overall Mn for the pancreatic islets as well as the contribution of the exocrine pancreas on the overall uptake of Mn in vivo remained unclear 23.…”