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Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes.

ABSTRACT: Diabetes is associated with hepatic metabolic dysfunction predisposing patients to drug-induced liver injury. Mouse models of type 2 diabetes (T2D) have dramatically reduced expression of organic anion transporting polypeptide (OATP)1A1, a transporter expressed in hepatocytes and in the kidneys. The effects of diabetes on OATP1B2 expression are less studied and less consistent. OATP1A1 and OATP1B2 both transport endogenous substrates such as bile acids and hormone conjugates as well as numerous drugs including gadoxetate disodium (Gd-EOB-DTPA). As master pharmacokinetic regulators, the altered expression of OATPs in diabetes could have a profound and clinically significant influence on drug therapies. Here, we report a method to noninvasively measure OATP activity in T2D mice by quantifying the transport of hepatobiliary-specific gadolinium-based contrast agents (GBCAs) within the liver and kidneys using dynamic contrast-enhanced MRI (DCE-MRI). By comparing GBCA uptake in control and OATP knockout mice, we confirmed liver clearance of the hepatobiliary-specific GBCAs, Gd-EOB-DTPA, and gadobenate dimeglumine, primarily though OATP transporters. Then, we measured a reduction in the hepatic uptake of these hepatobiliary GBCAs in T2D ob/ob mice, which mirrored significant reductions in the mRNA and protein expression of OATP1A1 and OATP1B2. As these GBCAs are U.S. Food and Drug Administration-approved agents and DCE-MRI is a standard clinical protocol, studies to determine OATP1B1/1B3 deficiencies in human individuals with diabetes can be easily envisioned.

SUBMITTER: Shuboni-Mulligan DD

PROVIDER: S-EPMC6341305 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes.

Shuboni-Mulligan Dorela D DD Parys Maciej M Blanco-Fernandez Barbara B Mallett Christiane L CL Schnegelberger Regina R Takada Marilia M Chakravarty Shatadru S Hagenbuch Bruno B Shapiro Erik M EM

Diabetes 20181128 2

Diabetes is associated with hepatic metabolic dysfunction predisposing patients to drug-induced liver injury. Mouse models of type 2 diabetes (T2D) have dramatically reduced expression of organic anion transporting polypeptide (OATP)1A1, a transporter expressed in hepatocytes and in the kidneys. The effects of diabetes on OATP1B2 expression are less studied and less consistent. OATP1A1 and OATP1B2 both transport endogenous substrates such as bile acids and hormone conjugates as well as numerous ...[more]

PMID: 30487262

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Project description:In the context of neurologic disorders, dynamic susceptibility contrast (DSC) and dynamic contrast enhanced (DCE) MRI provide valuable insights into cerebral vascular function, integrity, and architecture. Even after two decades of use, these modalities continue to evolve as their biophysical and kinetic basis is better understood, with improvements in pulse sequences and accelerated imaging techniques and through application of more robust and automated data analysis strategies. Here, we systematically review each of these elements, with a focus on how their integration improves kinetic parameter accuracy and the development of new hemodynamic biomarkers that provide sub-voxel sensitivity (e.g., capillary transit time and flow heterogeneity). Regarding contrast mechanisms, we discuss the dipole-dipole interactions and susceptibility effects that give rise to simultaneous T1, T2 and T2∗ relaxation effects, including their quantification, influence on pulse sequence parameter optimization, and use in methods such as vessel size and vessel architectural imaging. The application of technologic advancements, such as parallel imaging, simultaneous multi-slice, undersampled k-space acquisitions, and sliding window strategies, enables improved spatial and/or temporal resolution of DSC and DCE acquisitions. Such acceleration techniques have also enabled the implementation of, clinically feasible, simultaneous multi-echo spin- and gradient echo acquisitions, providing more comprehensive and quantitative interrogation of T1, T2 and T2∗ changes. Characterizing these relaxation rate changes through different post-processing options allows for the quantification of hemodynamics and vascular permeability. The application of different biophysical models provides insight into traditional hemodynamic parameters (e.g., cerebral blood volume) and more advanced parameters (e.g., capillary transit time heterogeneity). We provide insight into the appropriate selection of biophysical models and the necessary post-processing steps to ensure reliable measurements while minimizing potential sources of error. We show representative examples of advanced DSC- and DCE-MRI methods applied to pathologic conditions affecting the cerebral microcirculation, including brain tumors, stroke, aging, and multiple sclerosis. The maturation and standardization of conventional DSC- and DCE-MRI techniques has enabled their increased integration into clinical practice and use in clinical trials, which has, in turn, spurred renewed interest in their technological and biophysical development, paving the way towards a more comprehensive assessment of cerebral hemodynamics.

Project description:ObjectiveFew attempts have been made to investigate the prognostic value of dynamic contrast-enhanced (DCE) MRI or dynamic susceptibility contrast (DSC) MRI of non-enhancing, T2-high-signal-intensity (T2-HSI) lesions of glioblastoma multiforme (GBM) in newly diagnosed patients. This study aimed to investigate the prognostic values of DCE MRI and DSC MRI parameters from non-enhancing, T2-HSI lesions of GBM.Materials and methodsA total of 76 patients with GBM who underwent preoperative DCE MRI and DSC MRI and standard treatment were retrospectively included. Six months after surgery, the patients were categorized into early progression (n = 15) and non-early progression (n = 61) groups. We extracted and analyzed the permeability and perfusion parameters of both modalities for the non-enhancing, T2-HSI lesions of the tumors. The optimal percentiles of the respective parameters obtained from cumulative histograms were determined using receiver operating characteristic (ROC) curve and univariable Cox regression analyses. The results were compared using multivariable Cox proportional hazards regression analysis of progression-free survival.ResultsThe 95th percentile value (PV) of Ktrans, mean Ktrans, and median Ve were significant predictors of early progression as identified by the ROC curve analysis (area under the ROC curve [AUC] = 0.704, p = 0.005; AUC = 0.684, p = 0.021; and AUC = 0.670, p = 0.0325, respectively). Univariable Cox regression analysis of the above three parametric values showed that the 95th PV of Ktrans and the mean Ktrans were significant predictors of early progression (hazard ratio [HR] = 1.06, p = 0.009; HR = 1.25, p = 0.017, respectively). Multivariable Cox regression analysis, which also incorporated clinical parameters, revealed that the 95th PV of Ktrans was the sole significant independent predictor of early progression (HR = 1.062, p < 0.009).ConclusionThe 95th PV of Ktrans from the non-enhancing, T2-HSI lesions of GBM is a potential prognostic marker for disease progression.

Dataset Information

Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes.

Publications

Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes.

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