Dynamic Contrast–Enhanced MRI of OATP Dysfunction in Diabetes
| العنوان: | Dynamic Contrast–Enhanced MRI of OATP Dysfunction in Diabetes |
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| المؤلفون: | Barbara Blanco-Fernandez, Bruno Hagenbuch, Erik M. Shapiro, Maciej Parys, Christiane L. Mallett, Marilia Takada, Shatadru Chakravarty, Regina Schnegelberger, Dorela D. Shuboni-Mulligan |
| المصدر: | Diabetes |
| بيانات النشر: | American Diabetes Association, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Gadolinium DTPA, Organic Cation Transport Proteins, Endocrinology, Diabetes and Metabolism, Technological Advances, Contrast Media, Organic Anion Transporters, 030209 endocrinology & metabolism, Type 2 diabetes, Pharmacology, Gadoxetate Disodium, 03 medical and health sciences, Mice, 0302 clinical medicine, Pharmacokinetics, Diabetes mellitus, Internal Medicine, medicine, Animals, Liver injury, Mice, Knockout, biology, business.industry, Liver-Specific Organic Anion Transporter 1, Transporter, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Organic anion-transporting polypeptide, 030104 developmental biology, Diabetes Mellitus, Type 2, Knockout mouse, biology.protein, business |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1939-327X 0012-1797 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7e22ea14ddf0fbd293494fdf30484f5d http://europepmc.org/articles/PMC6341305 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7e22ea14ddf0fbd293494fdf30484f5d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1939327X 00121797 |
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