Department of Radiology, Michigan State University, East Lansing, MI.
Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI.
Diabetes. 2019 Feb;68(2):271-280. doi: 10.2337/db18-0525. Epub 2018 Nov 28.
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 / 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.
糖尿病与肝脏代谢功能障碍有关，使患者易发生药物性肝损伤。2 型糖尿病（T2D）的小鼠模型中，有机阴离子转运多肽（OATP）1A1 的表达显著降低，OATP1A1 表达于肝细胞和肾脏。糖尿病对 OATP1B2 表达的影响研究较少且结果不一致。OATP1A1 和 OATP1B2 均转运内源性底物，如胆汁酸和激素缀合物，以及许多药物，包括钆塞酸二钠（Gd-EOB-DTPA）。作为主要的药代动力学调节剂，糖尿病中 OATP 的表达改变可能对药物治疗产生深远而重要的影响。在这里，我们报道了一种通过使用动态对比增强 MRI（DCE-MRI）定量测量肝脏和肾脏中肝肠特异性镧系元素基造影剂（GBCA）转运来非侵入性地测量 T2D 小鼠中 OATP 活性的方法。通过比较对照和 OATP 敲除小鼠中的 GBCA 摄取，我们证实了肝肠特异性 GBCA、Gd-EOB-DTPA 和钆贝葡胺主要通过 OATP 转运体清除。然后，我们测量了这些肝肠 GBCA 在 T2D / 小鼠中的肝摄取减少，这与 OATP1A1 和 OATP1B2 的 mRNA 和蛋白表达显著减少相吻合。由于这些 GBCA 是美国食品和药物管理局批准的药物，DCE-MRI 是一种标准的临床方案，因此可以很容易地设想在患有糖尿病的人类个体中确定 OATP1B1/1B3 缺乏症的研究。
