Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes

Area of Science:

• Pharmacology
• Hepatology
• Medical Imaging

Background:

• Diabetes mellitus is linked to liver dysfunction and increased risk of drug-induced liver injury.
• Organic anion transporting polypeptides (OATPs) are crucial for drug and metabolite transport in the liver and kidneys.
• Reduced OATP expression in type 2 diabetes (T2D) mouse models suggests altered drug pharmacokinetics.

Purpose of the Study:

• To develop a noninvasive method for assessing OATP activity in T2D mouse models.
• To investigate the impact of T2D on OATP1A1 and OATP1B2 expression and function.
• To evaluate the potential of hepatobiliary gadolinium-based contrast agents (GBCAs) and DCE-MRI for measuring OATP activity.

Main Methods:

• Utilized dynamic contrast-enhanced MRI (DCE-MRI) to quantify GBCA uptake in the liver and kidneys of control and T2D mice.
• Employed OATP knockout mice to confirm GBCA clearance via OATP transporters.
• Measured mRNA and protein expression of OATP1A1 and OATP1B2 in T2D mice.

Main Results:

• Confirmed that hepatobiliary GBCAs like Gd-EOB-DTPA are cleared by OATP transporters in the liver.
• Demonstrated significantly reduced hepatic uptake of hepatobiliary GBCAs in T2D mice compared to controls.
• Observed corresponding reductions in OATP1A1 and OATP1B2 mRNA and protein expression in T2D mice.

Conclusions:

• Noninvasive DCE-MRI can effectively measure OATP activity in T2D mouse models.
• T2D is associated with decreased expression and function of hepatic OATPs (1A1 and 1B2).
• These findings suggest potential clinical implications for drug therapy in diabetic patients and support further investigation in humans.