PT - JOURNAL ARTICLE AU - Feng Xu AU - Liang Zhu AU - Chaoqun Qian AU - Junjie Zhou AU - Donghao Geng AU - Ping Li AU - Wenjing Xuan AU - Fangge Wu AU - Kaijing Zhao AU - Weimin Kong AU - Yuanyuan Qin AU - Limin Liang AU - Li Liu AU - Xiaodong Liu TI - Impairment of intestinal monocarboxylate transporter 6 function and expression in diabetic rats induced by combination of high-fat diet and low dose of streptozocin. Involvement of butyrate-PPARγ activation. AID - 10.1124/dmd.118.085803 DP - 2019 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.118.085803 4099 - http://dmd.aspetjournals.org/content/early/2019/03/28/dmd.118.085803.short 4100 - http://dmd.aspetjournals.org/content/early/2019/03/28/dmd.118.085803.full AB - Generally, diabetes remarkably alters expression and function of intestinal drug transporters. Nateglinide and bumetanide are substrates of monocarboxylate transporter 6 (MCT6). We aimed to report that diabetes downregulated function and expression of intestinal MCT6 and to investigate the possible mechanism in diabetic rats induced by combination of high-fat diet and low dose of streptozocin. The results indicated that diabetes significantly decreased oral plasma exposure of nateglinide. The plasma peak concentration and area under curve in diabetic rats were 16.9% and 28.2% of control rats, respectively. Diabetes significantly decreased protein and mRNA expressions of intestinal MCT6 and oligopeptide transporter 1 (PEPT1), but upregulated peroxisome proliferator-activated receptor-gamma (PPARγ) protein level. Single-pass intestinal perfusion (SPIP) demonstrated that diabetes prominently decreased absorption of nateglinide and bumetanide. MCT6 inhibitor bumetanide, but not PEPT1 inhibitor glycylsarcosine, significantly inhibited intestinal absorption of nateglinide in rats. Co-administration with bumetanide remarkably decreased oral plasma exposure of nateglinide in rats. High concentrations of butyrate were detected in intestine of diabetic rats. In Caco-2 cells, bumetanide and MCT6 knockdown remarkably inhibited uptake of nateglinide. Butyrate concentration-dependently downregulated function and expression of MCT6 but increased PPARγ expression. The decreased expressions of MCT6 by PPARγ agonist troglitazone or butyrate were reversed by both PPARγ knockdown and PPARγ antagonist GW9662. Four-week butyrate treatment significantly decreased oral plasma concentrations of nateglinide in rats, accompanied by significantly higher intestinal PPARγ and lower MCT6 protein levels. In conclusion, diabetes impaired expression and function of intestinal MCT6 partly via butyrate-mediated PPARγ activation, decreasing oral plasma exposure of nateglinide.