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–Peroxisome Proliferator-Activated Receptor-γ Activation

Abstract

Generally, diabetes remarkably alters the expression and function of intestinal drug transporters. Nateglinide and bumetanide are substrates of monocarboxylate transporter 6 (MCT6). We investigated whether diabetes down-regulated the function and expression of intestinal MCT6 and the possible mechanism in diabetic rats induced by a combination of high-fat diet and low-dose streptozocin. Our results indicated that diabetes significantly decreased the 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 the protein and mRNA expressions of intestinal MCT6 and oligopeptide transporter 1 (PEPT1) but up-regulated peroxisome proliferator-activated receptor g (PPARg) protein level. Single-pass intestinal perfusion demonstrated that diabetes prominently decreased the absorption of nateglinide and bumetanide. The MCT6 inhibitor bumetanide, but not PEPT1 inhibitor glycylsarcosine, significantly inhibited intestinal absorption of nateglinide in rats. Coadministration with bumetanide remarkably decreased the oral plasma exposure of nateglinide in rats. High concentrations of butyrate were detected in the intestine of diabetic rats. In Caco-2 cells (a human colorectal adenocarcinoma cell line), bumetanide and MCT6 knockdown remarkably inhibited the uptake of nateglinide. Butyrate down-regulated the function and expression of MCT6 in a concentration-dependent manner but increased PPARg expression. The decreased expressions of MCT6 by PPARg agonist troglitazone or butyrate were reversed by both PPARg knockdown and PPARg antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662). Four weeks of butyrate treatment significantly decreased the oral plasma concentrations of nateglinide in rats, accompanied by significantly higher intestinal PPARg and lower MCT6 protein levels. In conclusion, diabetes impaired the expression and function of intestinal MCT6 partly via butyrate-mediated PPARg activation, decreasing the oral plasma exposure of nateglinide.

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

“…All these results demonstrate that alterations in the expressions of hepatic CYP450s were involved in various mechanisms. In contrast to CYP2C6 induction, diabetes significantly lowered the expression of CYP2C11 [26,[47][48][49][50], impairing the metabolism of diclofenac [49], glibenclamide [48] and nateglinide [47]. The increase in CYP2C6 expression and decrease in CYP2C11 expression may partly explain why the AUC values of both phenytoin and 4 -hydroxylphenytoin in diabetic rats were comparable to control rats [51].…”

“…In Caco-2 cells, it was reported that short-term exposure to sodium nitroprusside impaired P-gp function and expression, whereas long-term exposure stimulated P-gp function and expression [92]. Increased levels of short chain fatty acids (SCFAs) were also found in the intestinal content of diabetic rats [47]. A recent study showed that SCFAs downregulated the expression of intestinal P-gp via inhibiting histone deacetylase and NF-κB pathways [93].…”

“…PepT1, located on the luminal membrane of enterocytes, is responsible for intestinal absorption of peptidomimetic drugs, dipeptides and tripeptides resulting from the dietary breakdown of proteins and bacterial peptidomimetics. Several investigations have demonstrated that diabetes downregulated the expression and function of intestinal PepT1 in experimental animals [47,[97][98][99], decreasing oral plasma exposures of cephalexin and acyclovir following oral dose of cephalexin and valacyclovir [99]. Importantly, altered expression and function of intestinal PepT1 are also dependent on sex.…”

Monocarboxylate Transporter 6-Mediated Interactions with Prostaglandin F2α: In Vitro and In Vivo Evidence Utilizing a Knockout Mouse Model

“…While there were significant changes between the wild-type and Mct6 −/− mice associated with lipid metabolism, there were no significant differences reported in major enzymes involved in PG elimination or synthesis, such as dehydrogenase and synthase/reductase enzymes. Additionally, Xu et al suggested the involvement of butyrate-mediated Pparγ activation on Mct6 regulation in diabetic rats [12]. This suggests that Mct6 is regulated, in part, via PPAR-dependent mechanisms, which play a role in regulation of lipid metabolism, and effectively, PG homeostasis.…”

“…From this study, Zhang et al found that Slc16a5 was upregulated~5-fold following a fasted diet compared to a normal diet, making it one of the top 15 fold-change genes upregulated by fasting out of the 2305 genes found to be significantly regulated by food availability. More recently, Xu et al showed that MCT6 may play a role in dietary metabolic pathways using a rat model of diabetes [12]. While the amino acid sequence identity between murine Mct6 (mMct6) and human MCT6 (hMCT6) is relatively similar (~68% according to Clustal Omega), very little data exists regarding the correlation between mMct6 and hMCT6 activity.…”