Peroxisome proliferator-activated receptor-␥ (PPAR␥) agonists have been shown to have significant therapeutic benefits such as desirable glycemic control in type 2 diabetic patients; however, these agents may cause fluid retention in susceptible individuals. Since PPAR␥ is expressed selectively in distal nephron epithelium, we studied the mechanism of PPAR␥ agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPAR␥ agonist. GI262570 (20 mg/kg/day) induced a plasma volume expansion. The plasma volume expansion was accompanied by a small but significant decrease in plasma potassium concentration. Small but significant increases in plasma sodium and chloride concentrations were also observed. These changes in serum electrolytes suggested an activation of the renal mineralocorticoid response system; however, GI262570-treated rats had lower plasma levels of aldosterone compared with vehicle-treated controls. mRNA levels for a group of genes involved in distal nephron sodium and water absorption are changed in the kidney medulla with GI262570 treatment. In addition, due to a possible rebound effect on epithelial sodium channel (ENaC) activity, a low dose of amiloride did not prevent GI262570-induced fluid retention. On the contrary, the rebound effect after amiloride treatment potentiated GI262570-induced plasma volume expansion. This is at least partially due to a synergistic effect of GI262570 and the rebound from amiloride treatment on ENaC␣ expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,KATPase system. This may be an important mechanism for PPAR␥ agonist-induced fluid retention.

Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.

Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagonlike peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic ␤-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.In the last decade, the traditional view of bile acids as essential players in dietary lipid absorption and cholesterol catabolism has changed. The discovery of bile acids as endogenous ligands for the nuclear receptor farnesoid X receptor (FXR; NR1H4) and the G-protein-coupled bile acid receptor (TGR5; GPBAR1) transformed bile acids from lipid absorption facilitator into autocrine, paracrine, and endocrine factors (Parks et al., 1999;Kawamata et al., 2003). In addition to negative feedback regulation of bile acid synthesis in the liver (Makishima et al., 1999), FXR influences many pathways involved in lipid and glucose metabolism (Lefebvre et al., 2009). FXR agonists have been shown to lower circulating cholesterol, triglycerides, and glucose and improve insulin sensitivity in multiple preclinical models (Duran-Sandoval et al., 2005;Stayrook et al., 2005;Cariou et al., 2006;Ma et al., 2006;Zhang et al., 2006). Similar to FXR, TGR5 mediates some hormonal actions of bile acids, including glucose metabolism. It has been demonstrated that bile acids promote glucagon-like-peptide 1 (GLP-1) secretion through TGR5 in STC-1, a murine enteroendocrine cell line (Katsuma et al., Article, publication date, and citation information can be found at

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