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A study was conducted to evaluate and compare the increased risk of acute myocardial infarction, stroke, heart failure, and death in the case of elderly Medicare patients treated with rosiglitazone as against pioglitazone. Results indicated that rosiglitazone resulted in an increased risk of negative outcomes in the case of such patients.

The development of alcoholic fatty liver is associated with reduced adipocyte-derived adiponectin levels, decreased hepatic adiponectin receptors, and deranged hepatic adiponectin signaling in animals. Peroxisomal proliferator-activated receptor-[gamma] (PPAR-[gamma]) plays a key role in the regulation of adiponectin in adipose tissue. The aim of the present study was to test the ability of rosiglitazone, a known PPAR-[gamma] agonist, to reverse the inhibitory effects of ethanol on adiponectin expression and its hepatic signaling, and to attenuate alcoholic liver steatosis in mice. Mice were fed modified Lieber-DeCarli ethanol-containing liquid diets for 4 wk or pair-fed control diets. Four groups of mice were given a dose of either 3 or l0 mg x kg body [w.sup.-1] x [day.sup.-1] of rosiglitazone with or without ethanol in their diets for the last 2 wk of the feeding study. Coadministration of rosiglitazone and ethanol increased the expression and circulating levels of adiponectin and enhanced the expression of hepatic adiponectin receptors (AdipoRs) in mice. These increases correlated closely with the activation of a hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling system. In concordance with stimulated SIRT1-AMPK signaling, rosiglitazone administration enhanced expression of fatty acid oxidation enzymes, normalized lipin 1 expression, and blocked elevated expression of genes encoding lipogenic enzymes which, in turn, led to increased fatty acid oxidation, reduced lipogenesis, and alleviation of steatosis in the livers of ethanol-fed mice. Enhanced hepatic adiponectin-SIRT1-AMPK signaling contributes, at least in part, to the protective action of rosiglitazone against alcoholic fatty liver in mice. lipid metabolism; signal transduction; transcriptional regulators; acetylation doi:10.1152/ajpgi.00456.2009.

Sirolimus, an antiproliferative immunosuppressant, induces hypomagnesemia and hypokalemia. Rosiglitazone activates renal sodium- and water-reabsorptive pathways. We evaluated whether sirolimus induces renal wasting of magnesium and potassium, attempting to identify the tubule segments in which this occurs. We tested the hypothesis that reduced expression of the cotransporter NKCC2 forms the molecular basis of this effect and evaluated the possible association between increased urinary excretion of magnesium and renal expression of the epithelial [Mg.sup.2+] channel TRPM6. We then analyzed whether rosiglitazone attenuates these sirolimus-induced tubular effects. Wistar rats were treated for 14 days with sirolimus (3 mg/kg body wt in drinking water), with or without rosiglitazone (92 mg/kg body wt in food). Protein abundance of NKCC2, aquaporin-2 (AQP2), and TRPM6 was assessed using immunoblotting. Sirolimus-treated animals presented no change in glomerular filtration rate, although there were marked decreases in plasma potassium and magnesium. Sirolimus treatment reduced expression of NKCC2, and this was accompanied by greater urinary excretion of sodium, potassium, and magnesium. In sirolimus-treated animals, AQP2 expression was reduced. Expression of TRPM6 was increased, which might represent a direct stimulatory effect of sirolimus or a compensatory response. The finding that rosiglitazone prevented or attenuated all sirolimus-induced renal tubular detects has potential clinical implications. antiproliferative immunosuppressant; urinary excretion doi:10.1152/ajprenal.90256.2008.

Oxidative stress contributes to cardiovascular complications of diabetes, in part, by reducing the bioavailability of nitric oxide (NO). We investigated the mechanisms whereby the insulin sensitizer rosiglitazone may ameliorate oxidative stress in the vasculature of spontaneously hypertensive rats (SHR). Nine-week-old SHR were treated by gavage for 7 wk with rosiglitazone (5 mg x [kg.sup.-1] x [day.sup.-1]) or vehicle control. Treatment of SHR with rosiglitazone lowered systolic blood pressure, reduced fasting plasma insulin and asymmetrical dimethylarginine, and increased insulin sensitivity (when compared with vehicle treatment). In vessel homogenates and serum from rosiglitazone-treated SHR, SOD activity was enhanced, while 8-iso-[PGF.sub.2[alpha]], (lipid peroxidation product) was reduced (when compared with samples from vehicle-treated SHR). Moreover, expression of p22phox (catalytic subunit of NADPH oxidase) as well as nitrotyrosine and superoxide content were all reduced in the aortas of rosiglitazone-treated SHR. In mesenteric vascular beds (MVB) isolated ex vivo from rosiglitazone-treated SHR, NO-dependent vasodilator actions of insulin were improved when compared with MVB from vehicle-treated SHR. Acute pretreatment of MVB from vehicle-treated SHR with apocynin (NADPH oxidase inhibitor) enhanced vasodilator actions of insulin (results comparable to those in MVB from rosiglitazone-treated SHR). In Langendorff heart preparations from rosiglitazone-treated SHR, ischemia/reperfusion injury caused infarcts 40% smaller than in hearts from vehicle-treated SHR. Acute pretreatment of hearts from vehicle-treated SHR with apocynin produced similar results. Finally, rosiglitazone treatment of endothelial cells in primary culture reduced superoxide induced by insulin-resistant conditions. We conclude that rosiglitazone therapy in SHR increases SOD activity and decreases p22phox expression in the vasculature to reduce oxidant stress leading to an improved cardiovascular phenotype. oxidative stress

The thiazolidinedione (TZD) drugs rosiglitazone (Ro) and pioglitazone (Po) are PPAR[gamma] agonists in widespread clinical use as insulin-sensitizing agents in Type 2 diabetes. On the basis of recent evidence implicating PPAR[gamma] as a positive modulator of intestinal epithelial differentiation, we hypothesized that TZD drugs might attenuate intestinal secretory function. To evaluate this possibility, we examined the effects of Ro and Po on electrogenic [Cl.sup.-] secretion [short-circuit current ([I.sub.sc])] in mouse intestinal segments and in cultured human intestinal epithelial cells (HT29-Cl.19A). As hypothesized, oral administration of Ro (20 mg x [kg.sup.-1] x [day.sup.-1]) to mice for 8 days markedly reduced intestinal [I.sub.sc] responses to cAMP (forskolin)- and [Ca.sup.2+] (carbachol)-dependent stimuli. In these Ro-treated mice, cholera toxin-induced intestinal fluid accumulation was reduced 65%. With continued Ro treatment, the [I.sub.sc] response to carbachol recovered significantly, whereas that to forskolin remained attenuated. Treatment of HT29 cells for 5 days with 10 [micro]M Ro or Po in vitro brought about a similar hyposecretory state. In HT29 cells, the loss of cAMP-dependent [Cl.sup.-] secretion was attributable to a reduced expression of CFTR [Cl.sup.-] channel, KCNQ1 [K.sup.+] channel, and Na-K-2Cl cotransporter-1 proteins. The transient loss of [Ca.sup.2+]-dependent [Cl.sup.-] secretion involved an impairment of basolateral [Ca.sup.2+]-stimulated [K.sup.+] channel activity without a detectable loss of [K.sub.Ca]3.1 channel protein. Our results establish TZD drugs as important modulators of intestinal [Cl.sup.-] secretory function. rosiglitazone; pioglitazone; KCNQ1; [K.sub.v]7.1; [K.sub.v]LQT1; KCNE3; MiRP2; [K.sub.Ca]3.1; KCNN4; mouse intestine; HT29 cells; secretory diarrhea; antidiarrheal

We investigated the mechanisms whereby peroxisome proliferator-activated receptor-[gamma], (PPAR[gamma]) agonism affects glucose and lipid metabolism in brown adipose tissue (BAT) by studying the impact of PPAR[gamma] activation on BAT glucose uptake and metabolism, lipogenesis, and mRNA levels plus activities of enzymes involved in triacylglycerol (TAG) synthesis. Interscapular BAT of rats treated or not with rosiglitazone (15 mg x [kg.sup.-1] x [day.sup.-1], 7 days) was evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (PAP or lipin-1), and diacylglycerol acyltransferase (DGAT). Rosiglitazone increased BAT mass without affecting whole tissue glucose uptake. BAT glycogen content (-80%), its synthesis from glucose (-50%), and mRNA levels of UDP-glucose pyrophosphorylase (-40%), which generates UDP-linked glucose for glycogen synthesis, were all reduced by rosiglita-zone. In contrast, BAT TAG-glycerol synthesis in vivo and glucose incorporation into TAG-glycerol in vitro were stimulated by the agonist along with the activities and mRNA levels of glycerol 3-phosphate-generating phosphoenolpyruvate carboxykinase and glycerokinase. Furthermore, rosiglitazone markedly increased the activities of GPAT and DGAT but not those of lipin-l-mediated PAP-l, enzymes involved in the sequential acylation of glycerol 3-phosphate and TAG synthesis. Because an adequate supply of fatty acids is essential for BAT nonshivering thermogenesis, the enhanced ability of BAT to synthesize TAG under PPAR[gamma] activation may constitute an important mechanism by which lipid substrates are stored in preparation for an eventual thermogenic activation. glycogen; glycerokinase; phosphoenolpyruvate carboxykinase; glycerolphosphate acyltransferase; lipin; diacylglycerol acyltransferase; peroxisome proliferator-activated receptor-[gamma]

Peroxisome proliferator-activated receptor (PPAR) agonists were shown to inhibit atherosclerosis through augmentation of endothelial nitric oxide synthase (eNOS) activity. In addition, rosiglitazone exerts a beneficial effect in chronic renal failure (CRF). Since L-arginine transport by CAT-1 (the specific arginine transporter for eNOS) is inhibited in uremia, we aimed to explore the effect of rosiglitazone on arginine transport in CRF. Arginine uptake by aortic rings was studied in control animals, rats, 6 wk following 5/6 nephrectomy (CRF) and rats with CRF treated with rosiglitazone. The decrease of arginine transport in CRF was prevented by rosiglitazone. Immunobloting revealed that CAT-1 protein was decreased in CRF but remained unchanged following rosiglitazone administration. Protein content of the membrane fraction of PKC[alpha] and phosphorylated CAT-I increased significantly in CRF, effects that were prevented by rosiglitazone. PKC[alpha] phosphorylation was unchanged but significantly attenuated by rosiglitazone in CRF. Ex vivo administration of phorbol-12-myristate13-acetate to rosiglitazone-treated CRF rats significantly attenuated the effect of rosiglitazone on arginine uptake. The decrease in cGMP response to carbamyl-choline (eNOS agonist) was significantly attenuated by rosiglitazone in CRF. Western blotting and immunohistochemistry analysis revealed that protein nitration was intensified in the endothelium of CRF rats and this was attenuated by rosiglitazone. In conclusion, rosiglitazone prevents the decrease in arginine uptake in CRF through both depletion and inactivation of PKC[alpha]. These findings are associated with restoration of eNO generation and attenuation of protein nitration and therefore may serve as a novel mechanism to explain the beneficial effects of rosiglitazone on endothelial function in uremia. uremia; protein nitration; endothelial function

A study was conducted to determine the effects of rosiglitazone on cardiovascular morbidity and mortality, which indicated an association of rosiglitazone with increase in the risk of myocardial infraction.

Results of a study to evaluate and compare the increased risk of acute myocardial infarction, stroke, heart failure, and death in the case of elderly Medicare patients treated with rosiglitazone as against pioglitazone have revealed that rosiglitazone resulted in an increased risk of negative outcomes in the case of such patients. The general view is that rosiglitazone should not be prescribed; however, further research on the subject is warranted.