Background-Angiotensin type 1 receptor (AT 1 R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator-activated receptor-␥ (PPAR␥) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPAR␥ function by ARBs. Methods and Results-The ARBs irbesartan and telmisartan (10 mol/L) potently enhanced PPAR␥-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3Ϯ0.1-fold induction; telmisartan: 3.1Ϯ0.3-fold induction; both PϽ0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 mol/L: 3.6Ϯ0.3-fold induction; PϽ0.01), whereas eprosartan up to 100 mol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 mol/L) markedly induced transcriptional activity of PPAR␥ by 3.4Ϯ0.9-fold and 2.6Ϯ0.6-fold (PϽ0.05), respectively, compared with 5.2Ϯ1.1-fold stimulation by the PPAR␥ ligand pioglitazone (10 mol/L). Irbesartan and telmisartan also induced PPAR␥ activity in an AT 1 R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPAR␥ activity independent of their AT 1 R blocking actions. Conclusions-The present study demonstrates that a specific subset of ARBs induces PPAR␥ activity, thereby promoting PPAR␥-dependent differentiation in adipocytes. 3 The underlying mechanism of the insulin-sensitizing/antidiabetic effect of ARBs is widely unknown.The nuclear hormone receptor peroxisome proliferator-activated receptor-␥ (PPAR␥) plays an important role in the regulation of insulin sensitivity. 4 Activated by its ligands such as prostaglandins or synthetic insulin-sensitizing thiazolidinediones/glitazones, PPAR␥ functions as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism, thereby ameliorating type 2 diabetes. 4 To elucidate the underlying mechanisms of the antidiabetic effect of ARBs, we investigated the effects of different ARBs on PPAR␥ function in 3T3-L1 cells, an established cell model to study PPAR␥ function. Methods Cell CultureMouse 3T3-L1 preadipocytes were cultured and differentiated as previously described by using a standard differentiation mixture Semiquantitative RT-PCR and Quantitative Real-Time PCRReal-time polymerase chain reaction (PCR) was performed as previously described with an ABI 7000 sequence detection system for real-time PCR. 6 Mouse 18S ribosomal RNA for real-time PCR and hypoxanthine guanine phosphoribosyl transferase or ␤-actin for semiquantitative reverse transcription (RT)-PCR were chosen as endogenous controls (housekeeping genes). Transfection and Luciferase AssayTransient transfection and...

Abstract-The adipose-specific protein adiponectin has been recently discovered to improve insulin sensitivity.Angiotensin type-1 receptor (AT1R) blockers (ARBs) reduce the incidence of type 2 diabetes mellitus by mostly unknown molecular mechanisms. To identify new antidiabetic mechanisms of ARBs, we studied the regulation of adiponectin by angiotensin II (Ang II) and different ARBs in murine 3T3-L1 adipocytes and obese Zucker rats. Adiponectin protein expression was markedly stimulated by Ang II (5 nmol/L), which was inhibited by blockade of the AT2R, and further enhanced by the ARB irbesartan. Irbesartan-mediated adiponectin upregulation started beyond the concentrations needed for AT1R blockade and was also present in the absence of Ang II, implicating an AT1R-independent mechanism of action. Recently, certain ARBs (irbesartan, telmisartan) were identified as ligands of the peroxisome proliferator-activated receptor (PPAR)␥. Telmisartan also stimulated adiponectin protein expression, whereas the non-PPAR␥-activating ARB eprosartan had no effect. Blockade of PPAR␥ activation by the PPAR␥ antagonist GW9662 markedly inhibited irbesartan-induced adiponectin expression. Cognate mRNA levels of adiponectin were not affected by ARBs. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that irbesartan prevented the cellular depletion of adiponectin protein. Finally, administration of irbesartan to obese Zucker rats improved insulin sensitivity and attenuated adiponectin serum depletion. The present study demonstrates that AT2R activation and certain ARBs induce adiponectin in adipocytes, which was associated with an improvement of parameters of insulin sensitivity in vivo. ARB-induced adiponectin stimulation is likely to be mediated via PPAR␥ activation involving a post-transcriptional mechanism. (Hypertension. 2005;46:137-143.)

After withdrawal of 400 ml whole blood and subsequent infusion of 500 ml of a colloidal plasma substituent, the intravascular and renal colloid elimination was investigated in 40 test subjects. The individual colloidal solutions could no longer be demonstrated in the intravascular space after the following times: 10% hydroxyethyl starch 200/0.5 (anthrone method) after six weeks, 10% dextran 40 (anthrone method) after two weeks, 6% hydroxyethyl starch 200/0.5 (anthrone method) after four weeks and 5.5% oxypolygelatine (hydroxyproline method) after two days. Colloidal plasma substitutes are polydisperse solutions with various molecular weights and degree of hydroxyethylation and therefore, also have a large number of different elimination constants. With repeated application, the intravascular colloid concentration shifts in favour of the molecules with a longer half life which are difficult to eliminate. The elimination of the clinically employed dextran 40 and oxypolygelatine solution could be best described with an open two-compartment model. As a result of its greater heterogeneity, the elimination of the moderately high molecular weight hydroxyethyl starch 200/0.5 could only be characterized approximately even assuming three elimination constants. In the first four days, the hydroxyethyl starch 200/0.5 was more rapidly eliminated compared to dextran 40. However, subsequently a very much lower elimination from the intravascular space was found for about 3% of the administered hydroxyethyl starch 200/0.5. Oxypolygelatine was eliminated especially rapidly. Accordingly, the greatest renal clearance was found for oxypolygelatine, which showed a close relation to the molecular weight. On the other hand, a rapid elimination simultaneously is followed by a correspondingly lower volume effect.