eprosartan and Insulin-Resistance

The subjects of the study were 30 patients with type II diabetes mellitus and mild or moderate arterial hypertension. Clinical-and-hemodinamic organoprotective effects of eprosartan, a new angiotensin II blocker, was evaluated in these patients within 16 weeks. The study found a good hypotensive effect of monotherapy with eprosartan in a mean therapeutic dose of 600 mg/day--the target blood pressure levels were achieved in 63.3% of the patients. Fasting insulin level and insulin resistance decreased, which improved hydrocarbonate and lipid exchange parameters. Eprosartan was significantly effective as an organoprotective agent: the patients displayed improvement of eye ground vessel condition, decrease of microalbuminuria, improvement of cardiodynamic parameters i.e. decrease of the thickness of left ventricular (LV) back wall and intravenricular septum, as well as reduction of myocardial mass index. 70% of the patients demonstrated improvement of LV diastolic function.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Diastole; Female; Humans; Hypertension; Imidazoles; Insulin; Insulin Resistance; Lipid Metabolism; Male; Middle Aged; Receptor, Angiotensin, Type 1; Thiophenes; Time Factors; Treatment Outcome; Ventricular Function, Left

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-gamma (PPARgamma) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARgamma function by ARBs.. The ARBs irbesartan and telmisartan (10 micromol/L) potently enhanced PPARgamma-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: 3.3+/-0.1-fold induction; telmisartan: 3.1+/-0.3-fold induction; both P<0.01). 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 micromol/L: 3.6+/-0.3-fold induction; P<0.01), whereas eprosartan up to 100 micromol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 micromol/L) markedly induced transcriptional activity of PPARgamma by 3.4+/-0.9-fold and 2.6+/-0.6-fold (P<0.05), respectively, compared with 5.2+/-1.1-fold stimulation by the PPARgamma ligand pioglitazone (10 micromol/L). Irbesartan and telmisartan also induced PPARgamma activity in an AT1R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPARgamma activity independent of their AT(1)R blocking actions.. The present study demonstrates that a specific subset of ARBs induces PPARgamma activity, thereby promoting PPARgamma-dependent differentiation in adipocytes. The activation of PPARgamma demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.

Topics: 3T3 Cells; Acrylates; Adipocytes; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Biphenyl Compounds; Cell Differentiation; Genes, Reporter; Imidazoles; Insulin Resistance; Irbesartan; Losartan; Luciferases; Mice; PC12 Cells; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoid X Receptors; Telmisartan; Tetrazoles; Thiophenes; Transcription Factors; Transfection

Acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril enhances insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat. The present study was designed to assess whether this effect is mediated by an increase in the nonapeptide bradykinin (BK), by a decrease in action of ANG II, or both. Obese Zucker rats (8-9 wk old) were treated for 2 h with either captopril (50 mg/kg orally), bradykinin (200 micrograms/kg ip), or the ANG II receptor (AT(1) subtype) antagonist eprosartan (20 mg/kg orally). Captopril treatment enhanced in vitro insulin-stimulated (2 mU/ml) 2-deoxyglucose uptake in the epitrochlearis muscle by 22% (251 +/- 7 vs. 205 +/- 9 pmol. mg(-1). 20 min(-1); P < 0.05), whereas BK treatment enhanced this variable by 18% (249 +/- 15 vs. 215 +/- 7 pmol. mg(-1). 20 min(-1); P < 0.05). Eprosartan did not significantly modify insulin action. The BK-mediated increase in insulin action was completely abolished by pretreatment with either the specific BK-B(2) receptor antagonist HOE 140 (200 micrograms/kg ip) or the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (50 mg/kg ip). Collectively, these results indicate that the modulation of insulin action by BK likely underlies the metabolic effects of ACE inhibitors in the insulin-resistant obese Zucker rat. Moreover, this modulation of insulin action by BK is likely mediated through B(2) receptors and by an increase in nitric oxide production and/or action in skeletal muscle tissue.

Topics: Acrylates; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Female; Glucose; Imidazoles; Insulin Resistance; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Zucker; Thiophenes