Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity.

The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPARgamma; influence the expression of PPARgamma target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet.

Transgenic and recombinant resistin impair skeletal muscle glucose metabolism in the spontaneously hypertensive rat.

Increased serum levels of resistin, a molecule secreted by fat cells, have been proposed as a possible mechanistic link between obesity and insulin resistance. To further investigate the effects of resistin on glucose metabolism, we derived a novel transgenic strain of spontaneously hypertensive rats expressing the mouse resistin gene under the control of the fat-specific aP2 promoter and also performed in vitro studies of the effects of recombinant resistin on glucose metabolism in isolated skeletal muscle. Expression of the resistin transgene was detected by Northern blot analysis in adipose tissue and by real-time PCR in skeletal muscle and was associated with increased serum fatty acids and muscle triglycerides, impaired skeletal muscle glucose metabolism, and glucose intolerance in the absence of any changes in serum resistin concentrations.

Use of a panel of congenic strains to evaluate differentially expressed genes as candidate genes for blood pressure quantitative trait loci.

Candidate gene(s) for multiple blood pressure (BP) quantitative trait loci (QTL) were sought by analysis of differential gene expression patterns in the kidneys of a panel of eight congenic strains, each of which carries a different low-BP QTL allele with a genetic composition that is otherwise similar to that of the hypertensive Dahl salt-sensitive (S) rat strain. First, genes differentially expressed in the kidneys of one-month-old Dahl S and salt-resistant (R) rats were identified. Then, Northern filter hybridization was used to examine the expression patterns of these genes in a panel of congenic strains.

Pharmacogenetic evidence that cd36 is a key determinant of the metabolic effects of pioglitazone.

Pioglitazone, like other thiazolidinediones, is an insulin-sensitizing agent that activates the peroxisome proliferator-activated receptor gamma and influences the expression of multiple genes involved in carbohydrate and lipid metabolism. However, it is unknown which of these many target genes play primary roles in determining the antidiabetic and hypolipidemic effects of thiazolidinediones. To specifically investigate the role of the Cd36 fatty acid transporter gene in the insulin-sensitizing actions of thiazolidinediones, we studied the metabolic effects of pioglitazone in spontaneously hypertensive rats (SHR) that harbor a deletion mutation in Cd36 in comparison to congenic and transgenic strains of SHR that express wild-type Cd36.