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Ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) are calcium (Ca2+) release channels on the endo/sarcoplasmic reticulum (ER/SR). Here we summarize the latest advances in the field, describing the recently discovered mechanistic roles of intracellular Ca2+ release channels in the regulation of mitochondrial fitness and endothelial function, providing novel therapeutic options for the treatment of heart failure, hypertension, and diabetes mellitus. [ABSTRACT FROM AUTHOR]

Rivo is a novel PPARgamma agonist and potent antidiabetic agent. Expression of PPARalpha target genes and genes implicated in cardiac function was studied in the liver and heart of Zucker diabetic fatty rats treated with Rivo (1mg/kg) for 2 weeks, using pioglitazone (Pio; 100mg/kg), a PPARgamma agonist, and Wy-14,643 (Wy; 100mg/kg), a PPARalpha agonist, as comparators. Rivo and Pin normalized plasma concentrations of glucose, triglycerides (TG) and free fatty acids (FFA), while Wy decreased only plasma TG and FFA. In the heart and liver, Wy strongly increased expression of typical PPARalpha target genes such as acyl-coenzyme A oxidase 1 (ACO) and pyruvate dehydrogenase kinase 4 (PDK4), which may promote beta-oxidation of FFA as an energy source (Table). Rivo and Pio did not increase expression of these genes in the liver and Rivo decreased expression of ACO. In the heart, Rivo and Pin decreased the expression of ACO and medium chain acyl-CoA dehydrogenase (MCAD), suggesting reduced beta-oxidation of FFA and oxidative stress. They reduced expression of PDK4 and upregulated that of glucose transporter 4 (GLUT4) suggesting increased utilization of glucose. In addition, Rivo and Pin did not alter the expression of myosin heavy chain alpha and beta (MHCalpha and beta) or sarco/endoplasmic reticulum Ca[sup 2+] ATPase 2 (SERCA2), implicated in cardiac function. One week of treatment with Rivo (0.1 and 1mg/kg) or Wy (100mg/kg) reduced plasma TG primarily by accelerating TG clearance and reducing hepatic TG production, respectively. These results suggest that Rivo produces antidiabetic effects without augmenting the activity of PPARalpha and may have a desirable effect on cardiac function by improving cardiac energy homeostasis. Gene expression (% of control, meanSE; n=5, (*) p<0.05 vs control, ND=determined) [ABSTRACT FROM AUTHOR]

Abstract: The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia. [Copyright &y& Elsevier]