1-2-dielaidoylphosphatidylethanolamine and Insulin-Resistance

To enhance the solubility of rosiglitazone, rosiglitazone-loaded cationic lipid emulsion was formulated using cationic lipid DOTAP, DOPE, castor oil, tween 20, and tween 80. The formulation parameters in terms of droplet size were optimized focused on the effect of the cationic lipid emulsion composition ratio on drug encapsulating efficiency, in vitro drug release, and cellular uptake of the rosiglitazone-loaded emulsion. Droplet sizes of a blank cationic emulsion and a rosiglitazone-loaded cationic emulsion ranged between 195-230 nm and 210-290 nm, respectively. The encapsulation efficiency of the rosiglitazone-loaded emulsion was more than 90%. The rosiglitazone-loaded cationic emulsion improved in vitro drug release over the drug alone and showed a much higher cellular uptake than rosiglitazone alone. Moreover, drug loading in cationic emulsions increased cellular uptake of rosiglitazone in insulin-resistant HepG2 cells more than the normal HepG2 cells. Taken together, these results indicate that cationic lipid emulsions could be a potential delivery system for rosiglitazone and could enhance its cellular uptake efficiency into target cells.

Topics: Biological Transport; Carcinoma, Hepatocellular; Castor Oil; Cations; Chemistry, Pharmaceutical; Drug Carriers; Drug Stability; Emulsions; Fatty Acids, Monounsaturated; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Hypoglycemic Agents; Insulin Resistance; Lipids; Liver Neoplasms; Nanoparticles; Particle Size; Phosphatidylethanolamines; Polysorbates; Quaternary Ammonium Compounds; Rosiglitazone; Solubility; Surface-Active Agents; Technology, Pharmaceutical; Thiazolidinediones

Glycogen synthase (GS) is the rate-limiting enzyme controlling nonoxidative glucose disposal in skeletal muscle. A reduction in GS activity and an impaired insulin responsiveness are characteristic features of skeletal muscle in type 2 diabetes. These properties also exist in human skeletal muscle cell cultures from type 2 diabetic subjects. To determine the effect of an isolated reduction in GS on skeletal muscle insulin action, cultures from nondiabetic subjects were treated with antisense oligonucleotides (ODNs) to GS to interfere with expression of the gene. Treatment with antisense ODNs reduced GS protein expression by 70% compared with control (scrambled) ODNs (P < .01). GS activity measured at 0.01 mmol/L glucose-6-phosphate (G-6-P) was reduced by antisense ODN treatment. The insulin responsiveness of GS was impaired. Insulin also failed to stimulate glucose incorporation into glycogen after antisense ODN treatment. The cellular glycogen content was lower in antisense ODN-treated cells compared with control ODN. The insulin responsiveness of glucose uptake was abolished by antisense ODN treatment. Thus, reductions in GS expression in human skeletal muscle cells lead to impairments in insulin responsiveness and may play an important role in insulin-resistant states.

Topics: Adult; Amino Acid Transport System X-AG; ATP-Binding Cassette Transporters; Culture Techniques; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Silencing; Glucose; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Humans; Insulin; Insulin Resistance; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Oligoribonucleotides, Antisense; Phosphatidylethanolamines; RNA, Messenger