Abstract

Background:Attenuation of hyperinsulinemia in obese Zucker rats by diazoxide (DZ) enhanced insulin sensitivity and insulin-stimulated glucose uptake in isolated adipocytes. To determine if these metabolic effects are due to changes in glucose transporter (Glut)-4 gene products and intracellular signaling, we studied the effects DZ on adipose tissue Glut-4 gene products, insulin receptor substrate (IRS)-1, total and phosphorylated protein kinase B (PKB)/Akt.Material/Methods: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for 6 weeks.Results: While adipose Glut-4 mRNA levels from control obese and lean rats were similar, Glut-4 protein content was 60% lower in obese than lean animals (p<0.05). DZ treatment increased mRNA in both obese (1.4 fold) and lean (1.7 fold) animals compared to controls (p<0.05), which was associated with a 3.7 fold and a 1.4 fold increase in Glut-4 protein content in DZ obese (p<0.01) and lean (p<0.05) rats, respectively. IRS-1 protein expression was lower in obese compared to lean rats (p<0.01) and was enhanced in DZ-treated obese (p<0.02) and lean (p<0.05) rats. While the PKB/Akt protein levels were similar in both strains, obese had lower p-Akt levels than lean rats (p<0.01). DZ-treated obese and lean rats had higher levels of p-Akt than their controls (p<0.05).
Conclusions: Chronic suppression of hyperinsulinemia in obese Zucker rats improved intracellular insulin signaling and Glut-4 gene expression, corresponding to enhanced glucose uptake in isolated adipocytes. The discrepancy between adipose tissue Glut-4 mRNA and protein content in response to DZ treatment suggests post-transcriptional regulatory effects resulting from enhanced metabolic efficiency of insulin action.

Keywords: Glucose - metabolism, Proto-Oncogene Proteins - metabolism, Adipose Tissue - enzymology, Biological Transport, Blood Glucose - metabolism, Blotting, Northern, Cell Membrane - metabolism, Diazoxide - pharmacology, Enzyme Activation, Glucose - pharmacokinetics, Glucose Transporter Type 4, Insulin - metabolism, Insulin Receptor Substrate Proteins, Monosaccharide Transport Proteins - biosynthesis, Muscle Proteins, Phosphoproteins - metabolism, Phosphorylation, Protein-Serine-Threonine Kinases, RNA - chemistry, RNA Processing, Post-Transcriptional, RNA, Messenger - metabolism, Rats, Zucker, Signal Transduction, Subcellular Fractions - metabolism, Time Factors, Vasodilator Agents - pharmacology