Peroxisome proliferator-activated receptor-gamma agonist improves skeletal muscle insulin signaling in the pregestational intrauterine growth-restricted rat offspring.

Abstract

The effect of early intervention with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist on skeletal muscle GLUT4 translocation and insulin signaling was examined in intrauterine (IUGR) and postnatal (PNGR) growth-restricted pregestational female rat offspring. Rosiglitazone [11 mumol/day provided from postnatal day (PN)21 to PN60] improved skeletal muscle insulin sensitivity and GLUT4 translocation in prenatal nutrient restriction [50% calories from embryonic day (e)11 to e21; IUGR] with (IUGR+PNGR) and without (IUGR) postnatal nutrient restriction (50% calories from PN1 to PN21; PNGR) similar to that of control (ad libitum feeds throughout; Con) (n = 6 each). This was accomplished by diminished basal and improved insulin-responsive GLUT4 association with the plasma membrane in IUGR, IUGR+PNGR, and PNGR mimicking that in Con (P < 0.005). While no change in p85-phosphatidylinositol 3-kinase (PI3-K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed, a decrease in protein tyrosine phosphatase 1B (PTP1B; P < 0.0002) and SH2-containing protein tyrosine phosphatase 2 (SHP2; P < 0.05) contributing to the rosiglitazone-induced insulin sensitivity was seen only in IUGR+PNGR. In contrast, an increase in phosphorylated 5'-adenosine monophosphate kinase (pAMPK; P < 0.04) and insulin responsiveness of phosphorylated phosphoinositide-dependent protein kinase-1 (pPDK1; P < 0.05), pAkt (P < 0.01), and particularly pPKCzeta (P < 0.0001) and its corresponding enzyme activity (P < 0.005) were observed in all four experimental groups. We conclude that early introduction of PPARgamma agonist improved skeletal muscle activation of AMPK and insulin signaling, resulting in insulin-independent AMPK and insulin-responsive GLUT4 association with plasma membranes in IUGR, IUGR+PNGR, and PNGR adult offspring, similar to that of Con. These findings support a role for insulin sensitizers in preventing the subsequent development of gestational or type 2 diabetes mellitus in intrauterine and postnatal growth-restricted offspring.

• Authors: Shilpa Oak, Cang Tran, Maria-Olivia Castillo, Shanthie Thamotharan, Manikkavasagar Thamotharan, Sherin U Devaskar
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 297 Issue 2 Pg. E514-24 (Aug 2009) ISSN: 1522-1555 [Electronic] United States
• PMID: 19491300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Glucose Transporter Type 4
• Hypoglycemic Agents
• Insulin
• PPAR gamma
• Slc2a4 protein, rat
• Thiazolidinediones
• Rosiglitazone

Topics

• Algorithms
• Animals
• Drug Evaluation, Preclinical
• Female
• Fetal Growth Retardation (metabolism, pathology, physiopathology, rehabilitation)
• Glucose Transporter Type 4 (metabolism)
• Growth (drug effects)
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism)
• Models, Biological
• Muscle, Skeletal (drug effects, metabolism)
• PPAR gamma (agonists)
• Pregnancy
• Prenatal Exposure Delayed Effects (metabolism, physiopathology, rehabilitation)
• Rats
• Rosiglitazone
• Signal Transduction (drug effects)
• Thiazolidinediones (pharmacology)