S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

Journal Article · Fri Jul 23 04:00:00 EDT 2010 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2010.06.070· OSTI ID:22202703

Vikram, Ajit ^[1]; Jena, Gopabandhu ^[1]

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1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India)

Research highlights: {yields}Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. {yields}Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. {yields}Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. {yields}Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ({approx}18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPAR{gamma}) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 {+-} 16.32 vs. 126.37 {+-} 27.07 mg/dl) and glucose intolerance ({approx}78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

• OSTI ID: 22202703
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 398; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADIPOSE TISSUE
GLUCOSE
GLYCOGEN
HOMEOSTASIS
HYPERGLYCEMIA
INSULIN
LIVER
METABOLISM
PEPTIDES
RATS
RECEPTORS