Saroglitazar is a novel dual PPARα/γ agonist that shows significant triglyceride-lowering and insulin-sensitizing effects in animal models and humans. Saroglitazar causes insulin sensitization and increases flux of lipids in adipocytes thereby preventing the glucotoxicity and lipotoxicity. It also improves mitochondrial bioenergetics potential and increased the ATP production rate and reduces the expression of pro-inflammatory (TNFα, IL1β and IL6) genes. In this study, we have evaluated the potential of saroglitazar to delay the onset or prevent development of T2DM in db/db mice. The db/db mouse is a widely used model for T2DM and shows progressive changes starting with development of obese phenotype at the age of 4 weeks followed by hyperglycemia and hyperinsulimenic condition between 4-8 weeks of age and hypoinsulinemia accompanied by hyperglycemia at 12-16 weeks of age. Group of male db/db mice were treated with saroglitazar (0.8 and 2.5 mg/kg, p.o.) or metformin (250 mg/kg, p.o.) starting at the age of 4 weeks (prediabetes condition) and continued the treatment for 12 weeks (till animals become 16 weeks old and develop frank T2DM). Saroglitazar treatment for 12 weeks completely prevented diabetes onset as reflected by normal fed and fasting blood glucose levels during 6-16th week, whereas metformin treated animals showed elevated fasting blood glucose levels after 8 weeks. Saroglitazar also caused almost 100% improvement in glucose tolerance and insulin sensitivity which was not shown by metformin. Furthermore, as compared to placebo and metformin treated db/db mice, saroglitazar-treated showed HbA1c levels similar to normal C57 mice indicating total protection from development of diabetes. It appears that by unique engagement of PPARα and PPARγ, saroglitazar not only normalizes lipids and glucose, but it also preserves the pancreatic β cell function and prevents development of T2DM by a combination of mechanisms involving anti-inflammatory, anti-oxidant, lipid regulating and glucose regulatory pathways.
S.R. Giri: None. B.B. Bhoi: None. C.J. Trivedi: None. A.C. Rath: None. R.M. Rathod: None. M.R. Jain: None.