Sc-26196, a delta-6 desaturase inhibitor, normalizes glucose tolerance in ob/ob mice
Date
2012
Authors
Routh, Melissa Anne, author
Chicco, Adam J., advisor
Bouma, Gerrit, committee member
Frye, Melinda, committee member
Paul, Laybourn, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
The incidence of diabetes has reached epidemic levels worldwide, and while researchers know more about the phenomenon than ever, an effective treatment still remains elusive. Recently, chronic low-grade inflammation has been shown to play a key role in insulin resistance and diabetes. The purpose of this study was to demonstrate a role for the delta-6 desaturase (D6D) in diabetes, and furthermore to elucidate the potential mechanism by which inhibition of D6D by sc-26196 treatment could restore glucose tolerance in obese insulin resistant ob/ob mice. Treatment of 4-month-old male ob/ob mice with the selective D6D inhibitor sc-26196 (SC, 100 mg/kg/d for 4 weeks) improved response to an acute glucose challenge (1 mg/g BW i.p.), as indicated by lower peak (146% vs. 219% of fasting) and final (85% vs. 180% of fasting 2 hours-post bolus) blood glucose levels versus untreated ob/ob mice (p<0.01). Increased hepatic macrophage infiltration in addition to increased phosphorylation of JNK proteins and inhibitory IRS phosphorylation in untreated ob mice was attenuated by sc-26196 treatment, which suggests that D6D inhibition improves glucose tolerance by decreasing inflammation and restoring insulin signaling by way of the IRS/PI3K pathway. This study demonstrates the effectiveness of sc-26196 treatment for glucose intolerance in ob/ob mice and results warrant future studies for use of sc-26196 in the clinical treatment of insulin resistance and diabetes.