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Sc-26196, a delta-6 desaturase inhibitor, normalizes glucose tolerance in ob/ob mice




Routh, Melissa Anne, author
Chicco, Adam J., advisor
Bouma, Gerrit, committee member
Frye, Melinda, committee member
Paul, Laybourn, committee member

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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.


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