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Loss of Stearoyl-CoA Desaturase-1 Improves Insulin Sensitivity in Lean Mice but Worsens Diabetes in Leptin-Deficient Obese Mice

¹ Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin
² Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin

Address correspondence and reprint requests to Alan D. Attie, Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Dr., Madison, WI 537606. E-mail: attie{at}biochem.wisc.edu

Abbreviations: FFA, free fatty acid; HGO, hepatic glucose output; MUFA, monounsaturated fatty acid; saturated fatty acid; SCD, stearoyl-CoA desaturase; SFA, saturated fatty acid

The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet- and leptin deficiency–induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptin^ob/ob mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased 70%. In response to a glucose challenge, Scd1^–/– leptin^ob/ob mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1^–/– leptin^ob/ob mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of ß-cells, resulting in an increased risk of diabetes.

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