Loss of SCD1 unexpectedly worsens diabetes in leptin‐deficient obese mice

Abstract

The lipogenic gene stearoyl-CoA desaturase (SCD1) is a promising new target for obesity-related diabetes as mice deficient in this enzyme are resistant to diet and leptin deficiency-induced obesity. To determine if reduced adiposity in Scd1 -/- mice is sufficient to prevent diabetes in a diabetes-susceptible obese model we generated leptin-deficient BTBR Scd1 -/- mice. Despite a reduction in body weight, loss of SCD1 unexpectedly accelerated the progression to severe diabetes with 6-week 4-hr fasting glucose values of 484.6 ± 29.5 mg/dl (288.6 ± 19.3 in wild-type (WT)), insulin of 9.3 ± 2.2 ng/ml (14.9 ± 0.8 in WT), and triglyceride levels of 186.3 ± 17.9 mg/dl (98.1 ± 4.1 in WT). Values are mean ± SE with Scd1 -/- n=17, WT n=46. Diabetes progression is characterized by diminished β-cell function. To assess β-cell function we compared the responsiveness of islets isolated from 6-week old WT and Scd1 -/- mice to low (1.7 mM) and high (16.7 mM) glucose and saw no difference in insulin secretion. A distinct class of islets isolated from the Scd1 -/- mice had a 6-fold reduction in insulin content and a 4-fold and 3-fold increase in triglyceride and free fatty acids, respectively. We predict that there is a net decrease in insulin secretion in vivo due to the high prevalence (up to 80%) of this distinct class of islets in the Scd1 -/- mice. Our data support recent evidence that upregulation of SCD1 in β-cells is a compensatory mechanism to prevent the cytotoxic effects of fatty acids. Therefore although loss of this enzyme has beneficial effects on weight loss, this benefit may come at the expense of β-cells, resulting in an increased risk of diabetes development. Research supported by grants from NIH, NIDDK, ADA, and USDA.