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

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.