Dgat1 Inhibitors Protect Pancreatic Beta-Cells From Palmitic Acid-Induced Apoptosis

Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic beta-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic beta-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4aand LCQ908) at the concentration of 1 mu M significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic beta-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets indb/dbmice. Meanwhile,4aadministration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance indb/dbmice. Furthermore, we revealed that pretreatment with 4a(1 mu M) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic beta-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.