Olive oil lipophenols induce insulin secretion in 832/13 beta cell models

Glycemic control is the mainstay of Type 2 Diabetes Mellitus (T2DM) clinical management. Despite the continuous improvement in knowledge and progress in terms of treatment, the achievement of the physiologic metabolic profile is still an ongoing challenge in diabetic patients. As a receptor of medium- and long-chain free fatty acids (FFAs), G-protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1, has been well documented to contribute to insulin secretion and several agonists to this receptor have been developed. However, their use is hampered by the occurrence of serious adverse effects such as hepatotoxicity. Herein, we demonstrated the insulin secretagogue activity of Hydroxytyrosol oleate (HtyOle) and Tyrosyl oleate (TyOle), two naturally occurring lipo-phenols deriving from the conjugation of oleic acid (OA) and Hydroxytyrosol (Hty) and Tyrosol (Ty), respectively, in pancreatic β-cell line INS-1 832/13. Furthermore, we provided evidence of HtyOle and TyOle as natural modulators of FFAR1 receptor as revealed by functional and molecular docking approaches. Of note, the facilitatory activity on insulin secretion under glucose-induced insulin secretion (GSIS) condition of HtyOle and TyOle occurred at low concentrations of these compounds thus limiting the lipotoxic risk of oleic acid itself. Our results paved the way for the use for pharmacological of a new class of anti-diabetic agents’ plant derivative with a more favorable safety profile.