Protective role of Pollen Typhae total flavone against the palmitic acid-induced impairment of glucose-stimulated insulin secretion involving GPR40 signaling in INS-1 cells

Abstract

Prolonged elevated levels of free fatty acids (FFAs) contribute to the impairment of insulin secretion function of pancreatic β cells, a hallmark of type 2 diabetes, which is partly attributed to the dysfunction of G-protein-coupled receptor 40 (GPR40) signaling. Pollen Typhae total flavone (PTF), an extract from a Chinese herbal medicine named Pollen Typhae, has been reported to effectively treat type 2 diabetes, but the underlying mechanisms remain to be fully elucidated. In the present study, palmitic acid (PA), a saturated fatty acid, severely impaired glucose-stimulated insulin secretion (GSIS) in a time-dependent manner in INS-1 cells, and PTF treatment prevented the impairment in a dose-dependent manner. Moreover, PTF improved insulin secretion function in rats presenting with type 2 diabetes induced by a high-fat diet and low-dose streptozotocin. Furthermore, PA exposure for 24 h decreased the protein expression of GPR40, phospholipase C (PLC)β1, PLCβ3, and protein kinase C (PKC), and inhibited the activity of PLC and PKC stimulated by GW9508, a GPR40 agonist. In addition, PTF enhanced the protein expression of GPR40 and to a certain extent strengthened the protein expression of PKC, increased cellular levels of triphosphoinositide (IP3) and diacylglycerol (DAG), and promoted GW9508-stimulated activity of PLC and PKC reduced by PA in INS-1 cells, which were blocked by PLC inhibitor U-73122 and PKC inhibitor staurosporine, respectively. Additionally, the improvement in PA-induced impairment of GSIS by PTF in INS-1 cells was restrained by U-73122, staurosporine, and calcium channel inhibitor nifedipine, respectively. The results indicate that PTF exerts a protective role against PA-induced impairment of GSIS involving GPR40 signaling in INS-1 cells.

Calcium channel blockers do not protect against saturated fatty acid-induced ER stress and apoptosis in human pancreatic β-cells

“…However, we did not test the effect of calcium influx inhibitors on insulin secretion. Thus there is still a possibility that these compounds may exert a certain protective effect in human β-cells via inhibition of saturated FA-induced impairment of insulin secretion as found in rodent β-cells [ 27 , 48 ]. Tested compounds themselves (especially verapamil) had when using higher concentrations even pro-apoptotic effect on β-cells.…”

Pioglitazone Ameliorates Atorvastatin-Induced Islet Cell Dysfunction through Activation of FFA1 in INS-1 Cells

“…The free fatty acid (FFA) receptor, free fatty acid receptor 1 (FFA1), or G protein-coupled receptor 40 (GPR40) is a member of the G protein-coupled receptors highly expressed in rodent and human pancreatic β -cells [8, 9]. FFA1 has been recognized to mediate insulin secretion in a phospholipase C- (PLC-) dependent manner; hence, it plays an important role in type 2 diabetes mellitus [10–14]. It is well known that thiazolidinediones (TZDs), synthetic ligands for peroxisome proliferator-activated receptor- γ (PPAR- γ ), cause their glucose-lowering effects principally via reversing insulin resistance.…”