Effects And Mechanism Of Arachidonic Acid On Pancreatic β-cell Functions

Effects and Mechanism of Arachidonic Acid on Pancreatic B-cell FunctionsDiabetes has globally become a serious public health problem, and some 170 million people now have this condition. In China, the people with Diabetes are about 40 million, with more than 90% Diabetes being type 2 Diabetes. The morbidity of type 2 Diabetes, obesity and hyperlipidemia is yearly increasing, and the incidence of Diabetes among the Youngers is increasing alarmingly. Insulin resistance may play a pivotal role in those disorders which are commonly characterized by dyslipidemia. More than 80% of type 2 diabetic individuals are obese or overweight, a strongly risk factor for developing type 2 diabetes. Subjects with obesity and type 2 diabetes exclusively have a disturbance of lipid metabolism, with an increase of plasma FFA, cholesterol, low density lipoprotein, triglyceride, and a decrease of high density lipoprotein.In the typical patient with type 2 diabetes, damage to the P-cells is not caused by hyperglycemia, glycosylation of proteins, or amyloid deposition. Rather, it appears to occur because of lipotoxicity (i.e., elevated serum FFA and depoisition of triglyceride in pancreatic islet), which is also associated with the insulin resistance syndrome. An autopsy study in humans showed that fat content of p-cells, but not a- or duct cells, increased with the age. Interestingly, only one third of insulin-resistant patients developed diabetes; in the other two thirds, insulin production and release increase to overcome the insulin resistance. The pathophysioligical basis for this is increased FFA, especially SFA reducing the biosynthesis and secretion of insulin, and deposition of triglyceride in pancreatic p-cells leads to apoptosis which decreases insulin secretion of islet p-cell.T2DM are characterized of obesity and or elevated plasma FFA level. It is now wellestablished, both in vitro and in vzvo, that short exposure to FFA can stimulate glucose-induced insulin secretion in the fast state, whereas long-term exposure decreases the insulin secretion, and inhibits insulin-mediated glucose uptake in the muscles and liver. FFA concentration of 0.5 mM can stimulate the pancreatic P-cell insulin release, while further elevation of FFA inhibits glucose-induced insulin secretion, referred to as pancreatic p-cell lipotoxicity. A raise of FFA can increase the intracellular content of long-chain acyl-CoA (LC-CoA). LC-CoA, as a signaling molecule, it might modulate the activity of glucokinase or glucose-6-phosphatase, exocytosis, the docking or fusion of the insulin vesicle, endoplasm Ca2+ influx, protein kinase C (PKC), carnitine palmitoyltransfease (CPT-1), acetyl-CoA carboxylase (ACC). An increase in the cytosolic concentration of LC-CoA influences the pancreatic P-cell insulin secretion via the above process. In addition, the effectiveness of individual FFA is different, with increased insulinotropic potency with prolongs of carbon chain and raised degree of saturation.Our previous data indicated that arachidonic acid (AA) more than 1-20 times physiological concentration could inhibit the apoptosis of ovarian granulosa and Leydig cells induced by saturated fatty acids, but AA itself, at the level more than 50 times physiological concentration was cytotoxic, even led to cell apoptosis. It suggested that the ratio of saturated fatty acids and AA might be very important factor for cell function. Different level of AA has different effects on the pancreatic P-cell, Based on our previous data, we hypothesis that AA might antagonize impaired pancreatic P-cell biosynthesis or secretion of insulin and prevent the p-cell cytotoxicity induced by saturated fatty acids. In review of this, we investigate whether AA can relieve the impaired pancreatic p-cell function, decreased insulin biosynthesis and secretion, induced by saturated fatty acids, and whether AA can prevent the pancreatic p-cell apoptosis induced by saturated fatty acids. Material and MethodsPancreatic p-cell line NIT-1 established from a transgenic NOD/Lt mouse were grown in...