Abstract
Type 2 diabetes results from defects in both insulin sensitivity and insulin secretion. Elevated cholesterol content within pancreatic β-cells has been shown to reduce β-cell function and increase β-cell apoptosis. Hyperglycemia and dyslipidemia contribute to glucolipotoxicity that leads to type 2 diabetes. Here we examined the capacity of glucolipotoxicity to induce free cholesterol accumulation in human pancreatic islets and the INS-1 insulinoma cell line. Glucolipotoxicity treatment increased free cholesterol in β-cells, which was accompanied by increased reactive oxygen species (ROS) production and decreased insulin secretion. Addition of AAPH, a free radical generator, was able to increase filipin staining indicating a link between ROS production and increased cholesterol in β-cells. We also showed the ability of stigmasterol, a common food-derived phytosterol with anti-atherosclerotic potential, to prevent the increase in both free cholesterol and ROS levels induced by glucolipotoxicity in INS-1 cells. Stigmasterol addition also inhibited early apoptosis, increased total insulin, promoted actin reorganization, and improved insulin secretion in cells exposed to glucolipotoxicity. Overall, these data indicate cholesterol accumulation as an underlying mechanism for glucolipotoxicity-induced defects in insulin secretion and stigmasterol treatment as a potential strategy to protect β-cell function during diabetes progression.
Highlights
As of 2014, an estimated 422 million people have diabetes worldwide, with type 2 diabetes representing approximately 90% of the adult cases[1]
To determine if glucolipotoxicity treatment can increase free cholesterol within β-cells, INS-1 insulinoma cells and human islets were treated with HGP (30 mM glucose, 0.5 mM palmitate) or normal growth medium (LG) for 72 h
Cholesterol accumulation may occur through increased uptake of LDL, increased biosynthesis, or decreased efflux to acceptors such as HDL
Summary
As of 2014, an estimated 422 million people have diabetes worldwide, with type 2 diabetes representing approximately 90% of the adult cases[1]. Type 2 diabetes is marked by insulin resistance and pancreatic β-cell dysfunction. Glucolipotoxicity is shown in vitro to increase β-cell death and decrease insulin secretion[7,8,9]. Glucolipotoxicity may lead to increased cholesterol in β-cells as evidenced by studies performed in mouse and cell lines[10, 13, 14]. (HMG-CoA reductase, the rate-limiting enzyme for cholesterol synthesis), are best at reducing serum cholesterol in order to prevent cardiovascular diseases, they present a modestly increased risk for the onset of new diabetes cases[16,17,18,19]. Possible mechanisms include side effects that are independent of statin’s cholesterol-lowering property, such as a statin-specific immune response leading to insulin resistance[20]. Alternative ways to reduce cholesterol in β-cells are needed
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