Effects of High-Density Lipoproteins on Pancreatic β-Cell Insulin Secretion

Abstract

Objective-Type 2 diabetes is characterized by impaired ␤-cell secretory function, insulin resistance, reduced high-density lipoprotein (HDL) levels, and increased cardiovascular risk. Given the current interest in therapeutic interventions that raise HDLs levels, this study investigates the effects of HDLs on insulin secretion from ␤-cells. Methods and Results-Incubation of Min6 cells and primary islets under basal or high-glucose conditions with either apolipoprotein (apo) A-I or apoA-II in the lipid-free form, as a constituent of discoidal reconstituted HDLs (rHDLs), or with HDLs isolated from human plasma increased insulin secretion up to 5-fold in a calcium-dependent manner. The increase was time and concentration dependent. It was also K ATP channel and glucose metabolism dependent under high-glucose, but not low-glucose, conditions. The lipid-free apolipoprotein-mediated increase in insulin secretion was ATP binding cassette (ABC) transporter A1 and scavenger receptor-B1 dependent. The rHDL-mediated increase in insulin secretion was ABCG1 dependent. Exposure of ␤-cells to lipid-free apolipoproteins also increased insulin mRNA expression and insulin secretion without significantly depleting intracellular insulin or cholesterol levels. Conclusion-These results establish that lipid-free and lipid-associated apoA-I and apoA-II increase ␤-cell insulin secretion and indicate that interventions that raise HDLs levels may be beneficial in type 2 diabetes. ␤-Cell dysfunction and insulin resistance are major pathophysiological characteristics of type 2 diabetes. Although insulin resistance occurs early in disease onset, it causes diabetes only when ␤-cell dysfunction is also present. [1][2][3] The UK Prospective Diabetes Study found that at the time of disease diagnosis, ␤-cell secretory function was about 50% of normal and predicted that this was the culmination of at least 10 years of prior functional deterioration. 4 This progressive decline in ␤-cell function eventually leads to ␤-cell loss by apoptosis. 1,5 See accompanying article on page 1497Normoglycemia is maintained in insulin-resistant individuals by ␤-cell compensation, which enhances insulin secretion. Type 2 diabetes develops when ␤-cells can no longer maintain this compensatory response. The reasons why ␤-cells become dysfunctional in some individuals but not in others have not been elucidated. Recent evidence suggests that cholesterol accumulation compromises ␤-cell function and reduces insulin secretion and that this can be alleviated by depleting the cells of cholesterol. 6 As high-density lipoproteins (HDLs) are the predominant acceptors of cell cholesterol, it follows that they may be important for maintaining normal ␤-cell function and insulin secretion. Indeed, it has recently been reported that infusing supraphysiological (80 mg/kg) doses of discoidal reconstituted HDLs (rHDL) containing apolipoprotein (apo) A-I complexed with phosphatidylcholine, (A-I)rHDL, into humans with type 2 diabetes increases plasma insulin levels, reduces plasma...

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

“…Indeed, ABCG1 promotes cholesterol efflux to HDL particles and acts at the same level with ABCA1 to remove cellular cholesterol. Finally, in animal models, mice carrying a deletion of ABCG1 also presented an impaired glucose-induced insulin secretion [56]. ABCA1 and ABCG1 have complementary roles also in macrophage function.…”

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…HDLs have antidiabetic properties. They reduce hyperglycaemia via their capacity to decrease pancreatic β-cell apoptosis (Abderrahmani et al 2007;Fryirs et al 2010;Rutti et al 2009) and to stimulate glucose disposal in skeletal muscle (Han et al 2007). They decrease dyslipidaemia via lowering adipocyte lipolysis (Van Linthout et al 2010a) and induce insulin sensitivity (Berg et al 2001) via upregulating the expression of adiponectin (Van Linthout et al 2010a), which abrogates the development of hyperinsulinaemia.…”

“…Despite the well-described antidiabetic effects of HDL involving their ability to reduce pancreatic β-cell apoptosis (Abderrahmani et al 2007;Fryirs et al 2010;Rutti et al 2009), apo A-I transfer did not reduce blood glucose levels , potentially due to the severity of the streptozotocin model, which is associated with a remaining insulin production below 1 % (Hughes et al 2001). The decline in triglycerides and in the triglyceride-rich lipoproteins VLDL and IDL (Sztalryd and Kraemer 1995) after apo A-I transfer suggests an HDL-mediated decrease in lipolysis in adipose tissue, leading to less free fatty acids in the circulation, less triglyceride synthesis in the liver, and subsequent less VLDL and IDL synthesis (Tunaru et al 2003).…”

HDLs, Diabetes, and Metabolic Syndrome

“…Fryirs and collaborators showed that stimulation of the Min6 insulinoma cell line for 1 h with lipid-free recombinant ApoA-I, ApoA-II, or discoidal reconstituted HDLs dose-dependently increased both basal and glucosestimulated insulin secretion (Fryirs et al 2010). By RNA interference, the authors showed that the stimulatory effect of lipid-free ApoA-I and reconstituted HDLs on insulin secretion depended on ABCA1 and ABCG1, respectively (Fryirs et al 2010).…”