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...

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