Diabetes is associated with significant changes in plasma concentrations of lipoproteins. We tested the hypothesis that lipoproteins modulate the function and survival of insulin-secreting cells. We first detected the presence of several receptors that participate in the binding and processing of plasma lipoproteins and confirmed the internalization of fluorescent low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin-secreting ␤-cells. Purified human very low

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... ity lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and ␤-cell proliferation and induced a dose-dependent increase in the rate of apoptosis. In mice lacking the LDL receptor, islets showed a dramatic decrease in LDL uptake and were partially resistant to apoptosis caused by LDL. VLDLinduced apoptosis of ␤-cells involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal kinase-interacting protein-1. In contrast, the proapoptotic signaling of lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In conclusion, human lipoproteins are critical regulators of ␤-cell survival and may therefore contribute to the ␤-cell dysfunction observed during the development of type 2 diabetes. 1 The abbreviations used are: HDL, high density lipoprotein; Akt/ PKB, protein kinase B; apoER2, apolipoprotein E receptor 2; BrdUrd, bromodeoxyuridine; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase; IB1/JIP-1, islet-brain 1/c-Jun N-terminal kinase-interacting protein-1; JNK, c-Jun N-terminal kinase; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; LDLR Ϫ/Ϫ , LDL receptor knock-out; LRP, LDL receptor-related protein; PBS, phosphate-buffered saline; SR-BI, scavenger receptor class B type I; TUNEL, terminal nucleotidyl transferase-mediated UTP nick end labeling; VLDL, very low density lipoprotein; VLDLR, very low density lipoprotein receptor; WT, wild-type.