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Low- and High-Density Lipoproteins Modulate Function, Apoptosis, and Proliferation of Primary Human and Murine Pancreatic β-Cells

Division of Endocrinology and Diabetes (S.R., J.A.E., R.A.S., R.P., D.T.M., M.Y.D.), Institute of Clinical Chemistry (S.R., L.R., A.v.E.), and Centre for Integrated Human Physiology (S.R., J.A.E., R.A.S., R.P., L.R., D.T.M., M.Y.D., A.v.E.), University Hospital of Zurich, Zurich 8091, Switzerland; Department of Cell Biology (S.G.), Centre for Basic Research 1, Biomedical Research Foundation, Academy of Athens, 10679 Athens, Greece; and Cell Isolation and Transplantation Centre (N.N., T.B.), Department of Surgery, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland

Address all correspondence and requests for reprints to: Dr. Marc Donath, Division of Endocrinology and Diabetes, University Hospital of Zürich, Rämistrasse 100, Zurich 8091, Switzerland. E-mail: marc.donath{at}usz.ch.

A low high-density lipoprotein (HDL) plasma concentration and the abundance of small dense low-density lipoproteins (LDL) are risk factors for developing type 2 diabetes. We therefore investigated whether HDL and LDL play a role in the regulation of pancreatic islet cell apoptosis, proliferation, and secretory function. Isolated mouse and human islets were exposed to plasma lipoproteins of healthy human donors. In murine and human β-cells, LDL decreased both proliferation and maximal glucose-stimulated insulin secretion. The comparative analysis of β-cells from wild-type and LDL receptor-deficient mice revealed that the inhibitory effect of LDL on insulin secretion but not proliferation requires the LDL receptor. HDL was found to modulate the survival of both human and murine islets by decreasing basal as well as IL-1β and glucose-induced apoptosis. IL-1β-induced β-cell apoptosis was also inhibited in the presence of either the delipidated protein or the deproteinated lipid moieties of HDL, apolipoprotein A1 (the main protein component of HDL), or sphingosine-1-phosphate (a bioactive sphingolipid mostly carried by HDL). In murine β-cells, the protective effect of HDL against IL-1β-induced apoptosis was also observed in the absence of the HDL receptor scavenger receptor class B type 1. Our data show that both LDL and HDL affect function or survival of β-cells and raise the question whether dyslipidemia contributes to β-cell failure and hence the manifestation and progression of type 2 diabetes mellitus.