Insulin-secreting β-Cell Dysfunction Induced by Human Lipoproteins

Abstract

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 density 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.

Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels

“…Our results complement those on lipoprotein-induced beta cell dysfunction [18] to suggest that changes in plasma lipoproteins observed in type 2 diabetes may not only be a consequence of this disease but also a cause of it.…”

“…According to a widely held view, these characteristic changes in lipoprotein pattern are a consequence of insulin resistance and type 2 diabetes. However, a recent study using mouse pancreatic islets and a transformed insulin-secreting beta cell line demonstrated that purified TGRL and LDL particles may induce insulin-secreting beta cell dysfunction, indicating that the changes in plasma lipoproteins characteristic of type 2 diabetes are not only a consequence but also a cause of this disease [18]. To our knowledge, however, nothing is known as to whether intact lipoprotein particles are also capable of inducing insulin resistance.…”

Métabolisme du cholestérol et function β-cellulaire

“…Des études menées chez la souris montrent que l'invalidation de ABCA1 dans l'ensemble des tissus entraîne une intolérance au glucose mais est sans effet sur la sensibilité à l'insuline [10]. Lorsque l'invalidation d'ABCA1 est restreinte aux seules cellules , il n'y a pas d'altération systémique SYNTHÈSE REVUES un grand nombre de modèles cellulaires : cultures primaires d'îlots et de cellules  isolés de tissus humains et de rongeurs (rat et souris) [13,14], ou lignées tumorales de souris comme MIN-6 et TC3 [14], de rat comme les INS-1 [15] ou encore de hamster, les HIT-15 [16]. Les VLDL, les LDL et les HDL ont la capacité de modifier la fonction et la survie des cellules .…”

“…Les VLDL, les LDL et les HDL ont la capacité de modifier la fonction et la survie des cellules . L'exposition aux LDL in vitro est toxique pour ces cellules [4] : elle induit la mort par nécrose des cellules  isolées de rat et par apopotose des îlots isolés de souris [14], et une diminution de l'ARNm de l'insuline. De même, l'exposition aux VLDL apparaît délé-tère pour les cellules  [14].…”

“…L'exposition aux LDL in vitro est toxique pour ces cellules [4] : elle induit la mort par nécrose des cellules  isolées de rat et par apopotose des îlots isolés de souris [14], et une diminution de l'ARNm de l'insuline. De même, l'exposition aux VLDL apparaît délé-tère pour les cellules  [14]. L'effet pro-apoptotique des LDL et VLDL fait intervenir l'activation de la voie JNK (c-jun amino(N)-terminal kinase) et l'induction du clivage de la caspase 3 [14].…”