Insulin-secreting -Cell Dysfunction Induced by Human Lipoproteins
University of Texas at Dallas, Richardson, Texas, United StatesJournal of Biological Chemistry (Impact Factor: 4.57). 06/2003; 278(20):18368-75. DOI: 10.1074/jbc.M300102200
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 beta-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and beta-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. VLDL-induced apoptosis of beta-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 beta-cell survival and may therefore contribute to the beta-cell dysfunction observed during the development of type 2 diabetes.
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- "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). By contrast, other experiments in Min6 cells as well as islets of mice and humans did not find conclusive evidence that HDL enhances insulin production or basal and glucose-stimulated insulin secretion (Abderrahmani et al. 2007; Roehrich et al. 2003; Rutti et al. 2009). Therefore and considering the supraphysiological concentrations of lipid-free ApoA-I used by Fryirs et al., it appears uncertain of whether HDLs have a direct effect on the insulin secretory capacity of beta cells. "
ABSTRACT: The prevalence of type 2 diabetes mellitus and of the metabolic syndrome is rising worldwide and reaching epidemic proportions. These pathologies are associated with significant morbidity and mortality, in particular with an excess of cardiovascular deaths. Type 2 diabetes mellitus and the cluster of pathologies including insulin resistance, central obesity, high blood pressure, and hypertriglyceridemia that constitute the metabolic syndrome are associated with low levels of HDL cholesterol and the presence of dysfunctional HDLs. We here review the epidemiological evidence and the potential underlying mechanisms of this association. We first discuss the well-established association of type 2 diabetes mellitus and insulin resistance with alterations of lipid metabolism and how these alterations may lead to low levels of HDL cholesterol and the occurrence of dysfunctional HDLs. We then present and discuss the evidence showing that HDL modulates insulin sensitivity, insulin-independent glucose uptake, insulin secretion, and beta cell survival. A dysfunction in these actions could play a direct role in the pathogenesis of type 2 diabetes mellitus.Handbook of experimental pharmacology 01/2015; 224:405-421. DOI:10.1007/978-3-319-09665-0_12
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- "Whether, and through what pathways, statins may lead to increases in glycemia ,  remain unanswered questions relevant to this early pathogenesis. Altered lipoproteins are also implicated in the mechanisms that lead to or cause beta-cell dysfunction in diabetes . Follow-up proteomic and metabolomic studies of purified lipoprotein fractions from different classes of at-risk patients would now help identify the specific molecules more clearly and may in time be useful in improving the performance of classification models based on standard factors . "
ABSTRACT: Background Blood-vessel dysfunction arises before overt hyperglycemia in type-2 diabetes (T2DM). We hypothesised that a metabolomic approach might identify metabolites/pathways perturbed in this pre-hyperglycemic phase. To test this hypothesis and for specific metabolite hypothesis generation, serum metabolic profiling was performed in young women at increased, intermediate and low risk of subsequent T2DM. Methods Participants were stratified by glucose tolerance during a previous index pregnancy into three risk-groups: overt gestational diabetes (GDM; n = 18); those with glucose values in the upper quartile but below GDM levels (UQ group; n = 45); and controls (n = 43, below the median glucose values). Follow-up serum samples were collected at a mean 22 months postnatally. Samples were analysed in a random order using Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap mass spectrometer. Statistical analysis included principal component (PCA) and multivariate methods. Findings Significant between-group differences were observed at follow-up in waist circumference (86, 95%CI (79–91) vs 80 (76–84) cm for GDM vs controls, p<0.05), adiponectin (about 33% lower in GDM group, p = 0.004), fasting glucose, post-prandial glucose and HbA1c, but the latter 3 all remained within the ‘normal’ range. Substantial differences in metabolite profiles were apparent between the 2 ‘at-risk’ groups and controls, particularly in concentrations of phospholipids (4 metabolites with p≤0.01), acylcarnitines (3 with p≤0.02), short- and long-chain fatty acids (3 with p< = 0.03), and diglycerides (4 with p≤0.05). Interpretation Defects in adipocyte function from excess energy storage as relatively hypoxic visceral and hepatic fat, and impaired mitochondrial fatty acid oxidation may initiate the observed perturbations in lipid metabolism. Together with evidence from the failure of glucose-directed treatments to improve cardiovascular outcomes, these data and those of others indicate that a new, quite different definition of type-2 diabetes is required. This definition would incorporate disturbed lipid metabolism prior to hyperglycemia.PLoS ONE 09/2014; 9(9):e103217. DOI:10.1371/journal.pone.0103217 · 3.23 Impact Factor
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- "Moreover, cell survival is strongly improved in the presence of HDL [94, 95, 101, 102]. Although native LDL above 3.1 mM cholesterol perturbs insulin secretion and cell survival [103, 104], at 2 mM cholesterol the lipoprotein does not affect the accomplishment of the tasks and the viability of beta-cells [94, 95, 101, 102]. A global microarray profiling was done to investigate the contribution of miRNAs in the adverse effects elicited by oxidized LDL. "
ABSTRACT: Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.Journal of Diabetes Research 03/2014; 2014(2):618652. DOI:10.1155/2014/618652 · 2.16 Impact Factor
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