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      Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects

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          Abstract

          Background

          We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects.

          Methods

          We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta- 1HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption.

          Results

          In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta- 1HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities.

          Conclusions

          These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.

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          Most cited references43

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          High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus.

          Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDL=-2.6+/-0.4; placebo=-2.1+/-0.3 mmol/L; P=0.018). rHDL increased plasma insulin (at 4 hours rHDL=3.4+/-10.0; placebo= -19.2+/-7.4 pmol/L; P=0.034) and also the homeostasis model assessment beta-cell function index (at 4 hours rHDL=18.9+/-5.9; placebo=8.6+/-4.4%; P=0.025). Acetyl-CoA carboxylase beta phosphorylation in skeletal muscle biopsies was increased by 1.7+/-0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177+/-12% and 144+/-18%, respectively; P<0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (n=5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway. rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.
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            Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.

            Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.
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              Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion.

              Type 2 diabetes is characterized by impaired beta-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 beta-cells. 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 beta-cells to lipid-free apolipoproteins also increased insulin mRNA expression and insulin secretion without significantly depleting intracellular insulin or cholesterol levels. These results establish that lipid-free and lipid-associated apoA-I and apoA-II increase beta-cell insulin secretion and indicate that interventions that raise HDLs levels may be beneficial in type 2 diabetes.
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                Author and article information

                Contributors
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central
                1475-2840
                2013
                22 November 2013
                : 12
                : 173
                Affiliations
                [1 ]Lipids Laboratory (LIM-10), Endocrinology and Metabolism Division of Hospital das Clinicas, Faculty of Medical Sciences, University of Sao Paulo, Av. Dr. Arnaldo, 455 - room 3305, Sao Paulo CEP 01246-00, Brazil
                [2 ]Department of Clinical Pathology, School of Medical Sciences, State University of Campinas-UNICAMP, P.O. Box 6111, CEP 13083-970, Campinas, SP, Brazil
                [3 ]National Institute for Health and Welfare, Public Health Genomics Research Unit, Helsinki, Finland
                Article
                1475-2840-12-173
                10.1186/1475-2840-12-173
                4222276
                24267726
                821519ef-90b8-4597-acd4-915358151b09
                Copyright © 2013 Leança et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 August 2013
                : 7 November 2013
                Categories
                Original Investigation

                Endocrinology & Diabetes
                insulin resistance,hdl-c concentration,lipoprotein lipases,lecithin cholesterol acyl transferase,pre-beta1 hdl,plasma cholesterol metabolism markers,cholesteryl ester transfer protein,phospholipid transfer protein

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