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      Anti-Atherogenic Effect of Insulin in vivo

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          Abstract

          Metabolic syndrome is a risk factor for atherosclerosis and restenosis. In metabolic syndrome, insulin resistance coexists with hyperinsulinemia and hyperlipidemia. Hyperlipidemia has growth-promoting effects, whereas insulin has both growth-promoting and growth-inhibitory effects on vascular smooth muscle cells in vitro. The objective of this study was to investigate the effects of hyperlipidemia and hyperinsulinemia on vascular cell growth in vivo after arterial injury. Rats fed a low-fat diet were treated with either subcutaneous blank (LFC) or insulin (LFI) implants. Rats fed a high-fat diet also received blank (HFC) or insulin (HFI) implants. After 3 days, rats received balloon carotid injury, and 14 days later they were sacrificed to measure neointimal area and proliferation. Hyperinsulinemia was present in LFI and HFI and hyperlipidemia was present in HFC and HFI. Neointimal area was higher in HFC (0.153 ± 0.009 mm<sup>2</sup>, p < 0.05) but lower in LFI (0.098 ± 0.005, p < 0.01) than LFC (0.127 ± 0.005). In HFI (0.142 ± 0.008, p < 0.05) neointimal area was not different from HFC or LFC. In conclusion, insulin reduced neointimal growth, but the effect of insulin was diminished by the high-fat diet. Thus, our results demonstrate an anti-atherogenic effect of insulin in vivo and suggest that in metabolic syndrome insulin resistance rather than hyperinsulinemia is the atherogenic risk factor.

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          Most cited references 20

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          Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats.

          Muscle and hepatic insulin resistance are two major defects of non-insulin-dependent diabetes mellitus. Dietary factors may be important in the etiology of insulin resistance. We studied progressive changes in the development of high-fat-diet-induced insulin resistance in tissues of the adult male Wistar rat. In vivo insulin action was compared 3 days and 3 wk after isocaloric synthetic high-fat or high-starch feeding (59 and 10% cal as fat, respectively). Basal and insulin-stimulated glucose metabolism were assessed in the conscious 5- to 7-h fasted state with the euglycemic clamp (600 pM insulin) with a [3-3H]-glucose infusion. Fat feeding significantly reduced suppressibility of hepatic glucose output by insulin after both 3 days and 3 wk of diet (P less than 0.01). However, a significant impairment of insulin-mediated peripheral glucose disposal was only present after 3 wk of diet. Further in vivo [3H]-2-deoxyglucose uptake studies supported this finding and demonstrated adipose but not muscle insulin resistance after 3 days of high-fat feeding. Muscle triglyceride accumulation due to fat feeding was not significant at 3 days but had doubled by 3 wk in red muscle (P less than 0.001) compared with starch-fed controls. By 3 wk, high-fat-fed animals had developed significant glucose intolerance. We conclude that fat feeding induces insulin resistance in liver and adipose tissue before skeletal muscle with early metabolic changes favoring an oversupply of energy substrate to skeletal muscle relative to metabolic needs. This may generate later muscle insulin resistance.
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            Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats.

            Both insulin resistance and hyperinsulinemia have been reported to be independent risk factors for cardiovascular diseases. However, little is known regarding insulin signaling in the vascular tissues in insulin-resistant states. In this report, insulin signaling on the phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein (MAP) kinase pathways were compared in vascular tissues of lean and obese Zucker (fa/fa) rats in both ex vivo and in vivo studies. Ex vivo, insulin-stimulated tyrosine phosphorylation of insulin receptor beta subunits (IRbeta) in the aorta and microvessels of obese rats was significantly decreased compared with lean rats, although the protein levels of IRbeta in the 2 groups were not different. Insulin-induced tyrosine phosphorylation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) and their protein levels were decreased in the aorta of obese rats compared with lean rats. The association of p85 subunit to the IRS proteins and the IRS-associated PI 3-kinase activities stimulated by insulin in the aorta of obese rats were significantly decreased compared with the lean rats. In addition, insulin-stimulated serine phosphorylation of Akt, a downstream kinase of PI 3-kinase pathway, was also reduced significantly in isolated microvessels from obese rats compared with the lean rats. In euglycemic clamp studies, insulin infusion greatly increased tyrosine phosphorylation of IRbeta- and IRS-2-associated PI 3-kinase activity in the aorta of lean rats, but only slight increases were observed in obese rats. In contrast, insulin stimulated tyrosine phosphorylation of MAP kinase (ERK-1/2) equally in isolated microvessels of lean and obese rats, although basal tyrosine phosphorylation of ERK-1/2 was higher in the obese rats. To our knowledge, these data provided the first direct measurements of insulin signaling in the vascular tissues, and documented a selective resistance to PI 3-kinase (but not to MAP kinase pathway) in the vascular tissues of obese Zucker rats.
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              The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II Mortality Study.

               Earl S. Ford (2004)
              The prospective associations between the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP/ATP III) expert panel and mortality from cardiovascular disease and all-causes has not been extensively examined. Using data from the National Health and Nutrition Examination Survey II Mortality Study (1976-1992), the author examined the association between the metabolic syndrome and mortality from all-causes and cardiovascular disease among 2431 US adults aged 30-75 years. The NCEP/ATP III criteria were modified to substitute body mass index >/=25 kg/m(2) for waist circumference for women and >/=30 kg/m(2) for men. After multiple-adjustment, the hazard ratios for participants with the metabolic syndrome were 1.37 (95% confidence interval (CI): 1.02, 1.85) for mortality from cardiovascular disease, 1.29 (95% CI: 0.92, 1.82) for mortality from coronary heart disease, 1.68 (95% CI: 0.86, 3.27) for mortality from stroke, 1.23 (95% CI: 0.95, 1.59) for mortality from diseases of the circulatory system, and 1.15 (95% CI: 0.92, 1.45) for all-cause mortality compared with participants without the syndrome. The association between the number of metabolic syndrome criteria and mortality from cardiovascular disease was near linear (P = 0.007). Three criteria of the syndrome-excess weight, hypertriglyceridemia, and low high-density lipoprotein cholesterol concentration-were not independently associated with any of the outcomes. Additional prospective studies are needed to examine the association between the metabolic syndrome and the incidence of cardiovascular disease and mortality from cardiovascular disease and all-causes.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2005
                December 2005
                20 October 2005
                : 42
                : 6
                : 455-462
                Affiliations
                Departments of aPhysiology, and bLaboratory Medicine and Pathobiology, and cFaculty of Medicine, University of Toronto, Toronto, Canada
                Article
                88099 J Vasc Res 2005;42:455–462
                10.1159/000088099
                16155361
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 4, References: 36, Pages: 8
                Categories
                Research Paper

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