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      Peroxisome Proliferator-Activated Receptor-Alpha Deficiency Protects Aged Mice from Insulin Resistance Induced by High-Fat Diet

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          Abstract

          Background/Aims: Insulin resistance is a central feature of the metabolic syndrome and progressively increases with age, resulting in excessively high incidence of type II diabetes in the elderly population. Peroxisome proliferator-activated receptor-α (PPARα) is widely expressed in insulin target tissues, including those of the liver, kidney, and muscle, where it mediates expression of genes promoting fatty acid β-oxidation. The aim of this study was to evaluate the potential role of PPARα in insulin resistance in aging mice induced by a high-fat diet. Methods: We used male PPARα knockout (KO) mice and wild-type (WT) littermates that were 18 months old. Animals were fed with a high-fat diet (HFD) for 4 weeks, and metabolic parameters associated with insulin sensitivity were assessed. Results: Following HFD treatment, WT mice showed more severe insulin resistance than did mice lacking the PPARα gene, as assessed by both the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, WT mice exhibited significantly higher HOMA-IR, plasma total cholesterol levels and urinary albumin-creatinine ratio but less liver weight than did PPARα KO mice. Conclusion: These data suggest that PPARα gene deficiency may protect aged mice from developing insulin resistance and albuminuria induced by a HFD.

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          Most cited references 7

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          Mechanisms of insulin resistance in aging.

          We have studied 17 elderly and 27 non-elderly, nonobese subjects (mean age 69+/-1 and 37+/-2 yr, respectively) to assess the mechanisms responsible for the abnormal carbohydrate tolerance associated with aging. Serum glucose and insulin levels were significantly elevated in the elderly subjects compared with the nonelderly subjects during a 75-g oral glucose tolerance test, suggesting an insulin resistant state. Peripheral insulin sensitivity was assessed in both groups using the euglycemic glucose clamp technique during an insulin infusion rate of 40 mU/m(2) per min. Similar steady-state serum insulin levels led to a peripheral glucose disposal rate of 151+/-17 mg/m(2) per min in the elderly compared with a value of 247+/-12 mg/m(2) per min in the nonelderly, thus documenting the presence of insulin resistance in the elderly subjects. Insulin binding to isolated adipocytes and monocytes was similar in the elderly and nonelderly groups (2.34+/-0.33 vs. 2.62+/-0.24% and 5.04+/-1.10 vs. 5.12+/-1.07%), respectively. Thus, insulin resistance in the presence of normal insulin binding suggests the presence of a postreceptor defect in insulin action. This was confirmed by performing additional euglycemic clamp studies using infusion rates of 15 and 1,200 mU/m(2) per min to assess the contours of the dose-response relationship. These studies revealed a 39 and 25% decrease in the glucose disposal rate in the elderly subjects, respectively. The results confirm the presence of a postreceptor defect as well as a rightward shift in the dose-response curve. Insulin's ability to suppress hepatic glucose output was less in the elderly subjects during the 15 mU/m(2) per min insulin infusion (77+/-5 vs. 89+/-4% suppression), but hepatic glucose output was fully and equally suppressed in both groups during the 40 and 1,200 mU/m(2) per min infusion. Finally, a significant inverse relationship was observed between the degree of glucose intolerance in the individual elderly subjects, as reflected by the 2-h serum glucose level during the oral glucose tolerance test, and the degree of peripheral insulin resistance as assessed by the glucose disposal rate during the 40 mU/m(2) per min insulin infusion (r = 0.59, P < 0.01).We conclude that carbohydrate intolerance develops as part of the aging process. This carbohydrate intolerance appears to be the consequence of peripheral insulin resistance caused by a postreceptor defect in target tissue insulin action, which causes both a decrease in the maximal rate of peripheral glucose disposal and a rightward shift in the insulin action dose-response curve. In elderly subjects, the severity of the abnormality in carbohydrate tolerance is directly correlated to the degree of peripheral insulin resistance.
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            Peroxisome Proliferator-activated Receptor α Activators Improve Insulin Sensitivity and Reduce Adiposity

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              Peroxisome Proliferator--Activated Receptor (PPAR)-  Activation Lowers Muscle Lipids and Improves Insulin Sensitivity in High Fat--Fed Rats: Comparison With PPAR-  Activation

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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2007
                September 2007
                25 July 2007
                : 27
                : 5
                : 479-482
                Affiliations
                aDivision of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn., USA; bDivision of Nephrology, Korea University, Seoul, Republic of Korea; cPeking University Diabetes Center, Peking University Health Science Center, Beijing, China
                Article
                106485 Am J Nephrol 2007;27:479–482
                10.1159/000106485
                17652964
                © 2007 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: 1, Tables: 1, References: 10, Pages: 4
                Categories
                Original Report: Laboratory Investigation

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