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      Blunted Coronary Vasoreactivity to Insulin Is an Early Alteration in Hypertension


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          Insulin resistance in the heart is not localized to the myocardium, but may also occur in blood vessels. We studied the effects of insulin on coronary vasodilation in hypertension. Coronary vascular resistance was quantitated in 11 nonsmoking men with untreated mild essential hypertension and 9 healthy normotensive men using positron emission tomography and <sup>15</sup>O-labeled water. The measurements were performed at baseline and during adenosine infusion (140 µg·kg<sup>–1</sup>·min<sup>–1</sup>) with or without simultaneous euglycemic physiological (serum insulin approximately 70 mU/l) and supraphysiological (serum insulin approximately 460 mU/l) hyperinsulinemia. Coronary resistance was significantly higher in hypertensive than normotensive subjects at baseline and during adenosine infusion. Physiological hyperinsulinemia decreased hyperemic coronary resistance significantly in both groups. Supraphysiological hyperinsulinemia further decreased the hyperemic coronary resistance in normotensive but not in hypertensive subjects, leading to higher hyperemic coronary resistance in hypertensive than normotensive subjects (27.2 ± 8.7 vs. 19.2 ± 4.9 mm Hg·min·g·ml<sup>–1</sup>, p < 0.05). However, insulin-stimulated whole body glucose uptake values were similar between the groups during both insulin infusions. In conclusion, insulin-induced coronary vasodilation is blunted in young subjects with mild essential hypertension who are otherwise healthy. Coronary vascular resistance to insulin occurs although no change in peripheral glucose uptake can be detected. While we do not know whether the same results can be extrapolated to female or older subjects, these results indicate a novel defect in the regulation of coronary arteries in the early phase of hypertension.

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          Insulin Action in the Vasculature: Physiology and Pathophysiology

          Studies to date have provided convincing evidence that insulin has an important role in the normal functioning of the vasculature from the perspective of the regulated delivery of nutrients to a tissue bed. This is mediated by an effect on the endothelium analogous to other endothelial responses, and insulin resistance is reflected in, and in part due to, impaired vasodilatory actions of insulin. Because insulin normally stimulates the net production of nitric oxide, which is beneficial in both the short term for vasomotion and antithrombosis, and the long term for inhibition of smooth muscle cell growth and migration, vascular insulin resistance also has important implications for vascular pathophysiology. Further, recent evidence suggests that the hyperinsulinemia accompanying insulin resistance may aggravate this situation by augmenting the endothelial production and release of endothelin-1. The investigation of insulin resistance in the vasculature provides not only a unique and physiologically relevant window onto vascular pathology, but also an opportunity for therapeutic targeting in individuals affected by the clinical states of insulin resistance. The present review highlights the importance of insulin sensitivity in the maintenance of endothelial function and explores the relationships between vascular insulin resistance and whole body glucose disposal. In addition, the recent evidence linking insulin to endothelin-1 production is discussed. Improving insulin sensitivity with insulin sensitizers such as rosiglitazone may represent an important advance in our ability to improve vascular dysfunction in diabetes.
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            Insulin resistance in type I diabetes mellitus: a major role for reduced glucose extraction.

            We determined whether insulin resistance in Type I diabetes is caused by a defect in glucose extraction or blood flow and whether it is the rate of glucose metabolism rather than insulin that increases blood flow in these patients. To make this determination, 9 Type I diabetic patients (age 33 +/- 3 yr, body mass index 24 +/- 1 kg/m2, HbA1c 8.3 +/- 0.1%) and 10 matched normal subjects were first studied under normoglycemic hyperinsulinemic conditions. The diabetic patients were then restudied under similar conditions, but now whole body glucose uptake was normalized by glucose mass-action (glucose 8.7 +/- 0.6 mmol/L). During normoglycemia, rates of whole body (46 +/- 2 vs. 66 +/- 3 mumol/kg.min, P < 0.001) and forearm (47 +/- 9 vs. 78 +/- 7 mumol/kg forearm.min, P < 0.05) glucose uptake were decreased in the diabetic patients, because of a 32% decrease in the glucose AV-difference (1.5 +/- 0.2 vs. 2.2 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow was similar in the diabetic patients (3.6 +/- 0.7 mL/dl.min) and normal subjects (3.7 +/- 0.3 mL/dL.min). During matched rates of whole body glucose uptake (68 +/- 1 vs. 66 +/- 3 mumol/kg.min, normoglycemic study in controls vs. hyperglycemic study in the diabetic patients), the glucose AV-difference across the forearm was 64% higher than during normoglycemia (2.4 +/- 0.3 vs. 1.5 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow (3.6 +/- 0.4 mL/dL.min) under conditions of matched glucose flux was similar to that during the normoglycemic study. We conclude that a defect in glucose extraction rather than blood flow characterizes insulin resistance in uncomplicated Type I diabetes. The signal for the flow increase is insulin and not the rate of glucose metabolism.
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              Plasma 3, 4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4- hydroxyphenylglycol (MHPG) are insensitive indicators of α2-adrenoceptor mediated regulation of norepinephrine release in healthy human volunteers


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                February 2003
                26 March 2003
                : 40
                : 1
                : 58-67
                aTurku PET Centre, Departments of bMedicine and cClinical Physiology, Turku University, Turku, Finland
                68939 J Vasc Res 2003;40:58–67
                © 2003 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.

                : 03 July 2002
                : 23 October 2002
                Page count
                Figures: 5, Tables: 3, References: 44, Pages: 10
                Research Paper

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Insulin,Hypertension,Myocardial blood flow,Positron emission tomography,Adenosine,Hyperinsulinemia,Hyperemia,Coronary vasolidation


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