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      Cardiovascular Autonomic Neuropathy and Glucose Variability in Patients With Type 1 Diabetes: Is There an Association?

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          Abstract

          Introduction

          The oxidative stress associated with glucose variability might be responsible for neuronal damage while autonomic neuropathy (AN) has a detrimental effect on metabolism. The aim of the study was to find relationship between AN and GV in type 1 diabetic patients and to identify further factors that affect GV.

          Patients and methods

          Twenty type 1 diabetic patients were involved (age: 39.5 ± 3.4 years, duration of diabetes: 17.5 ± 2.5 years; HbA1c: 8.1 ± 0.2%, mean ± SE). AN was assessed by the cardiovascular reflex tests. The interstitial glucose levels were determined following insertion of a subcutaneous electrode during the continuous glucose monitoring (CGM) method on six consecutive days. GV was characterized by calculation of four parameters.

          Results

          SD of interstitial glucose values correlated positively with the overall AN score and the degree of the orthostatic reduction of systolic blood pressure (AN-score-SD ρ = 0.47, p < 0.05; orthostasis-SD: ρ = 0.51, p < 0.05). Mean absolute glucose (MAG) correlated with three parameters of AN (AN-score-MAG: ρ = 0.62, p < 0.01; 30/15 ratio-MAG: ρ = −0.50, p < 0.05; orthostasis-MAG: ρ = 0.59, p < 0.01). The HbA1c also correlated with two parameters of GV (HbA1c-continuous overlapping net glycemic action: ρ = 0.56, p < 0.05; HbA1c-MAG: ρ = 0.45, p < 0.05). The frequency of hypoglycemia did not exhibit any correlation with measures of GV.

          Conclusion

          Severity of glucose variability but not overall glucose load correlates with both parasympathetic and sympathetic dysfunctions in type 1 diabetes. Higher HbA1c is associated with more severe glucose variability. The observed correlation between increased glucose variability and the severity of AN necessitates the further exploration of this relationship.

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          Most cited references28

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          Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial--revisited.

          The Diabetes Control and Complications Trial (Diabetes 44:968-983, 1995) presented statistical models suggesting that subjects with similar A1C levels had a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group. That analysis has been cited to support the hypothesis that specific patterns of glucose variation, in particular postprandial hyperglycemia, contribute uniquely to an increased risk of microvascular complications above and beyond that explained by the A1C level. We performed statistical evaluations of these models and additional analyses to assess whether the original analyses were flawed. Statistically, we show that the original results are an artifact of the assumptions of the statistical model used. Additional analyses show that virtually all (96%) of the beneficial effect of intensive versus conventional therapy on progression of retinopathy is explained by the reductions in the mean A1C levels, similarly for other outcomes. Furthermore, subjects within the intensive and conventional treatment groups with similar A1C levels over time have similar risks of retinopathy progression, especially after adjusting for factors in which they differ. A1C explains virtually all of the difference in risk of complications between the intensive and conventional groups, and a given A1C level has similar effects within the two treatment groups. While other components of hyperglycemia, such as glucose variation, may contribute to the risk of complications, such factors can only explain a small part of the differences in risk between intensive and conventional therapy over time.
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            The Value of Cardiovascular Autonomic Function Tests: 10 Years Experience in Diabetes

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              Normal Reference Range for Mean Tissue Glucose and Glycemic Variability Derived from Continuous Glucose Monitoring for Subjects Without Diabetes in Different Ethnic Groups

              Glycemic variability has been proposed as a contributing factor in the development of diabetes complications. Multiple measures exist to calculate the magnitude of glycemic variability, but normative ranges for subjects without diabetes have not been described. For treatment targets and clinical research we present normative ranges for published measures of glycemic variability. Seventy-eight subjects without diabetes having a fasting plasma glucose of <120 mg/dL (6.7 mmol/L) underwent up to 72 h of continuous glucose monitoring (CGM) with a Medtronic Minimed (Northridge, CA) CGMS(®) Gold device. Glycemic variability was calculated using EasyGV(©) software (available free for non-commercial use at www.easygv.co.uk ), a custom program that calculates the SD, M-value, mean amplitude of glycemic excursions (MAGE), average daily risk ratio (ADRR), Lability Index (LI), J-Index, Low Blood Glucose Index (LBGI), High Blood Glucose Index (HBGI), continuous overlapping net glycemic action (CONGA), mean of daily differences (MODD), Glycemic Risk Assessment in Diabetes Equation (GRADE), and mean absolute glucose (MAG). Eight CGM traces were excluded because there were inadequate data. From the remaining 70 traces, normative reference ranges (mean±2 SD) for glycemic variability were calculated: SD, 0-3.0; CONGA, 3.6-5.5; LI, 0.0-4.7; J-Index, 4.7-23.6; LBGI, 0.0-6.9; HBGI, 0.0-7.7; GRADE, 0.0-4.7; MODD, 0.0-3.5; MAGE-CGM, 0.0-2.8; ADDR, 0.0-8.7; M-value, 0.0-12.5; and MAG, 0.5-2.2. We present normative ranges for measures of glycemic variability in adult subjects without diabetes for use in clinical care and academic research.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                19 April 2018
                2018
                : 9
                : 174
                Affiliations
                [1] 1First Department of Medicine, University of Szeged , Szeged, Hungary
                [2] 2Department of Pharmacology and Pharmacotherapy, University of Szeged , Szeged, Hungary
                [3] 3Department of Systems Medicine, University of Rome Tor Vergata , Rome, Italy
                [4] 4Unit of Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita Fatebenefratelli Hospital , Rome, Italy
                [5] 5First Department of Medicine, Semmelweis University , Budapest, Hungary
                Author notes

                Edited by: Solomon Tesfaye, Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom

                Reviewed by: Prashanth R. J. Vas, King’s College Hospital NHS Foundation Trust, United Kingdom; Vincenza Spallone, University of Rome Tor Vergata, Italy

                *Correspondence: Tamás Várkonyi, varkonyitamas@ 123456gmail.com

                Specialty section: This article was submitted to Diabetes, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2018.00174
                5916962
                cebc79c6-d502-4bc2-b219-0763bc0b2a38
                Copyright © 2018 Nyiraty, Pesei, Orosz, Coluzzi, Vági, Lengyel, Ábrahám, Frontoni, Kempler and Várkonyi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 January 2018
                : 03 April 2018
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 44, Pages: 8, Words: 5442
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                autonomic neuropathy,glucose variability,continuous glucose monitoring,type 1 diabetes,cardiovascular reflex tests

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