Download PDF
Exp Clin Endocrinol Diabetes 2022; 130(12): 767-772
DOI: 10.1055/a-1831-0991
Article

Correlation Between Skin Advanced Glycation End Products and Cardiac Autonomic Neuropathy Among Subjects with Type 2 Diabetes Mellitus

Stella Papachristou
1   Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
,
Kalliopi Pafili
1   Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
2   Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
3   German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
,
Grigorios Trypsianis
4   Department of Medical Statistics, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
,
Dimitrios Papazoglou
1   Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
,
Κonstantinos Vadikolias
5   Department of Neurology, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
,
Nikolaos Papanas
1   Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
› Author Affiliations Funding This research did not receive any specific grant from any funding agency.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Introduction Advanced glycation end products (AGEs) are frequently increased in the skin of subjects with type 2 diabetes mellitus (T2DM). This study aimed to examine the correlation of AGEs with cardiac autonomic neuropathy (CAN) in T2DM.

Methods To this aim, 132 participants (88 men) with a mean age of 64.57 years and a median T2DM duration of 14.5 years were included. Skin AGEs were measured with AGE reader mu connect (Diagnoptics) on the dominant arm (both single and automated triplicate measurements). Diagnosis of CAN, sympathetic and parasympathetic nervous system impairment was based on the four standardised cardiovascular reflex tests (CARTs).

Results On a single measurement, AGEs were increased in subjects with vs. those without CAN (3.20±0.74 vs. 2.66±0.66, p<0.001). As compared with normal results, AGEs were increased for each one of the 4 abnormal CARTs: Valsalva Ratio (3.36±0.67 vs. 2.66±0.72, p=0.004), E/I ratio (3.01±0.72 vs. 2.53±0.68, p=0.001), 30:15 ratio (3.08±0.76 vs. 2.75±0.69, p=0.011), postural hypotension (3.30±0.72 vs. 2.75±0.66, p<0.001). Similar results were obtained for triplicate measurements.

Discussion Among T2DM subjects, skin AGEs appear to increase in the presence of CAN. This holds true both for sympathetic and parasympathetic nervous system impairment.

Key words

advanced glycation end products - skin autofluorescence - cardiac autonomic neuropathy - complications - diabetic neuropathy - diagnosis - screening - type 2 diabetes mellitus


Publication History

Received: 24 January 2022
Received: 29 March 2022

Accepted: 19 April 2022

Accepted Manuscript online:
21 April 2022

Article published online:
07 November 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Spallone V, Ziegler D, Freeman R. et al. Cardiovascular autonomic neuropathy in diabetes: Clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011; 27: 639-653
    CrossrefPubMedGoogle Scholar
  • 2 Vinik AI, Maser RE, Ziegler D. Neuropathy: The crystal ball for cardiovascular disease?. Diabetes Care 2010; 33: 1688-1690
    CrossrefPubMedGoogle Scholar
  • 3 Vagi OE, Svebis MM, Domjan BA. et al. Association of cardiovascular autonomic neuropathy and distal symmetric polyneuropathy with all-cause mortality: A retrospective cohort study. J Diabetes Res 2021; 2021: 6662159
    PubMedGoogle Scholar
  • 4 Bönhof GJ, Herder C, Strom A. et al. Emerging biomarkers, tools, and treatments for diabetic polyneuropathy. Endocr Rev 2019; 40: 153-192
    CrossrefPubMedGoogle Scholar
  • 5 Hidmark A, Fleming T, Vittas S. et al. A new paradigm to understand and treat diabetic neuropathy. Exp Clin Endocrinol Diabetes 2014; 122: 201-207
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Papanas N, Ziegler D. Risk factors and comorbidities in diabetic neuropathy: An update 2015. Rev Diabet Stud 2015; 12: 48-62
    CrossrefPubMedGoogle Scholar
  • 7 Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms. Mol Metab 2014; 3: 94-108
    CrossrefPubMedGoogle Scholar
  • 8 Papachristou S, Pafili K, Papanas N. Skin ages and diabetic neuropathy. BMC Endocr Disord 2021; 21: 28
    CrossrefPubMedGoogle Scholar
  • 9 Papachristou S, Pafili K, Trypsianis G. et al. Skin advanced glycation end products among subjects with type 2 diabetes mellitus with or without distal sensorimotor polyneuropathy. J Diabetes Res 2021; 2021: 6045677
    CrossrefPubMedGoogle Scholar
  • 10 Orchard TJ, Lyons TJ, Cleary PA. et al. The association of skin intrinsic fluorescence with type 1 diabetes complications in the dcct/edic study. Diabetes Care 2013; 36: 3146-3153
    CrossrefPubMedGoogle Scholar
  • 11 Meerwaldt R, Links TP, Graaff R. et al. Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy. Diabetologia 2005; 48: 1637-1644
    CrossrefPubMedGoogle Scholar
  • 12 Osawa S, Katakami N, Sato IT. et al. Skin autofluorescence is associated with vascular complications in patients with type 2 diabetes. J Diabetes Complications 2018; 32: 839-844
    CrossrefPubMedGoogle Scholar
  • 13 Conway BN, Aroda VR, Maynard JD. et al. Skin intrinsic fluorescence correlates with autonomic and distal symmetrical polyneuropathy in individuals with type 1 diabetes. Diabetes Care 2011; 34: 1000-1005
    CrossrefPubMedGoogle Scholar
  • 14 Dimova R, Tankova T, Kirilov G. et al. Endothelial and autonomic dysfunction at early stages of glucose intolerance and in metabolic syndrome. Horm Metab Res 2020; 52: 39-48
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Dimova R, Tankova T, Guergueltcheva V. et al. Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance. J Diabetes Complications 2017; 31: 537-543
    CrossrefPubMedGoogle Scholar
  • 16 Malpas SC, Maling TJ. Heart-rate variability and cardiac autonomic function in diabetes. Diabetes 1990; 39: 1177-1181
    CrossrefPubMedGoogle Scholar
  • 17 Pafili K, Trypsianis G, Papazoglou D. et al. Correlation of cardiac autonomic neuropathy with small and large peripheral nerve function in type 2 diabetes mellitus. Diabetes Res Clin Pract 2019; 156: 107844
    CrossrefPubMedGoogle Scholar
  • 18 Pop-Busui R. Cardiac autonomic neuropathy in diabetes: A clinical perspective. Diabetes Care 2010; 33: 434-441
    CrossrefPubMedGoogle Scholar
  • 19 Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980; 49: 95-108
    PubMedGoogle Scholar
  • 20 Pafili K, Trypsianis G, Papazoglou D. et al. Cardiovascular autonomic neuropathy and distal symmetric sensorimotor polyneuropathy: These two diabetic microvascular complications do not invariably co-exist. Curr Vasc Pharmacol 2020; 18: 50-56
    CrossrefPubMedGoogle Scholar
  • 21 Pafili K, Papanas N. Diagnosis of cardiovascular autonomic neuropathy in diabetes: As simple as possible, but not simpler?. Acta Diabetol 2019; 56: 601-602
    CrossrefPubMedGoogle Scholar
  • 22 Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 8: 491-498
    CrossrefPubMedGoogle Scholar
  • 23 Bellavere F, Ragazzi E, Chilelli NC. et al. Autonomic testing: Which value for each cardiovascular test? An observational study. Acta Diabetol 2019; 56: 39-43
    CrossrefPubMedGoogle Scholar
  • 24 Pafili K, Trypsianis G, Papazoglou D. et al. Simplified diagnosis of cardiovascular autonomic neuropathy in type 2 diabetes using ewing’s battery. Rev Diabet Stud 2015; 12: 213-219
    CrossrefPubMedGoogle Scholar
  • 25 Stranieri A, Abawajy J, Kelarev A. et al. An approach for ewing test selection to support the clinical assessment of cardiac autonomic neuropathy. Artif Intell Med 2013; 58: 185-193
    CrossrefPubMedGoogle Scholar
  • 26 Migdalis I, Czupryniak L, Lalic N. et al. Diabetic microvascular complications. Int J Endocrinol 2018; 2018: 5683287
    CrossrefPubMedGoogle Scholar
  • 27 Yajnik CS, Kantikar V, Pande A. et al. Screening of cardiovascular autonomic neuropathy in patients with diabetes using non-invasive quick and simple assessment of sudomotor function. Diabetes Metab 2013; 39: 126-131
    CrossrefPubMedGoogle Scholar
  • 28 Selvarajah D, Cash T, Davies J. et al. Sudoscan: A simple, rapid, and objective method with potential for screening for diabetic peripheral neuropathy. PLoS One 2015; 10: e0138224
    CrossrefPubMedGoogle Scholar
  • 29 Casellini CM, Parson HK, Richardson MS. et al. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther 2013; 15: 948-953
    CrossrefPubMedGoogle Scholar
  • 30 D’Amato C, Greco C, Lombardo G. et al. The diagnostic usefulness of the combined compass 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy. J Peripher Nerv Syst 2020; 25: 44-53
    CrossrefPubMedGoogle Scholar
  • 31 He T, Wang C, Zuo A. et al. Electrochemical skin conductance may be used to screen for diabetic cardiac autonomic neuropathy in a Chinese population with diabetes. J Diabetes Res 2017; 2017: 8289740
    PubMedGoogle Scholar
  • 32 Yajnik CS, Kantikar VV, Pande AJ, Deslypere JP. Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy. ISRN Endocrinol 2012; 2012: 103714
    CrossrefPubMedGoogle Scholar
  • 33 Liatis S, Marinou K, Tentolouris N. et al. Usefulness of a new indicator test for the diagnosis of peripheral and autonomic neuropathy in patients with diabetes mellitus. Diabet Med 2007; 24: 1375-1380
    CrossrefPubMedGoogle Scholar
  • 34 Mendivil CO, Kattah W, Orduz A. et al. Neuropad for the detection of cardiovascular autonomic neuropathy in patients with type 2 diabetes. J Diabetes Complications 2016; 30: 93-98
    CrossrefPubMedGoogle Scholar
  • 35 Pafili K, Trypsianis G, Papazoglou D. et al. Clinical tools for peripheral neuropathy to exclude cardiovascular autonomic neuropathy in type 2 diabetes mellitus. Diabetes Ther 2020; 11: 979-986
    CrossrefPubMedGoogle Scholar
  • 36 Stirban A, Heinemann L. Skin autofluorescence – a non-invasive measurement for assessing cardiovascular risk and risk of diabetes. Eur Endocrinol 2014; 10: 106-110
    CrossrefPubMedGoogle Scholar
  • 37 Meerwaldt R, Graaff R, Oomen PHN. et al. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 2004; 47: 1324-1330
    CrossrefPubMedGoogle Scholar
  • 38 Fokkens BT, Smit AJ. Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabetes. Glycoconj J 2016; 33: 527-535
    CrossrefPubMedGoogle Scholar
  • 39 Pafili K, Maltezos E, Papanas N. Editorial: Limited utility of the handgrip test for the diagnosis of diabetic cardiovascular autonomic neuropathy: “There’s time enough, but none to spare”. Curr Vasc Pharmacol 2017; 15: 74-76
    CrossrefPubMedGoogle Scholar
  • 40 Ziegler D, Keller J, Maier C, Pannek J. Diabetic neuropathy. Exp Clin Endocrinol Diabetes 2021; 129: S70-S81
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Farrow F, Fountoulakis N, Cummins K. et al. Cardiac autonomic neuropathy is associated with improved diabetic foot ulcer healing: A single centre prospective cohort study. Exp Clin Endocrinol Diabetes 2021; 129: 895-898
    Article in Thieme ConnectPubMedGoogle Scholar