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

Stella Papachristou; Kalliopi Pafili; Grigorios Trypsianis; Dimitrios Papazoglou; Κonstantinos Vadikolias; Nikolaos Papanas

doi:10.1055/a-1831-0991

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

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

¹Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece

,

Kalliopi Pafili

¹Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece

²Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

³German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany

,

Grigorios Trypsianis

⁴Department of Medical Statistics, Medical School, Democritus University of Thrace, Alexandroupolis, Greece

,

Dimitrios Papazoglou

¹Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece

,

Κonstantinos Vadikolias

⁵Department of Neurology, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece

,

Nikolaos Papanas

¹Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece

› Author Affiliations

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

Full Text

References

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
2 Vinik AI, Maser RE, Ziegler D. Neuropathy: The crystal ball for cardiovascular disease?. Diabetes Care 2010; 33: 1688-1690
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
4 Bönhof GJ, Herder C, Strom A. et al. Emerging biomarkers, tools, and treatments for diabetic polyneuropathy. Endocr Rev 2019; 40: 153-192
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
6 Papanas N, Ziegler D. Risk factors and comorbidities in diabetic neuropathy: An update 2015. Rev Diabet Stud 2015; 12: 48-62
7 Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms. Mol Metab 2014; 3: 94-108
8 Papachristou S, Pafili K, Papanas N. Skin ages and diabetic neuropathy. BMC Endocr Disord 2021; 21: 28
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
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
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
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
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
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
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
16 Malpas SC, Maling TJ. Heart-rate variability and cardiac autonomic function in diabetes. Diabetes 1990; 39: 1177-1181
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
18 Pop-Busui R. Cardiac autonomic neuropathy in diabetes: A clinical perspective. Diabetes Care 2010; 33: 434-441
19 Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med 1980; 49: 95-108
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
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
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
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
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
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
26 Migdalis I, Czupryniak L, Lalic N. et al. Diabetic microvascular complications. Int J Endocrinol 2018; 2018: 5683287
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
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
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
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
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
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
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
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
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
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
37 Meerwaldt R, Graaff R, Oomen PHN. et al. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 2004; 47: 1324-1330
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
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
40 Ziegler D, Keller J, Maier C, Pannek J. Diabetic neuropathy. Exp Clin Endocrinol Diabetes 2021; 129: S70-S81
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