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. 2022 Oct 11:13:891442.
doi: 10.3389/fendo.2022.891442. eCollection 2022.

Advanced glycation end-products are associated with diabetic neuropathy in young adults with type 1 diabetes

Elaf Al-Saoudi  1 , Marie M B Christensen  2 , Peter Nawroth  3   4   5 , Thomas Fleming  3   4 , Eva E Hommel  6 , Marit E Jørgensen  2   7 , Jesper Fleischer  8 , Christian S Hansen  1
Affiliations

Advanced glycation end-products are associated with diabetic neuropathy in young adults with type 1 diabetes

Elaf Al-Saoudi et al. Front Endocrinol (Lausanne). .

Abstract

Aims/hypothesis: Advanced glycation end-products (AGEs) may contribute to the development of diabetic neuropathy. In young adults with type 1 diabetes, we aimed to investigate the association between AGEs and cardiovascular autonomic neuropathy (CAN) and distal symmetric polyneuropathy (DSPN).

Methods: This cross-sectional study comprised 151 young adults. CAN was assessed by cardiovascular autonomic reflex tests; lying-to-standing test, deep breathing test (E/I), Valsalva manoeuvre, and heart rate variability indices; and the mean square of the sum of the squares of differences between consecutive R-R intervals and standard deviation of normal-to-normal intervals (SDNN), high- (HF) and low-frequency (LF) power, total frequency power, and the LF/HF ratio. DSPN was assessed by light touch, pain and vibration perception threshold (VPT), neuropathy questionnaires, and objective measures. AGEs were analysed in four groups using z-scores adjusted for relevant confounders and multiple testing: i) "glycolytic dysfunction", ii) "lipid peroxidation", iii) "oxidative stress", and iv) "glucotoxicity".

Results: A higher z-score of "glycolytic dysfunction" was associated with higher VPT (4.14% (95% CI 1.31; 7.04), p = 0.004) and E/I (0.03% (95% CI 0.01; 0.05), p = 0.005), "lipid peroxidation" was associated with higher LF/HF ratio (37.72% (95% CI 1.12; 87.57), p = 0.044), and "glucotoxicity" was associated with lower SDNN (-4.20% (95% CI -8.1416; -0.0896), p = 0.047). No significance remained after adjustment for multiple testing.

Conclusions/interpretations: In young adults with type 1 diabetes, increased levels of AGEs involving different metabolic pathways were associated with several measures of CAN and DSPN, suggesting that AGEs may play a diverse role in the pathogeneses of diabetic neuropathy.

Keywords: AGEs; advanced-glycation end-products; cardiovascular autonomic neuropathy; distal symmetric polyneuropathy; peripheral neuropathy; type 1 diabetes.

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Conflict of interest statement

JF holds stocks in Medicus Engineering. EH, MC and MJ hold shares in Novo Nordisk AS. MJ has received research grants from AMGEN, Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi Aventis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Forest plot of the associations between “glycolytic dysfunction” and measures of diabetic neuropathy. Results are presented as estimates and 95% confidence intervals. Estimates show the percentage change in the outcomes for an increase of one unit of “glycolytic dysfunction”. Studies with confidence interval crossing the vertical line are inconclusive. Model 1 adjusted for age and gender, model 2 adjusted as model 1 + diabetes duration and HbA1c, and model 3 adjusted as model 2 + current smoking, total cholesterol, triglycerides, systolic blood pressure, and the use of beta blockers. CAN, cardiovascular autonomic neuropathy; HR, heart rate; 30:15, lying-to-standing test; E:I, deep breathing test; VM, Valsalva Manoeuvre; SDNN, standard deviation of normal-to-normal intervals; RMSSD, root mean square of the sum of the squares of differences between consecutive R-R intervals; LF, low-frequency power; HF, high-frequency power; DSPN, distal symmetric polyneuropathy; VPT, vibration perception threshold; SNAP, sural nerve amplitude potential; SNCV, sural nerve conduction velocity; ESC, electrochemical skin conduction. *p < 0.05.
Figure 2
Figure 2
Forest plot of the associations between “lipid peroxidation” and measures of diabetic neuropathy. Results are presented as estimates and 95% confidence intervals. Estimates show the percentage change in the outcomes for an increase of one unit of “lipid peroxidation”. Studies with confidence interval crossing the vertical line are inconclusive. Model 1 adjusted for age and gender, model 2 adjusted as model 1 + diabetes duration and HbA1c, and model 3 adjusted as model 2 + current smoking, total cholesterol, triglycerides, systolic blood pressure, and the use of beta blockers. CAN, cardiovascular autonomic neuropathy; HR, heart rate; 30:15, lying-to-standing test; E:I, deep breathing test; VM, Valsalva Manoeuvre; SDNN, standard deviation of normal-to-normal intervals; RMSSD, root mean square of the sum of the squares of differences between consecutive R-R intervals; LF, low-frequency power; HF, high-frequency power; DSPN, distal symmetric polyneuropathy; VPT, vibration perception threshold; SNAP, sural nerve amplitude potential; SNCV, sural nerve conduction velocity; ESC, electrochemical skin conduction. *p < 0.05.
Figure 3
Figure 3
Forest plot of the associations between “glucotoxicity” and measures of diabetic neuropathy. Results are presented as estimates and 95% confidence intervals. Estimates show the percentage change in the outcomes for an increase of one unit of “glucotoxicity”. Studies with confidence interval crossing the vertical line are inconclusive. Model 1 adjusted for age and gender, model 2 adjusted as model 1 + diabetes duration and HbA1c, and model 3 adjusted as model 2 + current smoking, total cholesterol, triglycerides, systolic blood pressure, and the use of beta blockers. CAN, cardiovascular autonomic neuropathy; HR, heart rate; 30:15, lying-to-standing test; E:I, deep breathing test; VM, Valsalva Manoeuvre; SDNN, standard deviation of normal-to-normal intervals; RMSSD, root mean square of the sum of the squares of differences between consecutive R-R intervals; LF, low-frequency power; HF, high-frequency power; DSPN, distal symmetric polyneuropathy; VPT, vibration perception threshold; SNAP, sural nerve amplitude potential; SNCV, sural nerve conduction velocity; ESC, electrochemical skin conduction. *p < 0.05.
Figure 4
Figure 4
Forest plot of the associations between “dicarbonyls” and measures of diabetic neuropathy. Results are presented as estimates and 95% confidence intervals. Estimates show the percentage change in the outcomes for an increase of one unit of “dicarbonyls”. Studies with confidence interval crossing the vertical line are inconclusive. Model 1 adjusted for age and gender, model 2 adjusted as model 1 + diabetes duration and HbA1c, and model 3 adjusted as model 2 + current smoking, total cholesterol, triglycerides, systolic blood pressure, and the use of beta blockers. CAN, cardiovascular autonomic neuropathy; HR, heart rate; 30:15, lying-to-standing test; E:I, deep breathing test; VM, Valsalva Manoeuvre; SDNN, standard deviation of normal-to-normal intervals; RMSSD, root mean square of the sum of the squares of differences between consecutive R-R intervals; LF, low-frequency power; HF, high-frequency power; DSPN, distal symmetric polyneuropathy; VPT, vibration perception threshold; SNAP, sural nerve amplitude potential; SNCV, sural nerve conduction velocity; ESC, electrochemical skin conduction. *p < 0.05.
Figure 5
Figure 5
Forest plot of the associations between “oxidative stress” and measures of diabetic neuropathy. Results are presented as estimates and 95% confidence intervals. Estimates show the percentage change in the outcomes for an increase of one unit of “oxidative stress”. Studies with confidence interval crossing the vertical line are inconclusive. Model 1 adjusted for age and gender, model 2 adjusted as model 1 + diabetes duration and HbA1c, and model 3 adjusted as model 2 + current smoking, total cholesterol, triglycerides, systolic blood pressure, and the use of beta blockers. CAN, cardiovascular autonomic neuropathy; HR, heart rate; 30:15, lying-to-standing test; E:I, deep breathing test; VM, Valsalva Manoeuvre; SDNN, standard deviation of normal-to-normal intervals; RMSSD, root mean square of the sum of the squares of differences between consecutive R-R intervals; LF, low-frequency power; HF, high-frequency power; DSPN, distal symmetric polyneuropathy; VPT, vibration perception threshold; SNAP, sural nerve amplitude potential; SNCV, sural nerve conduction velocity; ESC, electrochemical skin conduction. *p < 0.05.
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References

    1. Jack M, Wright D. Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy. Transl Res (2012) 159(5):355–65. doi: 10.1016/j.trsl.2011.12.004 - DOI - PMC - PubMed
    1. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. . Toronto Diabetic neuropathy expert group. diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care (2010) 33(10):2285–93. doi: 10.2337/dc10-1303 - DOI - PMC - PubMed
    1. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al. . Toronto Consensus panel on diabetic neuropathy. cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev (2011) 27(7):639–53. doi: 10.1002/dmrr.1239 - DOI - PubMed
    1. Tesfaye S, Stevens LK, Stephenson JM, Fuller JH, Plater M, Ionescu-Tirgoviste C, et al. . Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM complications study. Diabetologia (1996) 39(11):1377–84. doi: 10.1007/s001250050586 - DOI - PubMed
    1. Martin CL, Albers JW, Pop-Busui R, DCCT/EDIC Research Group . Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care (2014) 37(1):31–8. doi: 10.2337/dc13-2114 - DOI - PMC - PubMed

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