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. 2023 Mar;40(3):e14952.
doi: 10.1111/dme.14952. Epub 2022 Sep 12.

Multimodal testing reveals subclinical neurovascular dysfunction in prediabetes, challenging the diagnostic threshold of diabetes

Varo Kirthi  1   2 , Kate I Reed  2 , Komeil Alattar  1 , Benjamin P Zuckerman  1 , Catey Bunce  3 , Paul Nderitu  1   2 , Uazman Alam  4   5   6 , Bronagh Clarke  7 , Scott Hau  7   8 , Fatima Al-Shibani  9 , Ioannis N Petropoulos  9 , Rayaz A Malik  6   9 , Theodoros Pissas  1   8 , Christos Bergeles  1 , Prashanth Vas  1   2 , David Hopkins  1   2 , Timothy L Jackson  1   2
Affiliations

Multimodal testing reveals subclinical neurovascular dysfunction in prediabetes, challenging the diagnostic threshold of diabetes

Varo Kirthi et al. Diabet Med. 2023 Mar.

Abstract

Aim: To explore if novel non-invasive diagnostic technologies identify early small nerve fibre and retinal neurovascular pathology in prediabetes.

Methods: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent an exploratory cross-sectional analysis with optical coherence tomography angiography (OCT-A), handheld electroretinography (ERG), corneal confocal microscopy (CCM) and evaluation of electrochemical skin conductance (ESC).

Results: Seventy-five participants with normoglycaemia (n = 20), prediabetes (n = 29) and type 2 diabetes (n = 26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16-Td·s: 4.05 μV, 95% confidence interval [95% CI] 0.96-7.13) and high (32-Td·s: 5·20 μV, 95% CI 1.54-8.86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm2 , 95% CI 0.005-0.095) and deep (0.048 pixels/mm2 , 95% CI 0.003-0.093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA1c and peak ERG amplitude at 32-Td·s (r = -0.256, p = 0.028), implicit time at 32-Td·s (r = 0.422, p < 0.001) and 16-Td·s (r = 0.327, p = 0.005), OCT parafoveal vessel density in the superficial (r = -0.238, p = 0.049) and deep (r = -0.3, p = 0.017) retinal layers, corneal nerve fibre length (CNFL) (r = -0.293, p = 0.017), and ESC-hands (r = -0.244, p = 0.035) were observed. HOMA-IR was a predictor of CNFD (β = -0.94, 95% CI -1.66 to -0.21, p = 0.012) and CNBD (β = -5.02, 95% CI -10.01 to -0.05, p = 0.048).

Conclusions: The glucose threshold for the diagnosis of diabetes is based on emergent retinopathy on fundus examination. We show that both abnormal retinal neurovascular structure (OCT-A) and function (ERG) may precede retinopathy in prediabetes, which require confirmation in larger, adequately powered studies.

Keywords: neuropathy-somatic; prediabetes; retinopathy.

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Conflict of interest statement

None of the authors have any relevant financial disclosures to declare. LKC Technologies Inc. and Impeto Medical Inc. provided free use of the RETeval and SUDOSCAN devices, respectively, for this study. PN is funded by Diabetes UK. CaB is part‐funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of Diabetes UK, the NIHR or the Department of Health and Social Care.

Figures

FIGURE 1
FIGURE 1
Optical coherence tomography angiography (OCT‐A) image analysis protocol. Figures outline the image processing steps to calculate superficial vascular plexus (SVP) parafoveal vessel density and foveal avascular zone (FAZ) area: (a) raw OCT‐A image, (b) binarised image after optimally oriented flux filtering and thresholding, (c) overlay of raw OCT‐A image and binarised image, (d) FAZ area, (e) overlayed concentric rings with diameters of 1 mm (green) and 2.5 mm (blue) to define the parafoveal region, (f) the parafoveal region used to calculate vessel density by computing pixels against ring area.
FIGURE 2
FIGURE 2
Scatterplots of microvascular parameters compared with HbA1c. Data presented for (a) central cornea corneal nerve fibre length (CNFL‐CC), (b) electrochemical sweat conductance (ESC) in the hands, (c) electroretinography (ERG) peak amplitude (PA) at 32‐Td·S, (d) ERG implicit time (IT) at 32‐Td·S, (e) superficial vascular plexus (SVP) parafoveal vessel density (PVD) and (f) deep capillary plexus (DCP) PVD. Data logarithmically transformed and colour‐coded by study group: normoglycaemia (green), prediabetes (yellow) and type 2 diabetes (red).
See this image and copyright information in PMC

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