Multimodal Testing Reveals Subclinical Neurovascular Dysfunction in Prediabetes, Challenging the Diagnostic Threshold of Diabetes

Background: There is growing evidence that small nerve fibre and retinal neurovascular damage occur in prediabetes before the onset of type 2 diabetes.  Methods: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent corneal confocal microscopy (CCM), electrochemical skin conductance (ESC), optical coherence tomography angiography (OCT-A), and handheld electroretinography (ERG) measurements. Findings: 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 (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=0·0002) 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 hand ESC (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). Interpretation: The diagnosis of diabetes is based on historical data showing emergent retinopathy on fundus examination; newer tests reveal abnormal retinal neurovascular structure (OCT-A) and function (ERG) occurring before retinopathy.  Funding: This research received no funding support. Declaration of Interests: 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. CB 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 the NIHR or the Department of Health and Social Care. Ethics Approval Statement: This study adhered to the Declaration of Helsinki (2008) and was approved by an independent National Health Service Research Ethics Committee in November 2018 (REC ID: 18/LO/2126). Written informed consent was obtained from all participants.