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

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.