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

Abstract

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