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

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 (ß = -0.94, 95% CI -1.66 to -0.21, p = 0.012) and CNBD (ß = -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.

ASSOCIATIONS BETWEEN DYSGLYCEMIA, RETINAL NEURODEGENERATION, AND MICROALBUMINURIA IN PREDIABETES AND TYPE 2 DIABETES.

PURPOSE: To explore the association between retinal neurodegeneration and metabolic parameters in progressive dysglycemia. METHOD: A cross-sectional study was performed on 68 participants: normal glucose tolerance (n = 23), prediabetes (n = 25), and Type 2 diabetes without diabetic retinopathy (n = 20). Anthropometric assessment and laboratory sampling for HbA1c, fasting glucose, insulin, c-peptide, lipid profile, renal function, and albumin-to-creatinine ratio were conducted. Central and pericentral macular thicknesses on spectral domain optical coherence tomography were compared with systemic parameters. RESULTS: Baseline demographic characteristics were similar across all groups. Cuzick's trend test revealed progressive full-thickness macular thinning with increasing dysglycemia across all three groups (P = 0.015). The urinary albumin-to-creatinine ratio was significantly correlated with full-thickness superior (R = -0.435; P = 0.0002), inferior (R = -0.409; P = 0.0005), temporal (R = -0.429; P = 0.003), and nasal (R = -0.493; P < 0.0001) pericentral macular thinning, after post hoc Bonferroni adjustment. There was no association between macular thinning and waist circumference, body mass index, blood pressure, lipid profile, or insulin resistance. CONCLUSION: Progressive dysglycemia is associated with macular thinning before the onset of visible retinopathy and occurs alongside microalbuminuria. Retinal neurodegenerative changes may help identify those most at risk from dysglycemic end-organ damage.