Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

Abstract

Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.

ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents

“…84 • The ABCC8 encoded SUR-1 protein is crucial in retinal function and SU (glibenclamide) confers direct retinal neuroprotection through SUR-1 mediated mechanisms. 85,86 • A recent study utilized patient-derived iPSCs to generate cerebral organoids and found major defects in early development of cortical neuronal network in V59M mutants compared to controls, that could partially be rescued by the SU tolbutamide. 87 Activating mutations in KCNJ11 causing NDM are always heterozygous.…”

“…However, those with PNDM due to ABCC8 mutations had a similar range of difficulties as those with PNDM due to KCNJ11 mutations 84 The ABCC8 encoded SUR‐1 protein is crucial in retinal function and SU (glibenclamide) confers direct retinal neuroprotection through SUR‐1 mediated mechanisms 85,86 A recent study utilized patient‐derived iPSCs to generate cerebral organoids and found major defects in early development of cortical neuronal network in V59M mutants compared to controls, that could partially be rescued by the SU tolbutamide 87 …”

Sulfonylurea for improving neurological features in neonatal diabetes: A systematic review and meta‐analyses

“…48 Studies of effects on retinal function support these possibilities: low-dose oral glibenclamide failed to significantly lower Hb1Ac levels yet decreased retinal-cell death and improved retinal function. 57,58 Our subgroup analysis suggests that age at sulfonylurea initiation may be strongly associated with the likelihood of benefits. Thus, neurological improvements were more likely when the treatment was started before 4 years of age, in keeping with the greater neuronal plasticity in younger individuals.…”

“…Sulfonylureas may also decrease vasogenic cerebral oedema and cerebral inflammation, thereby promoting the reperfusion of ischaemic areas 48 . Studies of effects on retinal function support these possibilities: low‐dose oral glibenclamide failed to significantly lower Hb1Ac levels yet decreased retinal‐cell death and improved retinal function 57,58 …”

Targeting of neuroinflammation by glibenclamide in Covid-19: old weapon from arsenal

“…Of note, the medical use of glibenclamide is associated with the risk of hypoglycemia in diabetic and non-diabetic patients (Soydan et al 2013 ). However, the use of a non-hypoglycemic dose of glibenclamide 0.4 mg/kg still has an anti-inflammatory effect (Berdugo et al 2021 ). Therefore, the use of a lower effective dose of glibenclamide could be a promising therapeutic strategy in the management of SARS-CoV-2-induced neuroinflammation even in non-diabetic patients.…”