The role of cholesterol crystals and ocular crystal emboli in retinal pathology.

Cholesterol crystals (CC) can be responsible for a range of clinical syndromes in the retina from asymptomatic plaques to retinal artery occlusion with clinical trials providing evidence for the efficacy in lipid lowering therapies in preventing ocular pathology. Much of the literature has focused on CC in retinal circulation as a marker of poor systemic health and have attempted to use them to categorize risk of mortality and stroke. More recently cholesterol accumulation and CC formation have been linked to development of diabetic retinopathy with CC formation in the retina due to aberrant retinal cholesterol homeostasis and not simply systemic dyslipidemia.

Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy.

Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing.

Cholesterol crystal formation is a unifying pathogenic mechanism in the development of diabetic retinopathy.

Aims/hypothesis: Hyper-reflective crystalline deposits found in retinal lesions have been suggested to predict the progression of diabetic retinopathy, but the nature of these structures remains unknown.

Methods: Scanning electron microscopy and immunohistochemistry were used to identify cholesterol crystals (CCs) in human donor, pig and mouse tissue. The effects of CCs were analysed in bovine retinal endothelial cells in vitro and in db/db mice in vivo using quantitative RT-PCR, bulk RNA sequencing, and cell death and permeability assays.

Frontiers in diabetic retinal disease.

Diabetic retinal disease (DRD) remains a leading cause of vision loss and blindness globally. Although treatments can be effective when given at vision-threatening stages of DRD, there is a lack of knowledge about the earliest mechanisms leading to the development of clinically evident DRD. Recent advances in retinal imaging methods for patients with diabetes allow a more precise and granular characterization of the different stages of DRD than is provided by the classic Diabetic Retinopathy Severity Scale based on fundus photographs.

2-Hydroxypropyl-β-cyclodextrin mitigates pathological changes in a mouse model of retinal cholesterol dyshomeostasis.

CYP46A1 is a CNS-specific enzyme, which eliminates cholesterol from the brain and retina by metabolism to 24-hydroxycholesterol, thus contributing to cholesterol homeostasis in both organs. 2-Hydroxypropyl-β-cyclodextrin (HPCD), a Food and Drug Administration-approved formulation vehicle, is currently being investigated off-label for treatment of various diseases, including retinal diseases. HPCD was shown to lower retinal cholesterol content in mice but had not yet been evaluated for its therapeutic benefits.

Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus.

Objective: Beta cell dysfunction and death are critical steps in the development of both type 1 and type 2 diabetes (T1D and T2D), but the underlying mechanisms are incompletely understood. Activation of the essential tumor suppressor and transcription factor P53 (also known as TP53 and Trp53 in mice) was linked to beta cell death in vitro and has been reported in several diabetes mouse models and beta cells of humans with T2D. In this article, we set out to determine the beta cell specific role of P53 in beta cell dysfunction, cell death and development of diabetes in vivo.

Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction.

Aims/hypothesis: Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant high energy-density food availability in present-day society contributes to the pathogenesis of chronic diseases, including diabetes and its complications, with intermittent fasting (IF) and energy restriction shown to improve metabolic health.