Diabetes-related adduct formation and retinopathy

Bali

Korean J Physiol Pharmacol

et al. 2014

1,153

794

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.

Section: Ages and Diabetic Complicationsmentioning

confidence: 99%

Advanced Glycation End Products and Diabetic Complications

Bali

Korean J Physiol Pharmacol

et al. 2014

1,153

794

“…It has been shown that AGEs, by altering the surface charge of the protein, lead to conformational changes and consequently reduces the transparency of the lens of the eye [ 38 ]. AGEs also play an important role in the progression of diabetic retinopathy leading to dysfunction or death of retinal cells [ 39 ]. Recent reports indicate that detoxification of methylglyoxal reduces the accumulation of AGEs, which in turn can prevent the pathological changes in the retina and vessels [ 40 ].…”

Section: Glycationmentioning

confidence: 99%

Prevention of Protein Glycation by Natural Compounds

2015

Non-enzymatic protein glycosylation (glycation) contributes to many diseases and aging of organisms. It can be expected that inhibition of glycation may prolong the lifespan. The search for inhibitors of glycation, mainly using in vitro models, has identified natural compounds able to prevent glycation, especially polyphenols and other natural antioxidants. Extrapolation of results of in vitro studies on the in vivo situation is not straightforward due to differences in the conditions and mechanism of glycation, and bioavailability problems. Nevertheless, available data allow to postulate that enrichment of diet in natural anti-glycating agents may attenuate glycation and, in consequence, ageing.

“…During diabetes, hyperglycaemia is a chronic insult to circulating immune cells and vascular endothelial cells. Furthermore, various intermediate metabolic products such as advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALE) also constitute insults to tissue cells [6–8]. Vascular endothelial damage is a main pathology in DR and microaneurysms, a characteristic feature of DR, is believed to be the consequence of endothelial and pericyte cell death [1].…”

Section: Introductionmentioning

confidence: 99%

STAT3 activation in circulating myeloid-derived cells contributes to retinal microvascular dysfunction in diabetes

Chen

Obasanmi

Armstrong

et al. 2019

J Neuroinflammation

Background Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in retinal vessels in diabetes. In this study, we investigated the role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and its contribution to retinal microvascular degeneration. Methods Forty-one patients with type 1 diabetes (T1D) [mild non-proliferative diabetic retinopathy (mNPDR) ( n = 13), active proliferative DR (aPDR) ( n = 14), inactive PDR (iPDR) ( n = 14)] and 13 age- and gender-matched healthy controls were recruited to the study. C57BL/6 J WT mice, SOCS3 fl/fl and LysM Cre/+ SOCS3 fl/fl mice were rendered diabetic by Streptozotocin injection. The expression of the phosphorylated human and mouse STAT3 (pSTAT3), mouse LFA-1, CD62L, CD11b and MHC-II in circulating immune cells was evaluated by flow cytometry. The expression of suppressor of cytokine signalling 3 (SOCS3) was examined by real-time RT-PCR. Mouse plasma levels of cytokines were measured by Cytometric Beads Array assay. Retinal leukostasis was examined following FITC-Concanavalin A perfusion and acellular capillary was examined following Isolectin B4 and Collagen IV staining. Results Compared to healthy controls, the expression of pSTAT3 in circulating leukocytes was statistically significantly higher in mNPDR but not aPDR and was negatively correlated with diabetes duration. The expression of pSTAT3 and its inhibitor SOCS3 was also significantly increased in leukocytes from diabetic mice. Diabetic mice had higher plasma levels of IL6 and CCL2 compared with control mice. LysM Cre/+ SOCS3 fl/fl mice and SOCS3 fl/fl mice developed comparative levels of diabetes, but leukocyte activation, retinal leukostasis and number of acellular capillaries were statistically significantly increased in LysM Cre/+ SOCS3 fl/fl diabetic mice. Conclusion STAT3 activation in circulating immune cells appears to contribute to retinal microvascular degeneration and may be involved in DR initiation in T1D. Electronic supplementary material The online version of this article (10.1186/s12974-019-1533-1) contains supplementary material, which is available to authorized users.