Hyperglycemia Impairs Acetylcholine-Induced Vasodilation of Retinal Arterioles Through Polyol Pathway–Independent Mechanisms in Rats

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

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Untargeted Plasma Metabolomics Unravels a Metabolic Signature for Tissue Sensitivity to Glucocorticoids in Healthy Subjects: Its Implications in Dietary Planning for a Healthy Lifestyle

Nutrients ◽

10.3390/nu13062120 ◽

2021 ◽

Vol 13 (6) ◽

pp. 2120

Author(s):

Nicolas C. Nicolaides ◽

Maria-Konstantina Ioannidi ◽

Eleni Koniari ◽

Ifigeneia Papageorgiou ◽

Anastasia Bartzeliotou ◽

...

Keyword(s):

Healthy Subjects ◽

Healthy Lifestyle ◽

Serum Cortisol ◽

Polyol Pathway ◽

Gas Chromatography Mass Spectrometry ◽

Multivariate Statistical ◽

Glucocorticoid Sensitivity ◽

Metabolic Signature ◽

Resistant Group ◽

One Carbon Metabolism

In clinical practice, differences in glucocorticoid sensitivity among healthy subjects may influence the outcome and any adverse effects of glucocorticoid therapy. Thus, a fast and accurate methodology that could enable the classification of individuals based on their tissue glucocorticoid sensitivity would be of value. We investigated the usefulness of untargeted plasma metabolomics in identifying a panel of metabolites to distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects who do not carry mutations in the human glucocorticoid receptor (NR3C1) gene. Applying a published methodology designed for the study of glucocorticoid sensitivity in healthy adults, 101 healthy subjects were ranked according to their tissue glucocorticoid sensitivity based on 8:00 a.m. serum cortisol concentrations following a very low-dose dexamethasone suppression test. Ten percent of the cohort, i.e., 11 participants, on each side of the ranking, with no NR3C1 mutations or polymorphisms, were selected, respectively, as the most glucocorticoid-sensitive and most glucocorticoid-resistant of the cohort to be analyzed and compared with untargeted blood plasma metabolomics using gas chromatography–mass spectrometry (GC–MS). The acquired metabolic profiles were evaluated using multivariate statistical analysis methods. Nineteen metabolites were identified with significantly lower abundance in the most sensitive compared to the most resistant group of the cohort, including fatty acids, sugar alcohols, and serine/threonine metabolism intermediates. These results, combined with a higher glucose, sorbitol, and lactate abundance, suggest a higher Cori cycle, polyol pathway, and inter-tissue one-carbon metabolism rate and a lower fat mobilization rate at the fasting state in the most sensitive compared to the most resistant group. In fact, this was the first study correlating tissue glucocorticoid sensitivity with serine/threonine metabolism. Overall, the observed metabolic signature in this cohort implies a worse cardiometabolic profile in the most glucocorticoid-sensitive compared to the most glucocorticoid-resistant healthy subjects. These findings offer a metabolic signature that distinguishes most glucocorticoid-sensitive from most glucocorticoid-resistant healthy subjects to be further validated in larger cohorts. Moreover, they support the correlation of tissue glucocorticoid sensitivity with insulin resistance and metabolic syndrome-associated pathways, further emphasizing the need for nutritionists and doctors to consider the tissue glucocorticoid sensitivity in dietary and exercise planning, particularly when these subjects are to be treated with glucocorticoids.

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The Diameter of Retinal Arterioles Is Unaffected by Intravascular Administration of the Adenosine A2A Receptor Agonist Regadenoson in Normal Persons

Biomedicine Hub ◽

10.1159/000500563 ◽

2019 ◽

Vol 4 (2) ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Anna Dons-Jensen ◽

Line Petersen ◽

Hans-Erik Bøtker ◽

Toke Bek

Keyword(s):

Intravenous Administration ◽

Receptor Agonist ◽

Adenosine A2a Receptor ◽

Retinal Vessels ◽

Adenosine Receptor Agonists ◽

Retinal Arterioles ◽

A2a Receptor ◽

Adenosine A2a

Background: The neurotransmitter adenosine has been proposed to be involved in the pathogenesis of diabetic retinopathy, which may be due to the vasoactive properties of the compound. Previous studies have shown that adenosine can affect the tone of retinal arterioles in vitro to induce dilatation mediated by A2A and A2Breceptors and constriction mediated by A1 and A3 receptors. Purpose: To investigate effects of intravenous administration of the adenosine A2A receptor agonist regadenoson on the diameter of retinal vessels in vivo. Method: The diameter responses of larger retinal arterioles and venules were evaluated using the dynamic vessel analyser in 20 normal persons (age 22–31 years) after intravenous administration of the adenosine A2A receptor agonist regadenoson during exposure to systemic normoxia and hypoxia. Results: The diameter of retinal arterioles and venules increased significantly during stimulation with flickering light (p < 0.0001). Regadenoson reduced the flicker-induced dilatation of venules during normoxia (p = 0.0006), but otherwise had no effect on vessel diameters (p > 0.08 for all comparisons). Conclusions:Intravenous administration of the adenosine A2A receptor agonist regadenoson had no significant effect on the diameter of retinal arterioles. Future studies should investigate differential effects of intra- and extravascular administration of adenosine receptor agonists on retinal vessels.

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Retinal Redox Stress and Remodeling in Cardiometabolic Syndrome and Diabetes

Oxidative Medicine and Cellular Longevity ◽

10.4161/oxim.3.6.14786 ◽

2010 ◽

Vol 3 (6) ◽

pp. 392-403 ◽

Cited By ~ 29

Author(s):

Ying Yang ◽

Melvin R. Hayden ◽

Susan Sowers ◽

Sarika V. Bagree ◽

James R. Sowers

Keyword(s):

Metabolic Pathways ◽

Tissue Injury ◽

Disease Process ◽

Polyol Pathway ◽

The United States ◽

Redox Stress ◽

Blood Retinal Barrier ◽

Cardiometabolic Syndrome ◽

Hexosamine Pathway ◽

Pathway Flux

Diabetic retinopathy (DR) is a significant cause of global blindness; a major cause of blindness in the United States in people aged between 20–74. There is emerging evidence that retinopathy is initiated and propagated by multiple metabolic toxicities associated with excess production of reactive oxygen species (ROS). The four traditional metabolic pathways involved in the development of DR include: increased polyol pathway flux, advanced glycation end-product formation, activation of protein kinase Cisoforms and hexosamine pathway flux. These pathways individually and synergisticallycontribute to redox stress with excess ROS resulting in retinal tissue injury resulting in significant microvascular blood retinal barrier remodeling. The toxicity of hyperinsulinemia, hyperglycemia, hypertension, dyslipidemia, increased cytokines and growth factors, in conjunction with redox stress, contribute to the development and progression of DR. Redox stress contributes to the development and progression of abnormalities of endothelial cells and pericytes in DR. This review focuses on the ultrastructural observations of the blood retinal barrier including the relationship between the endothelial cell and pericyte remodeling in young nine week old Zucker obese (fa/ fa) rat model of obesity; cardiometabolic syndrome, and the 20 week old alloxan induced diabetic porcine model. Preventing or delaying the blindness associated with these intersecting abnormal metabolic pathways may be approached through strategies targeted to reduction of tissue inflammation and oxidative—redox stress. Understanding these abnormal metabolic pathways and the accompanying redox stress and remodeling mayprovide both the clinician and researcher a new concept of approaching this complicated disease process

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In vitro retinal and erythrocyte polyol pathway regulation by hormones and an aldose reductase inhibitor

Diabetes Research and Clinical Practice ◽

10.1016/0168-8227(91)90050-n ◽

1991 ◽

Vol 14 (1) ◽

pp. 29-35 ◽

Cited By ~ 5

Author(s):

N. Hotta ◽

H. Kakuta ◽

N. Koh ◽

H. Fukasawa ◽

T. Yasuma ◽

...

Keyword(s):

Aldose Reductase ◽

Reductase Inhibitor ◽

Polyol Pathway ◽

Aldose Reductase Inhibitor ◽

Pathway Regulation

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Diabetic Cataract—Pathogenesis, Epidemiology and Treatment

Journal of Ophthalmology ◽

10.1155/2010/608751 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 154

Author(s):

Andreas Pollreisz ◽

Ursula Schmidt-Erfurth

Keyword(s):

Experimental Studies ◽

Disease Process ◽

Basic Research ◽

Polyol Pathway ◽

Population Based ◽

Diabetic Patients ◽

Diabetic Cataract ◽

Cataract Development

Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process. Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Diabetic patients also have a higher risk of complications after phacoemulsification cataract surgery compared to nondiabetics. Aldose-reductase inhibitors and antioxidants have been proven beneficial in the prevention or treatment of this sightthreatening condition in in vitro and in vivo experimental studies. This paper provides an overview of the pathogenesis of diabetic cataract, clinical studies investigating the association between diabetes and cataract development, and current treatment of cataract in diabetics.

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