Glucose utilization by the polyol pathway in human erythrocytes

doi:10.1016/0006-291X(70)91066-1

Biochemical and Biophysical Research Communications

Volume 40, Issue 1, 13 July 1970, Pages 199-205

https://doi.org/10.1016/0006-291X(70)91066-1 Get rights and content

Abstract

Sorbitol is present in human erythrocytes in concentrations exceeding that in plasma, and is linearly related to the plasma glucose concentration. When erythrocytes are incubated in media containing increasing glucose concentrations, the intracellular sorbitol and fructose concentrations increase and free fructose appears in the media. At a medium glucose concentration of 5 mM approximately 3% of the glucose uptake is utilized for sorbitol and fructose synthesis.Glucose appears to be a physiological substrate for alditol:NADP oxidoreductase in the erythrocyte.

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Cited by (89)

Status of oxidative stress markers, advanced glycation index, and polyol pathway in age-related cataract subjects with and without diabetes
2020, Experimental Eye Research
Citation Excerpt :
These findings suggest that only the presence and duration of diabetes could have contributed to the increased plasma AGI values in DCAT. Under normoglycemic conditions, only a small fraction (~3%) of glucose is metabolized through the polyol pathway (Morrison et al., 1970), whereas during chronic hyperglycemia, more than 30% of glucose flux through the polyol pathway (González et al., 1984). The excess flux of glucose via the polyol pathway results in the accumulation of sorbitol and depletion of NADPH, which impose oxidative stress in general and diabetic complications in particular (Anil Kumar and Bhanuprakash Reddy, 2007).
One of the major public health issues is the rising prevalence of cataracts, a primary reason for preventable blindness. The causes for the development of age-related cataracts and accelerated cataractogenesis in diabetes are multifactorial. Hence, this study was designed to examine the status and relationship between the three majorly associated molecular events, namely, oxidative stress, non-enzymatic glycation, and polyol pathway in age-related cataracts with and without diabetes. A total of 472 subjects were distributed into four groups: non-diabetic subjects with clear lens (135), diabetic subjects with clear lens (40), non-diabetic subjects with cataract (174), and diabetic subjects with cataract (123). Cataracts were graded by slit-lamp examination according to the Lens Opacities Classification System III. Age at onset of cataract, type of opacity, anthropometric measurements, and sociodemographic characteristics were recorded, and clinical profile was examined. Plasma oxidative stress markers were assessed by estimating the lipid peroxidation end product malondialdehyde, protein oxidation products protein carbonyls, and DNA oxidative damage marker 8-hydroxy-2-deoxyguanosine. Plasma advanced glycation end products index, erythrocyte aldose reductase activity, and sorbitol levels were evaluated. After adjusting for age, plasma malondialdehyde levels were significantly higher in diabetic cataracts (P < 0.001) and non-diabetic cataract subjects (P < 0.05), compared to non-diabetic subjects with clear lens. Plasma advanced glycation end products index was significantly higher (P < 0.05) only in diabetic cataracts, but not in non-diabetic subjects with cataracts. Aldose reductase activity and sorbitol levels were significantly higher (P < 0.001) in both diabetic and non-diabetic subjects with cataract compared to non-diabetic subjects with clear lens. The data indicated that plasma lipid peroxidation in age-related cataracts was independent of diabetes. An association of pronounced glycation was observed only in diabetic cataracts but not in non-diabetic cataracts and polyol flux between diabetic cataracts and non-diabetic cataracts was comparable.
Mechanistic inhibition of non-enzymatic glycation and aldose reductase activity by naringenin: Binding, enzyme kinetics and molecular docking analysis
2020, International Journal of Biological Macromolecules
Citation Excerpt :
Sorbitol dehydrogenase then converts sorbitol into fructose [17]. The glucose flux through this pathway increases up to 30% in the hyperglycaemia state [18], while in normal glycaemic conditions, it remains at approximately 3% [19]. Therefore, AR enzyme is considered a potential target for the treatment of diabetic complications [20].
The aldose reductase (AR) enzyme is considered a potential target for the management of diabetic complications. In this study, we describe the binding and enzyme kinetics of AR by naringenin, a bioflavonoid present in many dietary sources. Naringenin showed an inhibitory effect on the activity of AR with an IC₅₀ value of 2.6 μM in an uncompetitive manner. Binding studies confirmed that the naringenin-AR complex has high spontaneous affinity (K_a = 1.94–7.88 × 10⁴) with negative ΔG° value (−5.78 kcal mol⁻¹). The interaction was enthalpy driven and the microenvironment of aromatic residues of AR was also altered. Various stages of protein oxidation and glycation were also measured. Naringenin inhibited fructosamine content by approximately 31.6% at 10 μM, and at the same concentration, >93% inhibition of fluorescent advanced glycation end-products (AGEs) was achieved. There was a significant recovery in free thiol groups and carbonyl content of bovine serum albumin (BSA). Furthermore, molecular docking of naringenin with AR revealed that naringenin formed two hydrogen bonds (Asn160 and Ile260), and three Pi-Pi interactions (two with Trp20 and one with His110). This study provides molecular insight of naringenin-AR interaction and mechanism of antiglycation which may be useful in the development of inhibitors for AGEs formation.
Glycation- and/or polyol pathway-inducing complications
2018, Encyclopedia of Endocrine Diseases
Glycation of proteins by glucose forms fructosamine residues. Glycated hemoglobin “A1C” thereby formed is an indicator of glycemic control in diabetes and a marker for diagnosis of diabetes and impaired glucose tolerance. Advanced glycation endproducts (AGEs) are formed by the degradation of fructosamine and glycation by reactive dicarbonyl metabolites such as methylglyoxal. Abnormal plasma and cellular concentrations of methylglyoxal are found in diabetes and is called the abnormal metabolic state of dicarbonyl stress. Chemically stable AGEs in skin collagen are risk markers of diabetic microvascular complications. Methylglyoxal forms major protein and nucleotide AGEs, hydroimidazolone MG-H1 and imidazopurinone MGdG and is a critical mediator of vascular complications of diabetes. MG is mainly metabolized by glyoxalase 1 (Glo1) of the glyoxalase pathway in cells. In obesity and diabetes, MG concentration increase by the synergistic increased formation of MG and downregulation of Glo1. Small molecule inducers of glyoxalase 1 expression have been developed. Glo1 inducer corrected insulin resistance, improved dysglycemia and decreased vascular inflammation in clinical diabetes and are in development for novel therapy for complications of obesity and diabetes. The polyol pathway is a two-step metabolic pathway that converts glucose to fructose via sorbitol where the first step is catalyzed by aldose reductase. Aldose reductase is highly expressed in the renal medulla to therein reduce glucose to sorbitol and counter osmotic pressure during antidiuresis. Aldose reductase inhibitors have been proposed for treatment of microvascular complication of diabetes.
Recent advances in understanding the role of oxidative stress in diabetic neuropathy
2015, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citation Excerpt :
Polyol pathway is extensively dependent upon the varied types of species, sites and tissues. Aldose reductase has a low affinity for glucose and normally only about 3% of glucose is metabolized by this pathway [16] (Fig. 2). But in hyperglycemic conditions up to 33% of total glucose utilization in some tissues can be through the polyol pathway [17].
Diabetic neuropathy (DN) is one of the most common and severe manifestations of diabetes mellitus. The mechanisms underlying the structural, functional and metabolic changes in diabetic neuropathy have been under study for a long time. In this review the biochemistry and implications of the four pathways responsible for the development of DN, polyol pathway; increased AGEs (advanced glycation end-products) formation; activation of PKC (protein kinase C) and hexosamine pathway have been discussed. Experimental and clinical evidences suggest a close link between neurodegeneration and oxidative stress which serves as a unifying mechanism, thus linking the four pathways. Recent studies indicate that oxidative stress mediated DNA damage causes poly(ADP-ribose) polymerase (PARP) overactivation and reduced activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a factor common to all the four pathways. The exact mechanism of PARP mediated cell death in DN needs further investigation. Based on current studies neuroprotective and antioxidant therapy have been suggested as potential treatment and preventive solutions for DN.
Inhibitory effect of banana (Musa sp. var. Nanjangud rasa bale) flower extract and its constituents Umbelliferone and Lupeol on α-glucosidase, aldose reductase and glycation at multiple stages
2014, South African Journal of Botany
Citation Excerpt :
Despite the studies suggesting the role of AR in detoxification of aldehydes which is a by-product of lipid peroxidation, its relevance in carbohydrate metabolism is unknown. However, inhibition of this enzyme renders a protective role against cataract development in case of diabetic patients (Anthony et al., 1970). This suggests the importance in targeting the inhibition of AR during diabetes.
Postprandial hyperglycaemia is characterized as the earliest symptom of diabetes and its management attenuates several of the associated secondary complications. In this context, we investigated the role of ethanol extract of banana flower (EF) for its antihyperglycaemic effects. The EF showed a strong inhibition towards α-glucosidase and pancreatic amylase which play a vital role in clinical management of postprandial hyperglycaemia. The major active compounds present in EF were identified as Umbelliferone (C1) and Lupeol (C2) using various spectroscopic methods. C1 (IC₅₀: 7.08 ± 0.17 μg/ml) and C2 (IC₅₀: 7.18 ± 0.14 μg/ml) were found to inhibit α-glucosidase in a non-competitive mode of inhibition, with low K_i values. Further, in vitro glycation assays showed that EF and its compounds prevented each stage of protein glycation and formation of its intermediary compounds. EF, C1 and C2 also exhibited a potent inhibition on aldose reductase with IC₅₀ values of 2.25 ± 0.29, 1.32 ± 0.22 & 1.53 ± 0.29 μg/ml respectively. Our results suggest that, the observed potential of EF in antihyperglycaemic activity via inhibition of α-glucosidase and in antidiabetogenic effect by inhibition of polyol pathway and protein glycation is more likely to be attributed to the presence of C1 and C2.
Response of a Human Lens Epithelial Cell Line to Hyperglycemic and Oxidative Stress: The Role of Aldose Reductase
2023, Antioxidants

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Glucose utilization by the polyol pathway in human erythrocytes

Abstract

Biochem. Biophys. Res. Comm

J. Biol. Chem

J. Neurochem

Science

Biochem. Biophys. Res. Comm

J. Am. Chem. Soc