Metabolic alterations in the human erythrocyte produced by increases in glucose concentration

Travis, Susan F.; Morrison, Anthony D.; Clements, Rex S.; Winegrad, Albert I.; Oski, Frank A.

doi:10.1172/jci106704

Cited by 127 publications

(62 citation statements)

References 26 publications

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“…Glucose, pyruvate, lactate, glucose 6-phosphate (G6P), fructose 6-phosphate (F6P), ATP, glutamate, 2-oxoglutarate, and ammonia in extracts of retina (and pyruvate and lactate in extracts of incubation medium) were quantified by standard enzymatic methods (10,39,40). Because the overall reaction catalyzed by aldolase and triose phosphate isomerase is in near equilibrium under steady-state conditions (7), fructose 1,6-bisphosphate (F1,6-BP) was converted to dihydroxyacetone phosphate (DHAP) by aldolase and measured together with endogenous DHAP and glyceraldehyde 3-phosphate (GA3P) as triose phosphates (7,10). Sorbitol in retinal extracts was quantified by gas chromatography/mass spectrometry as previously described (10).…”

Section: Methodsmentioning

confidence: 99%

“…Examples include an increased ratio of reduced to oxidized free cytosolic NADc (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), increased production of free radicals (3,(17)(18)(19)(20)(21)(22)(23)(24) and vascular endothelial growth factor (17,19,(25)(26)(27)(28), accumulation of triose phosphates (7,9,10,(13)(14)(15), activation of protein kinase C (PKC) (22,28 -30), decreased Na ϩ /K ϩ -ATPase activity (3,30 -33), early increases in blood flow (3,(33)(34)(35), and paradoxical protective effects of diabetes and brief periods of hypoxia/ ischemia (i.e., ischemic preconditioning) that attenuate dysfunction/injury evoked by subsequent more severe hypoxia/ischemia (3,29,36 -38).…”

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Interactions Between Hyperglycemia and Hypoxia

et al. 2004

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The primary aim of these experiments was to assess in vitro effects of hyperglycemia (30 mmol/l glucose) and hypoxia (PO 2 ‫؍‬ 36 torr) of 2-h duration, separately and in combination, on cytosolic and mitochondrial free NADH (NADHc and NADHm, respectively) in retinas from normal rats. NADH is the major carrier of electrons and protons that fuel ATP synthesis and several metabolic pathways linked to diabetic complications. T he importance of duration and severity of hyperglycemia in the development of diabetic retinopathy was clearly established by the Diabetes Control and Complications Trial (1); however, the mechanisms that mediate early and late retinal vascular dysfunction and structural changes remain unclear.Proliferative retinopathy is widely attributed to increased production of vascular endothelial growth factor evoked by hypoxia/ischemia caused by capillary closure and nonperfusion that develop relatively early after the onset of diabetes (2).The possibility that hyperglycemia and hypoxia may interact via a common metabolic imbalance(s) to initiate and/or exacerbate complications of diabetes is suggested by the correspondence of several redox, metabolic, and pathophysiological changes evoked by either condition alone. Examples include an increased ratio of reduced to oxidized free cytosolic NADc (3-16), increased production of free radicals (3,17-24) and vascular endothelial growth factor (17,19,(25)(26)(27)(28), accumulation of triose phosphates (7,9,10,13-15), activation of protein kinase C (PKC) (22,28 -30), decreased Na ϩ /K ϩ -ATPase activity (3,30 -33), early increases in blood flow (3,(33)(34)(35), and paradoxical protective effects of diabetes and brief periods of hypoxia/ ischemia (i.e., ischemic preconditioning) that attenuate dysfunction/injury evoked by subsequent more severe hypoxia/ischemia (3,29,36 -38).An increase in free NADH/NAD ϩ c appears to be the best candidate metabolic imbalance for mediating pathophysiological changes common to diabetes and hypoxia (3,38). This redox imbalance develops when electrons and protons are transferred to free oxidized NAD ϩ c (reducing it to NADHc) faster than electrons and protons carried by NADHc are used for ATP synthesis in mitochondria by oxidative phosphorylation. Hypoxia increases free NADHc because lack of O 2 impairs utilization of electrons and protons carried by mitochondrial NADHm for oxidative phosphorylation. The mass action effect of electrons and protons accumulating in NADHm restrains transfer of electrons and protons from free NADHc to NAD ϩ m by the malate-aspartate electron shuttle; thus, electrons and protons accumulate in, and elevate, free NADHc.In cells for which glucose uptake is insulin-independent, hyperglycemia augments glucose uptake and metabolism via the sorbitol pathway. In the second step of the pathway, sorbitol is oxidized to fructose by sorbitol dehydrogenase, which catalyzes transfer of a hydride ion (:H Ϫ ) from sorbitol to free NAD ϩ c (reducing it to NADHc) and removal of a second hydrogen atom that is released i...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Interactions Between Hyperglycemia and Hypoxia

et al. 2004

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“…Methylglyoxal is known to arise from triosephosphates (41) and potentially mediates the formation of N ε -(carboxyethyl)lysine, which is a homolog of CML (42). Triosephosphates were shown to be elevated in diabetes and decreased by aldose reductase inhibitors (43,44) as a result of redox changes (44), and the suppressive effects of the inhibitor were also reported with methylglyoxal (45). Fructose-3-phosphate and 3-DG are other reactive metabolites originating from fructose (46), which is a product of the polyol pathway.…”

Section: Hamada and Associatesmentioning

confidence: 99%

Epalrestat, an aldose reductase ihibitor, reduces the levels of Nepsilon-(carboxymethyl)lysine protein adducts and their precursors in erythrocytes from diabetic patients.

et al. 2000

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RESULTS -In diabetic patients not treated with epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 ± 5.0 vs. 31.0 ± 5.2 U/g protein, P Ͻ 0.05) and was significantly lower in patients receiving epalrestat (33.1 ± 3.8 U/g protein, P Ͻ 0.05). Similar results were observed with 3-DG. The treatment of patients with epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 ± 5.6 at baseline vs. 34.4 ± 5.0 U/g protein, P Ͻ 0.01) along with erythrocyte 3-DG (P Ͻ 0.05), triosephosphates (P Ͻ 0.05), fructose (P Ͻ 0.05), sorbitol (P Ͻ 0.05), and plasma TBARS (P Ͻ 0.05) without changes in plasma glucose and HbA 1c levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P Ͻ 0.01) or fructose (r = 0.40, P Ͻ 0.05) levels in diabetic patients.CONCLUSIONS -The results indicate that epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.

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“…It has been proposed that changes in the relative proportions of the sorbitol pathway intermediates in the red cell may initiate changes in the oxidized and reduced forms of the NAD+ and the NADP'^ redox systems and that this effect may lead to a pathabolic state within the cell (Travis et at, 1971;Ditzel, 1972). That similar changes may be expected in the retina is also possible.…”

Section: I-i-mentioning

confidence: 99%

“…The pathogenesis of diabetic cataract has been linked to the accumulation of sorbitol in lens tissue to concentrations sufficiently elevated to cause osmotic swelling and cellular disruption of the tissue (Van Heyningen, 1962;Ch\'lack and Kinoshita, 1969). A similar pathogenic basis of diabetic peripheral neuropathy has been snggested (Gabbay, Merola and Field, 1966;Stewart, Sherman, Kurien, Moonsammy and Wisgcrhof, 1967) and a hypothesis relating diabetic smalt vessel disease of the retina to changes in the activity of the sorbitol pathway in retina (Beaumont, Hollows, Schofield, Williams and Steinbeck, 1971) is currently under investigation in this laboratory.…”

Section: Introductionmentioning

confidence: 99%

Sorbitol Metabolism in the Retina: Accumulation of Pathway Intermediates in Streptozotocin Induced Diabetes in the Rat

Hutton

Schofield

Williams

et al. 1974

Aust J Exp Biol Med

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Summary. The capacities of rat lens and retina to accumulate sorbitol pathway intemiediates in streptozotocin induced diabetes were inve.stigated. The experiments performed were of two types:(i) investigations of the time course of the appearance of the pathway intermediates in lens and retina following the induction of diabetes, and (ii) investigation of the relationship of scirbitol pathway intermediate accumulations to varying doses of .strt'ptozotocin. The experimental objectives were to investigate the factors which control the activity of the pathway in vivo, and to a.ssfss the proposed relation.ship between sorbitol metabolism in the retina and the pathogenesis of diabetic small vessel disease in this tissue.The sorbitol which accumulated in the retina of the diabetic animal (approximately 1-5 iimolc/g protein) was formed by the intrinsic metabolic activity of the tissne and was not attributed to transport from an external metabolic site. The accunmlation of this intermediate was directly related to the plasma gincose concentration and could not be related to other parameters of the diabetic state, e.g. plasma free fatty acid concentration, ketonaemia.It was confirmed that the rat lens accumulated sorbitol (approximately 80 (imole/g protein) and fructose (approximately 20 n'Tiole/g protein) in diabetes, and that such accumulations were related to the glucose concentration of the aqueous humour. The possibility that factors associated with kctoacidosis aflected the relati\e concentration.s of lens sorbitol and fructose was suggested by the results.An hypothesis which invoked sorbitol iiccuninlation to osmotically signifieant concentrations within the retina as a pathogenic agent in diabetic small ve.ssel disease in this tissue conld not be directly supported by the results. Alternate mechanisms by which low concentrations of sorbitol iu diabetic retina could act as a pathogenic stimulus are discussed.

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Metabolic alterations in the human erythrocyte produced by increases in glucose concentration

Cited by 127 publications

References 26 publications

Interactions Between Hyperglycemia and Hypoxia

Interactions Between Hyperglycemia and Hypoxia

Epalrestat, an aldose reductase ihibitor, reduces the levels of Nepsilon-(carboxymethyl)lysine protein adducts and their precursors in erythrocytes from diabetic patients.

Sorbitol Metabolism in the Retina: Accumulation of Pathway Intermediates in Streptozotocin Induced Diabetes in the Rat

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