Early Neural and Vascular Dysfunctions in Diabetic Rats Are Largely Sequelae of Increased Sorbitol Oxidation

Ido, Yasuo; Nyengaard, Jens Randel; Chang, Kathy; Tilton, Ronald G.; Kilo, Charles; Mylari, Banavara L.; Oates, Peter J.; Williamson, Joseph R.

doi:10.1089/ars.2009.2502

Cited by 31 publications

(62 citation statements)

References 48 publications

(70 reference statements)

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“…G6PD activity was also found to be increased in the liver of Zucker diabetic rats [75]. Similarly, NADPH content in certain diabetic tissues has been reported to be elevated when compared with that in non-diabetic conditions [76], [77], [78]. Nonetheless, in our present study, we found that NADPH level declined in diabetic lung (Fig.…”

Section: Discussionsupporting

confidence: 70%

Redox imbalance and mitochondrial abnormalities in the diabetic lung

Jin

2017

Redox Biology

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Although the lung is one of the least studied organs in diabetes, increasing evidence indicates that it is an inevitable target of diabetic complications. Nevertheless, the underlying biochemical mechanisms of lung injury in diabetes remain largely unexplored. Given that redox imbalance, oxidative stress, and mitochondrial dysfunction have been implicated in diabetic tissue injury, we set out to investigate mechanisms of lung injury in diabetes. The objective of this study was to evaluate NADH/NAD+ redox status, oxidative stress, and mitochondrial abnormalities in the diabetic lung. Using STZ induced diabetes in rat as a model, we measured redox-imbalance related parameters including aldose reductase activity, level of poly ADP ribose polymerase (PAPR-1), NAD+ content, NADPH content, reduced form of glutathione (GSH), and glucose 6-phophate dehydrogenase (G6PD) activity. For assessment of mitochondrial abnormalities in the diabetic lung, we measured the activities of mitochondrial electron transport chain complexes I to IV and complex V as well as dihydrolipoamide dehydrogenase (DLDH) content and activity. We also measured the protein content of NAD+ dependent enzymes such as sirtuin3 (sirt3) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Our results demonstrate that NADH/NAD+ redox imbalance occurs in the diabetic lung. This redox imbalance upregulates the activities of complexes I to IV, but not complex V; and this upregulation is likely the source of increased mitochondrial ROS production, oxidative stress, and cell death in the diabetic lung. These results, together with the findings that the protein contents of DLDH, sirt3, and NQO1 all are decreased in the diabetic lung, demonstrate that redox imbalance, mitochondrial abnormality, and oxidative stress contribute to lung injury in diabetes.

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Section: Discussionsupporting

confidence: 70%

Redox imbalance and mitochondrial abnormalities in the diabetic lung

Jin

2017

Redox Biology

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“…Two groups implicated increased activity of the second enzyme of the sorbitol pathway, sorbitol dehydrogenase (SDH), in activation of the superoxide-generating enzyme, NAD(P)H oxidase [61,62]. Note, however, that these findings are not consistent with other reports describing 1) an important role of AR rather than SDH in DPN [46, 63], and 2) exacerbation, rather than amelioration, of oxidative stress with SDH inhibition in tissues of diabetic rats [64, 65].…”

Section: Discussionmentioning

confidence: 99%

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

Stavniichuk

Shevalye

Hirooka³

et al. 2012

Biochemical Pharmacology

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The interactions among multiple pathogenetic mechanisms of diabetic peripheral neuropathy largely remain unexplored. Increased activity of aldose reductase, the first enzyme of the sorbitol pathway, leads to accumulation of cytosolic Ca++, essentially required for 12/15-lipoxygenase activation. The latter, in turn, causes oxidative-nitrosative stress, an important trigger of MAPK phosphorylation. This study therefore evaluated the interplay of aldose reductase, 12/15-lipoxygenase, and MAPKs in diabetic peripheral neuropathy. In experiment 1, male control and streptozotocin-diabetic mice were maintained with or without the aldose reductase inhibitor fidarestat, 16 mg kg−1 d−1, for 12 weeks. In experiment 2, male control and streptozotocin-diabetic wild-type (C57Bl6/J) and 12/15-lipoxygenase-deficient mice were used. Fidarestat treatment did not affect diabetes-induced increase in glucose concentrations, but normalized sorbitol and fructose concentrations (enzymatic spectrofluorometric assays) as well as 12(S) hydroxyeicosatetraenoic concentration (ELISA), a measure of 12/15-lipoxygenase activity, in the sciatic nerve and spinal cord. 12/15-lipoxygenase expression in these two tissues (Western blot analysis) as well as dorsal root ganglia (immunohistochemistry) was similarly elevated in untreated and fidarestat-treated diabetic mice. 12/15-lipoxygenase gene deficiency prevented diabetesassociated p38 MAPK and ERK, but not SAPK/JNK, activation in the sciatic nerve (Western blot analysis) and all three MAPK activation in the dorsal root ganglia (immunohistochemistry). In contrast, spinal cord p38 MAPK, ERK, and SAPK/JNK were similarly activated in diabetic wild-type and 12/15-lipoxygenase−/− mice. These findings identify the nature and tissue specificity of interactions among three major mechanisms of diabetic peripheral neuropathy, and suggest that combination treatments, rather than monotherapies, can sometimes be an optimal choice for its management.

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“…High [glucose] or nutrient excess leads to down-regulation of AMPK activity in several cell types [120,121] and lowers SIRT1 expression in endothelial cells [122, 123, 124••]. Finally, the diabetic state lowers the NAD + /NADH ratio in retina and nerve through increased flux through the polyol pathway and the elevated activity of sorbitol dehydrogenase [125][126][127][128].…”

Section: Nutrient Stress In Diabetesmentioning

confidence: 99%

“…Work in adult sensory neurons, primary Schwann cells, and kidney reveals that respiratory complex activity is down leading to reduced rates of mitochondrial electron transport and thus suppressed leakage of electrons [45•, 53]. However, this does not preclude diabetes-induced ROS generation from other sources, e.g., glucose metabolism through the aldose reductase pathway leading to enhanced NADPH oxidase (NOX) activity [125,135].…”

Section: Links Between Mitochondrial Dysfunction and Oxidative Stressmentioning

confidence: 99%

Mitochondrial Dysfunction in Diabetic Neuropathy: a Series of Unfortunate Metabolic Events

Fernyhough

2015

Curr Diab Rep

118

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Diabetic neuropathy is a dying back neurodegenerative disease of the peripheral nervous system where mitochondrial dysfunction has been implicated as an etiological factor. Diabetes (type 1 or type 2) invokes an elevation of intracellular glucose concentration simultaneously with impaired growth factor support by insulin, and this dual alteration triggers a maladaptation in metabolism of adult sensory neurons. The energy sensing pathway comprising the AMP-activated protein kinase (AMPK)/sirtuin (SIRT)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) signaling axis is the target of these damaging changes in nutrient levels, e.g., induction of nutrient stress, and loss of insulin-dependent growth factor support and instigates an aberrant metabolic phenotype characterized by a suppression of mitochondrial oxidative phosphorylation and shift to anaerobic glycolysis. There is discussion of how this loss of mitochondrial function and transition to overreliance on glycolysis contributes to the diminishment of collateral sprouting and axon regeneration in diabetic neuropathy in the context of the highly energy-consuming nerve growth cone.

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Early Neural and Vascular Dysfunctions in Diabetic Rats Are Largely Sequelae of Increased Sorbitol Oxidation

Cited by 31 publications

References 48 publications

Redox imbalance and mitochondrial abnormalities in the diabetic lung

Redox imbalance and mitochondrial abnormalities in the diabetic lung

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

Mitochondrial Dysfunction in Diabetic Neuropathy: a Series of Unfortunate Metabolic Events

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