Hyperglycemic pseudohypoxia and diabetic complications

Williamson, Joseph R.; Chang, K.; Frangos, M.; Hasan, K. S.; Ido, Yasuo; Kawamura, T.; Nyengaard, Jens Randel; Enden, M. van den; Kilo, Charles; Tilton, Ronald G.

doi:10.2337/diabetes.42.6.801

Cited by 409 publications

(311 citation statements)

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“…This has previously been ascribed to several factors, predominantly 1,2-diacyl-sn-glycerol (DAG) [2] and IGF-1 [31,32], but also, for example, to TGF-β [33], angiotensin II [34] and atrial natriuretic peptide [35]. In the present study, kidney weight was reduced following treatment with AL-1576.…”

Section: Discussionsupporting

confidence: 53%

“…Imbalance in the lactate : pyruvate ratio may reflect hypoxia. However, during hyperglycaemia, similar changes have been shown to occur due to overactivity in the polyol pathway, causing an increased reduction rate of NAD + to NADH, and thereby an increased probability that the lactate : pyruvate equilibrium re-oxidises NADH [2]. Hyperglycaemiainduced mitochondrial production of ROS has been shown to induce activation of the polyol pathway [20].…”

Section: Discussionmentioning

confidence: 98%

“…In the present study, kidney weight was reduced following treatment with AL-1576. Inhibition of hyperglycaemia-induced aldose reductase activity is known to inhibit the synthesis of DAG and thus inhibit protein kinase C (PKC) activity [2]. Any direct effects of aldose reductase inhibitors on the expression of IGF-1 or its receptors have not, to our knowledge, been described.…”

Section: Discussionmentioning

confidence: 99%

“…In other organs known to be vulnerable to complications of diabetes mellitus, i.e. retina and nerves, changes in the microcirculation, oxygen tension and cellular metabolism have been thoroughly studied and seem to be crucial for the progression of organ failure [2,3,4]. The majority of studies on diabetic nephropathy have been conducted in vitro and/or have focused on glomerular changes.…”

Section: Introductionmentioning

confidence: 99%

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Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

et al. 2004

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Aims/hypothesis. The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. Methods. Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purinebased metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes.Results. The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. Conclusions/interpretation. Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

et al. 2004

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“…In many tissues, hyperglycaemia-induced metabolic imbalances increase the cytosolic ratio of free NADH:NAD+ (despite normal tissue PO 2 ) that results in pseudohypoxia [39]. On the contrary, in hypoxic and ischaemic myocardium, the redox imbalance results from impaired mitochondrial oxidation of NADH to NAD+ because of decreased PO 2 .…”

Section: Discussionmentioning

confidence: 99%

Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1

et al. 2002

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Aims/hypothesis. This study aimed to evaluate the effects of hyperglycaemia on the evolution of myocardial infarction and the expression of the transcriptional factor for angiogenesis hypoxia-inducible factor 1α (HIF-1α) in the rat. Methods. We studied the effects of streptozotocin induced diabetes on infarct size and HIF-1α gene expression. These parameters were also evaluated in isolated hearts of non-diabetic rat, in condition of high glucose concentration. Results. In streptozotocin (STZ)-diabetic rats (in vivo study), myocardial infarct size was greater (p<0.01) in hyperglycaemic rats (22 mmol/l) than in normoglycaemic (7 mmol/l) or non-diabetic rats. In euglycaemic conditions, basal expression of HIF-1α mRNA was not appreciable, but increased steadily after ischaemia (762±86%, p<0.001); this response was blunted in hyperglycaemic STZ-rats (6.8±6% of the control, p<0.001) and improved in euglycaemic STZ-rats (58±10%). The changes in myocardial Rac1 mRNA expression paralleled those of HIF-1α. In isolated hearts from non-diabetic rats (in vitro study), perfusion with high glucose (33 mmol/l) produced an infarct size (58±2% of the area at risk) not different from that obtained in hyperglycaemic STZ-rats (57±2%). Similar changes in the expression of HIF-1α and Rac1, which were prevented by glutathione infusion (0.3 mmol/l) were also observed. Conclusion/interpretation. Both hyperglycaemia and high glucose concentrations increased basal HIF-1α and Rac1 expression, suggesting a state of pseudohypoxia. These findings show that myocardial infarct size in the rat is increased in hyperglycaemic conditions and is associated with a reduced expression of the HIF-1α gene. These changes are reversed, totally or partially, by normoglycaemia or glutathione suggesting a role for reactive oxygen species generation brought about by hyperglycaemia. [Diabetologia (2002[Diabetologia ( ) 45:1172[Diabetologia ( -1181

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Characterization of polyol pathway in schwann cells isolated from adult rat sciatic nerves

et al. 1999

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To elucidate the molecular mechanisms underlying the development of diabetic neuropathy, we isolated the Schwann cells from the sciatic nerves of adult rats and characterized the polyol pathway activity. Despite the presence of aldose reductase (AR) activity, no accumulation of sorbitol was observed in the cells cultured under 30 mM glucose conditions. Increased levels of sorbitol were detected in the medium conditioned by these cells. SNK-860 (fidarestat), an inhibitor of AR, decreased the sorbitol levels at 10(-6)M, while addition of SDI-158, an inhibitor of sorbitol dehydrogenase, did not affect the level in the cells grown in high glucose. These observations suggested that sorbitol produced by AR in the isolated Schwann cells may be predominantly excreted. In contrast, a significant increase in sorbitol level was observed in cells cultured under hyperosmotic conditions with 30 mM glucose. A significant correlation was observed between sorbitol level and AR activity (r = 0.998). The increase was suppressed by addition of SNK-860, while SDI-158 augmented sorbitol accumulation in a dose-dependent manner. These results suggested that the isolated Schwann cells may not accumulate sorbitol unless the activity of AR is augmented by some as yet undetermined mechanism under high glucose conditions, such as the hyperosmotic stress induced in this study.

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Hyperglycemic pseudohypoxia and diabetic complications

Cited by 409 publications

References 0 publications

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1

Characterization of polyol pathway in schwann cells isolated from adult rat sciatic nerves

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