Fructose-3-phosphate production and polyol pathway metabolism in diabetic rat hearts

Lal, Sundeep; Randall, William C.; Taylor, Anne H.; Kappler, Francis; Walker, Michael; Brown, Truman R.; Szwergold, Benjamin S.

doi:10.1016/s0026-0495(97)90240-7

Cited by 32 publications

(20 citation statements)

References 46 publications

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“…Thus, the shift in myocardial substrate and energy metabolism may contribute to increased levels of CML and decreased levels of CEL. The diabetic heart is also characterized by increased levels of fructose, leading to the accumulation of fructose-3-phosphate and its decomposition product 3-DG [24,25]. In accordance, also in our study, we found increased levels of 3DG in the diabetic heart.…”

Section: Discussionsupporting

confidence: 91%

Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression

Brouwers

Vos-Houben

Niessen

et al. 2013

IJMS

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Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I) can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE Nɛ-(1-carboxymethyl)lysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation.

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Section: Discussionsupporting

confidence: 91%

Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression

Brouwers

Vos-Houben

Niessen

et al. 2013

IJMS

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“…Advanced glycation end products stimulates the proliferation of smooth muscle cells [51] and the polyol pathway hyperactivity induces an acceleration of AGE formation via 3-deoxyglucosone [52]. We also reported that epalrestat prevented the increase in carlboxymethyllysin, one of the AGE, in aortas of galactosemic dogs [53].…”

Section: Discussionmentioning

confidence: 55%

Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity

et al. 2001

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Diabetes mellitus is one of the major risk factors for atherosclerosis and is associated with an increased incidence of coronary heart diseases and cerebrovascular diseases [1,2]. The high prevalence of these macrovascular diseases in diabetic patients can be explained by hyperglycaemia in itself [3] as well as by the increased frequency of conventional risk factors such as hypertension, hyperlipidemia, obesity, and smoking.The proliferation of vascular smooth muscle cells is one of the characteristic features of atherosclerosis [4]. According to previous reports [4,5], platelet-derived growth factor (PDGF) plays an important part in the accelerated proliferation of smooth muscle Diabetologia (2001) Abstract Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-b specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-bII isoform and PDGF-b receptor protein, free cytosolic NAD + :NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/l glucose showed statistically significant increases in protein kinase C activities, the expression of PKCbII isoform and PDGF-b receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-b receptor were more prominent than those of LY333 531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD + :NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-bII isoform was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-b receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication. [Diabetologia (2001) 44: 480±487]

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“…Amadori adducts, produced under anaerobic conditions, rearrange to form more reactive dicarbonyl compounds such as 1-and 3-deoxyglucosone (DGs), which may react further to yield glyoxal (GO) or methylglyoxal (MGO) by reverse aldol reactions. Phosphorylated intermediates in anaerobic metabolism of carbohydrates, such as triose phosphates and fructose 3-phosphate, also eliminate phosphate to form methylglyoxal (Thornalley 1996) and 3-deoxyglucosone (Lal et al 1997), respectively. These dicarbonyl compounds can react with arginine residues, with the amino terminal amino group and also with the nucleophilic amino acids including lysine, histidine, tryptophan and cysteine.…”

Section: Mechanisms Of Ages and Ales Formation And Their Biological Imentioning

confidence: 99%

Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs

Vistoli

Carini

2012

Amino Acids

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The ability of carnosine to prevent advanced glycoxidation end products (AGEs) and advanced lipoxidation end products (ALEs) formation, on the one hand, and the convincing evidence that these compounds act as pathogenetic factors, on the other hand, strongly support carnosine as a promising therapeutic agent for oxidative-based diseases. The mechanism/s by which carnosine inhibits AGEs and ALEs is still under investigation but an emerging hypothesis is that carnosine acts by deactivating the AGEs and ALEs precursors and in particular the reactive carbonyl species (RCS) generated by both lipid and sugar oxidation. The ability of carnosine to inhibit AGEs and ALEs formation and the corresponding biological effects has been demonstrated in several in vitro studies and in some animal models. However, such effects are in line of principle, limited in humans, due to the effect of serum carnosinase (absent in rodents), which catalyzes the carnosine hydrolysis to its constitutive amino acids. Such a limitation has prompted a great interest in the design of carnosine derivatives, which maintaining (or improving) the reactivity with RCS, are more resistant to carnosinase. The present paper intends to critically review the most recent studies oriented to obtaining carnosine derivatives, optimized in terms of reactivity with RCS, selectivity (no reaction with physiological aldehydes) and the pharmacokinetic profile (mainly through an enhanced resistance to carnosinase hydrolysis). The review also includes a brief description of AGEs and ALEs as drug targets and the evidence so far reported regarding the ability of carnosine as inhibitor of AGEs and ALEs formation and the proposed reaction mechanisms.

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Fructose-3-phosphate production and polyol pathway metabolism in diabetic rat hearts

Cited by 32 publications

References 46 publications

Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression

Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression

Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity

Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs

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