Fructose-3-phosphate production and polyol pathway metabolism in diabetic rat hearts.
Previous studies have suggested that polyol-pathway and nonenzymatic glycation may be involved in the development of cardiac myopathy, a well-known manifestation of diabetes. Although the exact etiology of this complication is not fully understood, it is likely to be multifactorial. In this study, we investigated the metabolic consequences of diabetes and the effect of aldose reductase inhibitor (ARI) treatment on cardiac tissues of Sprague-Dawley rats. Perchloric acid (PCA) extracts of hearts from the animals were examined using 31P-nuclear magnetic resonance (NMR), gas chromatography/mass spectrometry (GC/MS), and high-performance liquid chromatography (HPLC). In 31P-NMR spectra of diabetic animals, a peak resonating at the chemical shift of 5.8 ppm with a coupling constant of 10 Hz was identified as fructose-3-phosphate (F3P). Undetectable in controls (< approximately 20 nmol/g), this metabolite was present at a concentration of 81.3 +/- 16.3 nmol/g wet weight (n = 4) in diabetic rat hearts. GC/MS analysis of these extracts from diabetics also identified a decomposition product of F3P, 3-deoxyglucosone (3DG), at a concentration of 9.4 +/- 3.5 nmol/g (n = 3), compared with 0.98 +/- 0.43 nmol/g (n = 3) in controls. No evidence was found for the expected detoxification products of 3-DG, 3-deoxyfructose and 2-keto 3-deoxygluconate. Concomitant with the elevation of F3P and 3DG, fructose and sorbitol levels were also elevated in diabetic animals. Surprisingly, ARI treatment was found to have no effect on the levels of these metabolites. These data suggest that either the heart may be unique in its production of fructose or it may not readily transport the ARI sorbinil. Production of the potent glycating agents F3P and 3DG in diabetics suggests that these compounds may be contributing factors in the glycation of cardiac proteins in the diabetic rat heart.
Lal
S
S
Department of Nuclear Magnetic Resonance, Fox Chase Cancer Center, Philadelphia, PA, USA.
Randall
W C
WC
Taylor
A H
AH
Kappler
F
F
Walker
M
M
Brown
T R
TR
Szwergold
B S
BS
D000284:Administration, Oral; D000665:Ampholyte Mixtures / Q000032:analysis; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D003847:Deoxyglucose / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005632:Fructose / Q000032:analysis; D005636:Fructosephosphates / Q000032:analysis* / Q000096:biosynthesis; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000032:analysis; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D048289:Imidazolidines; D007908:Lens, Crystalline / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D010472:Perchlorates / Q000737:chemistry; D010759:Phosphorus Isotopes; D011108:Polymers / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000032:analysis
D000665:Ampholyte Mixtures; D004791:Enzyme Inhibitors; D005636:Fructosephosphates; D007093:Imidazoles; D048289:Imidazolidines; D010472:Perchlorates; D010759:Phosphorus Isotopes; D011108:Polymers; C024617:polyol; C062519:fructose 3-phosphate; D005632:Fructose; D013012:Sorbitol; D003847:Deoxyglucose; C016350:3-deoxyglucosone; C026411:sorbinil; D005947:Glucose