sorbinil and alpha-glycerophosphoric-acid

Phosphorus-31 (31P) nuclear magnetic resonance (NMR) spectroscopic analyses of the crystalline lens from the experimental diabetic rat were performed. Qualitative and quantitative alterations in the phosphorus-31 NMR metabolic profile were observed over the course of 3 weeks after the induction of diabetes mellitus. Most striking was the appearance of two new, as yet unidentified, metabolites. These metabolites which resonate at 6.6 and 5.8 ppm were not detected in the normal lens. Compared to the normal lens, glycerol-3-phosphate (G3P) underwent an eightfold increase in concentration and phosphorylcholine decreased to one-third its initial level. The phosphodiesters, glycerophosphorylcholine (GPC) and glycerophosphorylethanolamine (GPE), decreased to barely detectable levels. Oral treatment of the diabetic animal with an aldose reductase inhibitor resulted in the preservation of an essentially normal lens 31P NMR spectrum. Except for the changes observed in glycerol-3-phosphate, these alterations have not been previously reported and raise new questions about the metabolic consequences of diabetes mellitus and the dependence of these alterations on the action of a single enzyme, aldose reductase.

Topics: Aldehyde Reductase; Animals; Diabetes Mellitus, Experimental; Glycerophosphates; Glycerylphosphorylcholine; Imidazoles; Imidazolidines; Lens, Crystalline; Magnetic Resonance Spectroscopy; Male; Phosphatidylethanolamines; Phosphorylcholine; Rats; Rats, Inbred Strains

Diabetic cataractogenesis, a multifactorial process, was examined with nuclear magnetic resonance (NMR). P-31 NMR spectroscopic studies showed substantial alteration of both energy and membrane metabolism in the diabetic lens. Findings from a C-13 NMR spectroscopic determination of the sorbitol pathway flux in lenses incubated in 35.5 mmol/L glucose revealed that (1) one-third of total glucose consumed was channeled through this pathway, and (2) the turnover rate of NADPH to NADP was 3,000%/hr. Furthermore, a competition for NADPH between aldose reductase and glutathione reductase was demonstrated. It is important to note that all metabolic changes in hyperglycemic/diabetic lenses can be prevented by aldose reductase inhibitors, eg, sorbinil.

Topics: Adenosine Triphosphate; Aldehyde Reductase; Animals; Cataract; Cell Membrane; Diabetes Complications; Glucose; Glycerophosphates; Humans; Imidazoles; Imidazolidines; Lens, Crystalline; Magnetic Resonance Spectroscopy; NADP; Oxidation-Reduction; Rats; Sorbitol; Sugar Alcohol Dehydrogenases

Intact paired rabbit lenses were incubated in media containing 5.5 mM and 35.5 mM glucose (both at 290 +/- 3 mOsm) and examined by phosphorus-31 nuclear magnetic resonance spectroscopy. Lenses in 35.5 mM glucose exhibited an altered metabolic steady-state characterized by elevated alpha-glycerophosphate and depressed adenosine triphosphate concentrations. Time course studies revealed that these metabolic changes occurred chiefly during the initial 48 hr of incubation under high glucose conditions. The inclusion of an aldose reductase inhibitor in the medium prevented these changes in lenticular metabolism.

Topics: Adenosine Triphosphate; Aldehyde Reductase; Animals; Culture Techniques; Glucose; Glycerophosphates; Imidazoles; Imidazolidines; Lens, Crystalline; Magnetic Resonance Spectroscopy; Phosphates; Rabbits; Sugar Alcohol Dehydrogenases