Strong inhibition of the polyol pathway diverts glucose flux to protein glycation leading to rapid establishment of secondary complications in diabetes mellitus

Abstract

Background: Polyol pathway and protein glycation are implicated in establishing secondary complications in diabetes. Their relative contribution to the process needs to be evaluated. It is essential to understand why some aldose reductase inhibitors (ARIs) trials are successful while some have failed and to study their effect on protein glycation.

Methods: Aldose reductase (AR) was assayed using xylose as substrate; protein glycation was evaluated using total and specific fluorescence, fructoseamine and protein bound carbonyl content (PCO) measurements. Long term studies were carried out on streptozotocin induced diabetic rats for evaluation of urine parameters, tissue fluorescence. Anti-cataract action was studied by lens culture studies.

Results: Epalrestat, a commercial ARI was also found to possess potent glycation inhibitory action. Long term experiments revealed strong protein glycation with higher concentration of citronellol (ARI) demonstrating shift in glucose flux. Treatment with epalrestat and limonene revealed improved urine parameters and tissue fluorescence. Lens culture studies revealed cataract formation at higher inhibition of AR while no lens opacity was observed at lower citronellol concentration and with limonene and epalrestat.

Conclusion: Strong inhibition of AR shifts the glucose flux to protein glycation causing damage. ARIs possessing protein glycation inhibition are more useful in amelioration of secondary complications.

Keywords: Aldose reductase; Citronellol; Combinatorial therapy; Epalrestat; Limonene; Protein glycation.