title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, Shivaji University, Kolhapur, 416004 Maharashtra, India.
authors.forename: Ashwini D
authors.initials: AD
authors.lastname: Jagdale
authors.affiliation: Department of Biochemistry, Shivaji University, Kolhapur, 416004 Maharashtra, India.
authors.forename: Laxman N
authors.initials: LN
authors.lastname: Bavkar
authors.affiliation: Department of Biochemistry, Shivaji University, Kolhapur, 416004 Maharashtra, India.
authors.forename: Tanaji A
authors.initials: TA
authors.lastname: More
authors.affiliation: Department of Biochemistry, Shivaji University, Kolhapur, 416004 Maharashtra, India.
authors.forename: Madhav M
authors.initials: MM
authors.lastname: Joglekar
authors.affiliation: Department of Biochemistry, Shivaji University, Kolhapur, 416004 Maharashtra, India. Electronic address: drauarvindekar@yahoo.co.in.
authors.forename: Akalpita U
authors.initials: AU
authors.lastname: Arvindekar
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D048909:Diabetes Complications / Q000139:chemically induced / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D011108:Polymers / Q000378:metabolism*; D051381:Rats; D013311:Streptozocin
chemical_list: D004791:Enzyme Inhibitors; D011108:Polymers; C024617:polyol; D013311:Streptozocin; D000449:Aldehyde Reductase; D005947:Glucose
keywords: Aldose reductase; Citronellol; Combinatorial therapy; Epalrestat; Limonene; Protein glycation