Metabolic interactions of AGE inhibitor pyridoxamine and antioxidant alpha-lipoic acid following 22 weeks of treatment in obese Zucker rats.
OBJECTIVE
The advanced glycation end product inhibitor pyridoxamine (PYR) and the antioxidant alpha-lipoic acid (LA) interact to ameliorate insulin resistance in obese Zucker rats following short-term (6-week) treatment. This study was designed to ascertain whether these unique interactive effects of PYR and LA remain manifest following longer-term (22-week) treatment.


METHODS
Female obese Zucker rats received vehicle (OV), PYR (OP, 60 mg/kg body wt), racemic LA (rac-LA; OM, 92 mg/kg), the R-(+)-enantiomer of LA (R-LA; OR, 92 mg/kg), or combined treatments with PYR and rac-LA (OPM) or PYR and R-LA (OPR), daily for 22 weeks.


RESULTS
Individual and combined treatments with PYR, rac-LA, and R-LA significantly (p<0.05) inhibited skeletal muscle protein carbonyls (28-36%), a marker of oxidative damage, and triglyceride levels (21-51%). Plasma free fatty acids were reduced in OM (9%), OR (11%), and OPM (16%), with the greatest decrease (26%) elicited in OPR. HOMA-IR, an index of fasting insulin resistance, was decreased in OP (14%) and OPM (17%) groups, with the greatest inhibition (22%) in OPR. Insulin resistance (glucose-insulin index) was lowered (20%) only in OPR. Insulin-mediated glucose transport in isolated skeletal muscle was improved in OM (34%), OR (33%), OPM (48%) and OPR (31%) groups.


CONCLUSIONS
Important interactions between PYR and LA for improvements in glucose and lipid metabolism in the female obese Zucker rat are manifest following a 22-week treatment regimen, providing further evidence for targeting oxidative stress as a strategy for reducing insulin resistance.
Muellenbach
Elizabeth M
EM
Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721, USA.
Diehl
Cody J
CJ
Teachey
Mary K
MK
Lindborg
Katherine A
KA
Hasselwander
Oliver
O
Matuschek
Markus
M
Henriksen
Erik J
EJ
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D004357:Drug Synergism; D005260:Female; D005951:Glucose Tolerance Test; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007333:Insulin Resistance; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011733:Pyridoxamine / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D008063:Thioctic Acid / Q000008:administration & dosage / Q000627:therapeutic use*
D000975:Antioxidants; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D011733:Pyridoxamine; D008063:Thioctic Acid