AIMS: 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. MAIN 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.
AIMS: 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. MAIN 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) orPYR and R-LA (OPR), daily for 22 weeks. KEY FINDINGS: 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. SIGNIFICANCE: 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.
Authors: Chunli Yu; Yan Chen; Gary W Cline; Dongyan Zhang; Haihong Zong; Yanlin Wang; Raynald Bergeron; Jason K Kim; Samuel W Cushman; Gregory J Cooney; Bronwyn Atcheson; Morris F White; Edward W Kraegen; Gerald I Shulman Journal: J Biol Chem Date: 2002-11-14 Impact factor: 5.157
Authors: Nathan L Alderson; Mark E Chachich; Nancy N Youssef; Robert J Beattie; Maurice Nachtigal; Suzanne R Thorpe; John W Baynes Journal: Kidney Int Date: 2003-06 Impact factor: 10.612
Authors: Alan Stitt; Thomas A Gardiner; Nathan L Alderson; Paul Canning; Norma Frizzell; Noel Duffy; Cliona Boyle; Andrzej S Januszewski; Mark Chachich; John W Baynes; Suzanne R Thorpe; Nathan L Anderson Journal: Diabetes Date: 2002-09 Impact factor: 9.461