The Effect of A-lipoic Acid (ALA) on Fatty Acid-induced Impairment of Glucose-stimulated Insulin Secretion
Chronically elevated free fatty acids impair insulin sensitivity and insulin secretion (ie lipotoxicity) by a combination of oxidative stress, endoplasmic reticulum (ER) stress and inflammation. This study will test whether alpha-lipoic acid, which has potent antioxidant and anti-inflammatory properties, prevents or ameliorates lipotoxicity.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
|Official Title:||The Effect of A-lipoic Acid (ALA) on Fatty Acid-induced Impairment of Glucose-stimulated Insulin Secretion|
- insulin secretion and insulin sensitivity To determine whether ALA ameliorates or prevents impairment of insulin secretion and insulin sensi [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- To determine the role of oxidative stress and inflammation in the pathogenesis of lipotoxicity [ Time Frame: 6 months ] [ Designated as safety issue: No ]
|Study Start Date:||February 2010|
|Study Completion Date:||June 2011|
|Primary Completion Date:||January 2011 (Final data collection date for primary outcome measure)|
|Experimental: alpha lipoic acid||
Drug: alpha lipoic acid
A 2 week treatment period with either oral ALA tablets or placebo tablets, followed by 30 hour hospital stay to infuse lipid or saline and to test insulin sensitivity and insulin secretion. For two weeks prior to each admission to hospital and during each hospital admission subjects will ingest 3 tablets 2 times per day with breakfast and supper, 1800mg per day
Alpha-Lipoic Acid (ALA) is a naturally occurring dithiol compound absorbed intact from dietary sources and synthesized enzymatically in the mitochondrion from octanoic acid. It serves a critical role in mitochondrial energy metabolism and is a potent biological antioxidant. It is widely available as an over-the-counter health supplement. It has generated considerable interest among the lay public and the research community for the use of ALA as a nutritive supplement and as a pharmacotherapy for diabetes and many other disorders. There is growing evidence that ALA has beneficial effects on the treatment of type 2 diabetes (T2DM) and some of its complications. It represents an attractive pharmacological target in the treatment of T2DM by modulating the signal transduction pathways in insulin resistance and antagonizing the oxidative and inflammatory stresses, which are major pathways in the pathogenesis of this disorder. Chronic elevation of plasma FFAs are believed to contribute to insulin resistance and defects in insulin secretion by promoting oxidative stress and inflammation. A potent antioxidant and free radical scavenger, ALA also targets cellular signal transduction pathways, which increases glucose uptake and utilization, thus providing specific targeted therapy in the treatment of insulin resistance. ALA has been shown to be safe when taken in high doses (2400mg/d) for prolonged time periods (6 months and longer), even in patients with renal and liver failure. In fact no upper limit for ALA consumption in humans has been established.
- Each subject will undergo 4 studies, 4 to 6 weeks apart. Each study will consist of a 2 week treatment period with either oral ALA tablets or placebo tablets, followed by 30 hour hospital stay to infuse lipid or saline and to test insulin sensitivity and insulin secretion.
- The study will be conducted as a single blind study, with the subject not knowing whether they are receiving a placebo or ALA. For safety reasons and since it will not influence the results of this study it will not be conducted as a double blind study.
- On each of four occasions, 4 weeks apart, after taking the tablets for 2 weeks, the subject will fast overnight for 12-hours prior to their admission to the Toronto General Hospital metabolic research ward for 30 hours to undergo testing as follows. The four studies will be conducted in random order:
|Toronto General Hospital|
|Toronto, Ontario, Canada, M5G 2C4|
|Principal Investigator:||gary F Lewis, MD||University Health Network, Toronto General Hospital|