The Effect of A-lipoic Acid (ALA) on Fatty Acid-induced Impairment of Glucose-stimulated Insulin Secretion
Condition: Type 2 Diabetes; Prediabetes
MeSH terms: Prediabetic State
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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:
    

Intervention name(s): alpha lipoic acid
Intervention type(s): Drug
Intervention description(s): 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
Other intervention name(s): lipoic acid; ALA
Intervention MeSH terms: Thioctic Acid
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: diabetes; alpha lipoic acid; endoplasmic reticulum (ER) stress; insulin secretion; insulin sensitivity