The Effect of A-lipoic Acid (ALA) on Fatty Acid-induced Impairment of Glucose-stimulated Insulin Secretion

Type 2 Diabetes Clinical Trial

Official title:

The Effect of A-lipoic Acid (ALA) on Fatty Acid-induced Impairment of Glucose-stimulated Insulin Secretion

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01056497
• Other study ID #: 090818B
• Secondary ID: Canadian Diabete
• Status: Completed
• Phase: Phase 4
• First received: December 17, 2009
• Last updated: September 28, 2012
• Start date: February 2010
• Est. completion date: June 2011

Study information

• Verified date: September 2012
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review Committee
• Study type: Interventional

Clinical Trial 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.

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:

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: June 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 20 Years to 65 Years

Eligibility

Inclusion Criteria:

Men and women aged 20-65 years:

1. Written informed consent obtained

2. Body mass index (BMI) > 27kg/m2

3. Glucose tolerance test may be normal or demonstrate impaired glucose tolerance but not frank diabetes

4. Hemoglobin above 130g/L

Exclusion Criteria:

1. Subject has a history of hepatitis/hepatic disease that has been active within the previous two years

2. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr > 1.5 mg/dL) genitourinary, hematological systems, or has severe uncontrolled treated or untreated hypertension (sitting diastolic BP > 100 or systolic > 180) or proliferative retinopathy

3. Type 2 diabetes by history or OGTT

4. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure

5. Any laboratory values: AST > 2x ULN; ALT > 2x ULN; TSH > 6 mU/l

6. A history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reactions. History of hypersensitivity to heparin

7. Current addiction to alcohol or substances of abuse as determined by the investigator

8. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation

9. Any lipid lowering of hypoglycemic agents

10. Previous history of asthma

11. Will not donate blood three months prior to and three months post study procedures

12. Thrombocytopenia

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Prediabetes
• Type 2 Diabetes

Intervention

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

Locations

Country	Name	City	State
Canada	Toronto General Hospital	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
University Health Network, Toronto	Canadian Diabetes Association

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	insulin secretion and insulin sensitivity To determine whether ALA ameliorates or prevents impairment of insulin secretion and insulin sensi		6 months	No
Secondary	To determine the role of oxidative stress and inflammation in the pathogenesis of lipotoxicity		6 months	No