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Reactive Oxygen Species in the Pathogenesis of Diabetic Complications

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ClinicalTrials.gov Identifier: NCT00703989
Recruitment Status : Completed
First Posted : June 24, 2008
Last Update Posted : June 24, 2008
Sponsor:
Collaborators:
Information provided by:

Study Description
Brief Summary:
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy and incipient nephropathy in these models. In cultured vascular cells, it also reduces aldose reductase gene expression, activity, and sorbitol levels. It does so by activating the enzyme transketolase. α-lipoic acid, a potent antioxidant, has also been reported to reduce both diabetic microvascular and macrovascular complications in animal models. To determine whether benfotiamine in combination with α-lipoic acid would normalize markers of ROS-induced pathways of complications in humans, we performed a pilot study in subjects with Type 1 diabetes using one daily dose of benfotiamine in combination with α-lipoic acid.

Condition or disease Intervention/treatment
Type 1 Diabetes Dietary Supplement: benfotiamine, α-lipoic acid

Detailed Description:

The glycemic status of study patients was assessed by measuring baseline values of HbA1c, fructosamine, and fasting plasma glucose. Mean HbA1c was 8.7+ 0.7%, mean fructosamine was 421+29 mg/dl (normal range 174-286 mg/dl), and mean fasting blood glucose was 198+44 mg/dl.

At day 0, subjects levels of markers of two benfotiamine-sensitive pathways were determined: intracellular advanced glycation endproduct (AGE) formation, as reflected by a marker of increased intracellular methylglyoxal adducts in endothelial cells, angiopoietin 2 and hexosamine pathway activity, measured by determination of N-acetylglucosamine-modified protein in circulating monocytes. PKC activity in circulating monocytes could not be measured because the amount of blood required exceeded that approved by the Committee on Clinical Investigations. Serum levels of 6-keto-PGF-1 , a stable product produced by the nonenzymatic hydration of the antiatherogenic mediator prostacyclin were also determined. Subjects then took benfotiamine 300 mg twice a day, (Advanced Orthomolecular Research, Calgary, AB,CANADA) and slow-release α-lipoic acid (600 mg twice a day) (MRI, San Francisco, CA) for 28 days. Blood was obtained at day 0, day 15, and day 28.

Data were analyzed using 1-factor analysis of variance to compare the means of all the groups. The Tukey−Kramer multiple comparisons procedure was used to determine which pairs of means were different.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Role of the Glucosamine Pathway and Reactive Oxygen Species in the Pathogenesis of Diabetic Complications
Study Start Date : February 2005
Primary Completion Date : October 2006
Study Completion Date : February 2008

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: I
Patients with Type 1 diabetes
Dietary Supplement: benfotiamine, α-lipoic acid
benfotiamine 300 mg twice a day, (Advanced Orthomolecular Research, Calgary, AB,CANADA) and slow-release α-lipoic acid (600 mg twice a day) (MRI, San Francisco, CA) for a total duration of four weeks
Other Names:
  • benfotiamine 300 mg .slow-release
  • α-lipoic acid (600 mg twice a day)
No Intervention: II
Age-matched male subjects without Type 1 diabetes


Outcome Measures

Primary Outcome Measures :
  1. intracellular advanced glycation endproducts [ Time Frame: four weeks ]
  2. hexosamine pathway [ Time Frame: four weeks ]
  3. prostacyclin synthase activity [ Time Frame: four weeks ]

Eligibility Criteria

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male
  • Type 1 diabetes duration between zero and fifteen years
  • current insulin therapy

Exclusion Criteria:

  • Female
  • proliferative retinopathy
  • microalbuminuria
  • symptomatic diabetic neuropathy
  • cardiovascular disease
  • taking medications
  • smoking
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00703989


Locations
United States, New York
GCRC, Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Sponsors and Collaborators
Albert Einstein College of Medicine, Inc.
Juvenile Diabetes Research Foundation
National Institutes of Health (NIH)
Investigators
Principal Investigator: Michael Brownlee, M.D. Albert Einstein College of Medicine, Inc.
More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Michael Brownlee, M.D., Albert Einstein College of Medicien
ClinicalTrials.gov Identifier: NCT00703989     History of Changes
Other Study ID Numbers: CCI#: 2004-582
JDRF grant #8-2003-784
GCRC grant # MO1-RR12248
First Posted: June 24, 2008    Key Record Dates
Last Update Posted: June 24, 2008
Last Verified: June 2008

Keywords provided by Albert Einstein College of Medicine, Inc.:
hyperglycemia
diabetic complications
advanced glycation endproducts
hexosamine pathway
prostacyclin synthase
reactive oxygen species

Additional relevant MeSH terms:
Diabetes Mellitus, Type 1
Diabetes Complications
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Thioctic Acid
Benphothiamine
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Adjuvants, Immunologic
Immunologic Factors
Chelating Agents
Sequestering Agents