Reactive Oxygen Species in the Pathogenesis of Diabetic Complications

The Role of the Glucosamine Pathway and Reactive Oxygen Species in the Pathogenesis of Diabetic Complications

Sponsors

Lead Sponsor: Albert Einstein College of Medicine

Collaborator: Juvenile Diabetes Research Foundation
National Institutes of Health (NIH)

Source Albert Einstein College of Medicine
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.

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.

Overall Status Completed
Start Date February 2005
Completion Date February 2008
Primary Completion Date October 2006
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
intracellular advanced glycation endproducts four weeks
hexosamine pathway four weeks
prostacyclin synthase activity four weeks
Enrollment 21
Condition
Intervention

Intervention Type: Dietary Supplement

Intervention Name: benfotiamine, α-lipoic acid

Description: 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

Arm Group Label: I

Eligibility

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

Gender: Male

Minimum Age: 18 Years

Maximum Age: 45 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Michael Brownlee, M.D. Principal Investigator Albert Einstein College of Medicine
Location
Facility: GCRC, Albert Einstein College of Medicine
Location Countries

United States

Verification Date

June 2008

Responsible Party

Name Title: Michael Brownlee, M.D.

Organization: Albert Einstein College of Medicien

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: I

Type: Experimental

Description: Patients with Type 1 diabetes

Label: II

Type: No Intervention

Description: Age-matched male subjects without Type 1 diabetes

Study Design Info

Allocation: Non-Randomized

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov