Clinical trial NCT00703989: Reactive Oxygen Species in the Pathogenesis of Diabetic Complications
Official title: The Role of the Glucosamine Pathway and Reactive Oxygen Species in the Pathogenesis of Diabetic Complications
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 1 Diabetes
Keywords: hyperglycemia
diabetic complications
advanced glycation endproducts
hexosamine pathway
prostacyclin synthase
reactive oxygen species
Lead sponsor: Albert Einstein College of Medicine
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
name: National Institutes of Health (NIH)
First posted: 2008-06-24
Enrollment: 21
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: intracellular advanced glycation endproducts
timeFrame: four weeks
measure: hexosamine pathway
timeFrame: four weeks
measure: prostacyclin synthase activity
timeFrame: four weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Bronx
country: United States
facility: GCRC, Albert Einstein College of Medicine
state: New York
Study officials:
affiliation: Albert Einstein College of Medicine
name: Michael Brownlee, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005 Jun;54(6):1615-25. doi: 10.2337/diabetes.54.6.1615. No abstract available.
citation: Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes. Diabetologia. 2008 Oct;51(10):1930-2. doi: 10.1007/s00125-008-1100-2. Epub 2008 Jul 29.