Reactive Oxygen Species in the Pathogenesis of Diabetic Complications
Reactive Oxygen Species in the Pathogenesis of Diabetic Complications
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.
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.
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