Benfotiamine Effect on Advanced Glycation End Products(AGEs) and Soluble Receptor for AGEs(sRAGE) in Diabetes Mellitus.
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Several mechanisms have been implicated in the pathophysiology of the complications of
      diabetes mellitus (DM), one of them is the formation and accumulation of a heterogeneous
      group of compounds called advanced glycation end products (AGEs). The interaction of these
      compounds with their receptor, the receptor for advanced glycation end products (RAGE)
      triggers several signalling pathways which will lead to increase in inflammatory molecules
      and enhanced reactive oxygen species. In addition, to the membrane receptor RAGE, there are
      two soluble forms, the soluble RAGE (sRAGE) and the endogenous secretory RAGE (esRAGE), these
      soluble receptors are capable to bind AGEs and block the AGE-RAGE axis. It has been observed
      that in diabetes the needs of thiamine are increased, and it could be an inhibition of the
      pentose phosphate pathway (thiamine is an essential cofactor in this pathway) and activation
      of other metabolic pathways among them AGEs formation. It has been proposed that
      supplementation of benfotiamine could decreased the risk of micro and macrovascular
      complications, and this could be in part because a decreased in the formation of AGEs. For
      this reason, the objective of this study was to evaluate the effect of benfotiamine on AGEs
      and its soluble receptors (sRAGE) in patients with type 2 diabetes.

      The specific objectives in the current study are:

        1. To evaluate and compare clinical and anthropometric characteristics in type 2 DM
           patients with and without benfotiamine treatment.

        2. To evaluate and compare in type 2 DM patients with and without benfotiamine treatment
           the following biochemical parameters: total AGEs, Carboxymethyl-lysine (CML), sRAGE,
           glucose, hemoglobin A1c, lipids (total cholesterol, C-HDL, C-LDL, and triglycerides).

        3. To evaluate and compare dietary data such as dietary AGEs and macro and macronutrients
           in type 2 DM patients with and without benfotiamine treatment.

      Type of study: This is a randomized, controlled, double-blind clinical trial

      Methods 34 patients will be recruited, 17 per group. After signing the inform consent
      subjects will be assessed for inclusion criteria. Subjects meeting the inclusion criteria and
      those whom accept to participate will be randomized to receive either a placebo or
      benfotiamine treatment for 12 weeks.

      At the end of the 12 weeks all the basal assessments will be repeated.
    

Detailed description: 
      Diabetes mellitus (DM) and its related complications are an increasing health burden all over
      the world. Insulin deficiency or the insulin resistance in patients with diabetes triggers
      hyperglycemia which is the main responsible for the micro and macrovascular complications.
      Several mechanisms have been implicated in the pathophysiology of these complications, one of
      them is the formation and accumulation of a heterogeneous group of compounds called advanced
      glycation end products (AGEs). The interaction of these compounds with their receptor, the
      receptor for advanced glycation end products (RAGE) triggers several signalling pathways
      which will lead to increase in inflammatory molecules and enhanced reactive oxygen species.
      In addition, to the membrane receptor RAGE, there are two soluble forms, the soluble RAGE
      (sRAGE) and the endogenous secretory RAGE (esRAGE), these soluble receptors are capable to
      bind AGEs and block the AGE-RAGE axis. It has been observed that in diabetes the needs of
      thiamine are increased, and it could be an inhibition of the pentose phosphate pathway
      (thiamine is an essential cofactor in this pathway) and activation of other metabolic
      pathways among them AGEs formation.

      It has been proposed that supplementation of benfotiamine could decreased the risk of micro
      and macrovascular complications, here we proposed that this could be because a decreased in
      the formation of AGEs. For this reason, the objective of this study was to evaluate the
      effect of benfotiamine on AGEs and its soluble receptors (sRAGE) in patients with type 2
      diabetes.

      The specific objectives in the current study are:

        1. To evaluate and compare clinical and anthropometric characteristics in type 2 DM
           patients with and without benfotiamine treatment.

        2. To evaluate and compare in type 2 DM patients with and without benfotiamine treatment
           the following biochemical parameters: Carboxymethyl-lysine (CML)(a marker for AGEs
           levels), sRAGE, glucose, hemoglobin A1c, lipids (total cholesterol, C-HDL, C-LDL, and
           triglycerides).

        3. To evaluate and compare dietary data such as dietary AGEs and macro and macronutrients
           in type 2 DM patients with and without benfotiamine treatment.

      Type of study: This is a randomized, controlled, double-blind clinical trial

      Methods 34 patients will be recruited, 17 per group, level of significance is 0.05 and power
      80%. Size was calculated by difference in group means divided by standard deviation.

      After signing the inform consent subjects will be assessed for inclusion criteria. Subjects
      meeting the inclusion criteria and those whom accept to participate will be randomly assigned
      to receive either a placebo or benfotiamine treatment for 12 weeks. The randomization will be
      done with a statistical Software (SPSS, V. 21, Chicago).

      After group assignment, subjects will be instructed to assist to the Research Center three
      times for initial assessments.

      During the first visit the subject will answer a questionnaire with personal data, medical
      history and current medications. Patients will be asked to have 10-12 hours of fasting for
      the blood sample and for the body composition assessment, weight, height and waist
      circumference will be measured too. Also the blood pressure will be measured during this
      first visit.

      For the dietary assessment 24-hour dietary recalls will be applied in 3 different days.
      Subjects will be instructed not to change their dietary habits and to maintain their exercise
      levels during the length of the study.

      Subject will visit the Research Center every two-weeks to receive a new bottle of pills and
      to answer an adherence questionnaire and also to ask for possible adverse events.

      At week six in addition to the adherence questionnaire another blood sample and blood
      pressure will be taken. In addition, another 24-hour dietary recall will be completed

      At the end of the 12 weeks all the basal assessments will be repeated.

      Main study parameters/ endpoints Change from basal serum levels of the following parameters:
      measured basal and at the end of study: Carboxymethyl-lysine (CML), and sRAGE

      Serum samples will be stored frozen at -80°C until assessment.

        -  Identification and quantification of CML will be measured with an immunoassay commercial
           kit (OxiSelect ™)

        -  Identification and quantification of sRAGE will be measured with Human RAGE Immunoassay
           commercial kit (Quantikine®)

      Statistical analysis

      Data will be presented as mean and standard deviation if presents normal distribution.
      Normality of data will be evaluated by Kolmogorov-Smirnov. To determinate basal differences
      between groups a t-Student test for independent samples will be applied. For the difference
      between groups before and after treatment a t-Student test for dependent samples will be
      applied. If data have not normal distribution, no parametrical tests will be used.
    

Intervention name(s): Benfotiamine; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Benfotiamine (S-Benzoylthiamine O-monophosphate) 900 mg per day; Placebo 900 mg per day
Intervention MeSH terms: Benphothiamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Benfotiamine; Advanced glycation end products; Soluble receptor for AGEs; Endogenous secretory receptor for AGEs