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Benfotiamine Inhibits Intracellular Formation of Advanced Glycation End Products in vivo
JIHONG LIN, ALEX ALT, JUTTA LIERSCH, REINHARD G. BRETZEL, MICHAEL BROWNLEE*, HANS-PETER HAMMES
Third Medical Department, Justus-Liebig-University Giessen, Germany
*Albert-Einstein College, New York, NY, USA
ABSTRACT
Glycolysis
We have demonstrated previously that intracellular formation of the
derivative with known AGE-inhibiting properties in-
R= - 0.51; P< 0.02
advanced glycation end product (AGE) N-epsilon-(carboxymethyl)-
vitro on the intracellular formation of (CML) and
Oxidative
lysine (CML) inversely correlates with diabetic vascular compli-
methylglyoxal-derived AGE in red blood cells of
Phosphorylation
cations independently from glycemia (Diabetologia 42, 603, 1999).
Pentose-Phosphate-Shunt
Here, we studied the effect of benfotiamine, a lipid-soluble thiamine
patients with type 1 diabetes.
derivative with known AGE-inhibiting properties in-vitro on the
intracellular formation of (CML) and methylglyoxal-derived AGE in
red blood cells. Blood was collected from 6 Type 1 diabetic patients
(2 m, 4 f, age 31.8 ± 5.5 years; diabetes duration 15.3 ± 7.0 years)
before and after treatment with 600 mg/day benfotiamin for 28 days.
In addition to HbA1c (HPLC), CML and methylglyoxal were
Retinopathy-free Diabetes Duration (Years)
Study group: six patients (2 males, 4 females), age
TCA cycle
Fig. 1a: Correlation of retinopathy-free diabetes duration with the concentration
measured using specific antibodies and a quantitative dot blot
of CML in memory T-cells. AU=arbitrary units (from Diabetologia 42, 603, 1999)
technique
31.8 ± 5.5 years; diabetes duration 15.3 ± 7.0 years.
While treatment with benfotiamin did not affect HbA1c levels (at
Treatment with 600 mg/day benfotiamine
entry: 7.18±0.86%; at conclusion 6.88±0.88%; p not significant),
(Milgamma, Wörwag, Böblingen, Germany) for 28
levels of CML decreased by 40 % (737 ± 51 arbitray unit/mg protein
days after informed consent and approval by the
Fig. 3: Thiamin as co-factor of enzyme systems possibly involved in AGE formation (red arrows: enzymes
(AU) vs 470 ± 86 AU; p<0.001). The levels of intracellular
involving thiamine as coenzyme; blue arrows: increased flux of glycolytic intermediates under hyperglycemic
conditions).
methylglyoxal-derived AGE were reduced by almost 70 % (1628 ±
local ethics committee.
1136 AU vs 500 ± 343 AU; p < 0.01). The data indicate that thiamine
Venous EDTA-blood (3 ml) drawn before and at the
Results of Benfotiamine treatment in Patients
derivatives are effective inhibitors of both intracellular glycoxidation
end of the study, samples lysed and centrifuged,
and AGE formation.
adjusted to identical hemoglobin concentrations.
Mean glycated hemoglobin (%)
a. Significant reduction of
Quantitative immunoblotting carried out essentially
Fig. 1b: No correlation of mean glycated hemoglobin with CML levels in memory
CML in RBC after a
4-week treatment with
INTRODUCTION
as described before (1). Statistical analysis was
benfotiamine. * p<0.001
performed using the alternate Welsh t test.
Intracellular formation of the advanced glycation
end product (AGE) Ne-(carboxymethyl)lysine (CML)
Glycolysis
inversely correlates with diabetic vascular
Conclusion
complications independently from glycemia (Figure
1) (1). Intracellular CML is generated by the
Thiamine derivatives, in particular the lipid.soluble
Amadori Product
Glyceraldehyde-3-Phosphate
MG-derived AGE
b. Significant reduction
oxidation of Amadori products or, alternatively, by
prodrug benfotiamine, are effective inhibitor of
of methylglyoxal-derived
AGE in RBC after a

lipid peroxidation (2,3). The dicarbonyl
intracellular formation of AGE and CML.
4-week treatment with
benfotiamine. * p<0.01

methylglyoxal is formed by non-oxidative
fragmentation of glycolysis-derived triose
phosphates (Figure 2) and is the most important
References
3-deoxyglucosone
Methylglyoxal
intracellular AGE (4,5).
1. Hammes HP et al.: Diabetologia 42, 603-607, 1999
Glyoxalase 1
Thiamin is a potent AGE-inhibitor in-vitro (6), and
2. Ahmed MU et al.: J Biol Chem 261, 4889-4894, 1986
c. No change in Amadori-
benfotiamine, the lipid-soluble prodrug of thiamin,
3. Fu MX et al.: J Biol Chem 271, 9982-9986, 1995
product formation by
benfotiamine treatment.
was shown to reduce CML and other AGE in target
4. Thornalley PJ: Biochem J 269, 1-11, 1990
Glyoxalase 2
5. Shinohara M et al.: J Clin Invest 101, 1142-1147, 1998
tissues of diabetic complications in-vivo (7). The
6. Booth AA et al.: Biochem Biophys Res Commun 220,
possible mechanisms by which thiamin/
D-Lactate
113-119, 1996
benfotiamine are thought to reduce intracellular
7. Hammes HP et al.: Diabetologia 41, Suppl. 1, A310, 1998
AGE formation, are shown in Figure 3. We studied
Fig. 2: Biochemical pathways of intracellular AGE/CML
the effect of benfotiamine, a lipid-soluble thiamine
formation (Shinohara et al., JCI 101, 1142, 1998)

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