World J Diabetes 2014 June 15; 5(3): 288-295

ISSN 1948-9358 (online)

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DOI: 10.4239/wjd.v5.i3.288

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TOPIC HIGHLIGHT
Kateina Kakov, MD, PhD, Series Editor

Evidence for altered thiamine metabolism in diabetes:

Is there a potential to oppose gluco- and lipotoxicity by
rational supplementation?
Luk Pcal, Katarna Kuricov, Kateina Kakov
thiamine deficiency in diabetics). Finally, we would like
to summarise the evidence for the beneficial effect of
thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its
importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it
could be concluded that although experimental studies
mostly resulted in beneficial effects, clinical studies of
appropriate size and duration focusing on the effect of
thiamine supplementation/therapy on hard endpoints
are missing at present. Moreover, it is not currently
clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies
on the molecular mechanisms of thiamine deficiency
in diabetes are critically needed before clear answer to
diabetes community could be given.

Luk Pcal, Katarna Kuricov, Kateina Kakov, Department of Pathophysiology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
Author contributions: Pcal L and Kuricov K performed literature search and wrote the manuscript; Kakov K edited and
supervised the manuscript.
Supported by The Grant from the Ministry of Health of Czech
Republic, No. NT13198
Correspondence to: Kateina Kakov, MD, PhD, Department of Pathophysiology, Faculty of Medicine, Masaryk University, Kamenice 5, 62500 Brno,
Czech Republic. kankov@med.muni.cz
Telephone: +420-549-494525 Fax: +420-549-494340
Received: November 29, 2013 Revised: April 14, 2014
Accepted: May 16, 2014
Published online: June 15, 2014

2014 Baishideng Publishing Group Inc. All rights reserved.

Abstract

Key words: Diabetes; Thiamine; Vitamin B1; Transketolase; Benfotiamine; Hyperglycemia; Nephropathy;
Metabolic syndrome; Cardiovascular disease; Chronic
kidney disease

Growing prevalence of diabetes (type 2 as well as type

1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide.
Understanding the molecular pathogenesis of chronic
micro-, macro- and avascular complications mediated
by hyperglycemia is of crucial importance since novel
therapeutic targets can be identified and tested. Thiamine (vitamin B1) is an essential cofactor of several
enzymes involved in carbohydrate metabolism and
published data suggest that thiamine metabolism in
diabetes is deficient. This review aims to point out the
physiological role of thiamine in metabolism of glucose
and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine
deficiency (either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are
increased in diabetes and to summarise data indicating thiamine mishandling in diabetics (by review of
the studies mapping the prevalence and the degree of

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Core tip: Published data suggest deficient action of thiamine in diabetes, however, it is not currently clear by
which mechanisms. Plasma levels might be decreased
in diabetics (although renal function has a prevailing
effect), nevertheless, intracellular concentration of thiamine diphosphate is the crucial parameter and there is
not a direct relationship with the plasma thiamine since
the rate of transmembrane transport (via thiamine
transporters) and intracellular activation by thiamine
pyrophosphokinase might affected by hyperglycemia
at first place. Experimental studies on the molecular
mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given.

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Pcal L et al . Altered thiamine metabolism in diabetes

longs to the large group of B vitamins. Several forms of

thiamine exist: (1) free thiamine; (2) thiamine monophosphate (TMP); (3) thiamine diphosphate (TDP); (4) thiamine triphosphate; and (5) adenosine thiamine triphosphate. The active form of thiamine-TDP-together with
magnesium is an essential cofactor of several enzymes
important for carbohydrate [transketolase (TKT), pyruvate dehydrogenase and -ketoglutarate dehydrogenase]
and amino acid (branched-chain -keto acid dehydrogenase) metabolism[3].

Pcal L, Kuricov K, Kakov K. Evidence for altered thiamine

metabolism in diabetes: Is there a potential to oppose glucoand lipotoxicity by rational supplementation? World J Diabetes 2014; 5(3): 288-295 Available from: URL: http://www.
wjgnet.com/1948-9358/full/v5/i3/288.htm DOI: http://dx.doi.
org/10.4239/wjd.v5.i3.288

INTRODUCTION
Diabetes mellitus, the most common metabolic disease
resulting from insufficient insulin action (either absolute
or relative), is characterized by various degree of chronic
hyperglycemia and is often accompanied by specific
microvascular complications including nephropathy,
retinopathy and neuropathy. Diabetes also substantially
increases the risk of macrovascular complications (coronary heart disease, stroke and peripheral vascular disease).
Both micro- and macrovascular complications affecting
diabetic patients are associated with reduced quality of
life and contribute substantially to considerable morbidity
and mortality.
Hyperglycemia (the cumulative exposure to excess
of glucose as well as individual pattern of glucose fluctuation) together with increased availability of free fatty
acids (a consequence of deregulated lipolysis in adipose
tissue as well as their spill over in case of adipocyte
saturation in obese subjects) are the two dominant metabolic alterations characterising gluco- and lipotoxicity in
diabetes and are causally responsible for the development
of vascular complications.
Although selected aspects of thiamine metabolism
abnormalities in relation to diabetes has been reviewed
earlier[1,2], comprehensive view and findings from recent
studies were not included. In this review we therefore
aim (A) to point out the physiological role of thiamine
in metabolism of glucose and amino acids, to present
overview of thiamine metabolism and to describe the
consequences of thiamine deficiency (either clinically
manifest or latent). Furthermore, (B) we want to explain
why thiamine demands are increased in diabetes and to
summarise data indicating thiamine mishandling in diabetics (review of the studies mapping the prevalence and
the degree of thiamine deficiency in diabetics). Finally, (C)
we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of
hyperglycemia-related pathology and, therefore, to justify
its importance in determining the harmful impact of hyperglycemia in diabetes.

Overview of thiamine metabolism

As thiamine is an essential micronutrient for humans
its needs are supplied from diet rich in thiamine, such
as yeast, pork, legume and cereal grains. Enzyme called
thiaminase I (EC2.5.1.2), present in raw fish, shellfish,
tea and coffee, decreases thiamine absorption. Thiamine
is absorbed in the small intestine, predominantly in the
duodenum. Thiamine esters are hydrolysed by pancreatic nucleotide pyrophosphatase (EC3.6.1.9) or alkaline
phosphatase (EC3.1.3.1) to form unphosphorylated
thiamine that is taken-up by enterocytes via thiamine
transporters at low concentrations or via passive diffusion
at higher concentrations[4]. Within enterocyte thiamine is
phosphorylated by thiamine pyrophosphokinase (TPK1,
EC2.7.6.2) to TDP preventing its return back to the intestinal lumen. Most of the TDP must be hydrolysed to
cross the basolateral membrane using specific ATP-dependent transporter or reduced folate carrier 1 (RFC-1)[5].
Thiamine and TMP are the most abundant forms in plasma. Uptake of thiamine and TMP by cells is mediated
by specific thiamine transporters 1 (THTR1 encoded by
SLC19A2 gene) and 2 (THTR2 encoded by SLC19A3)
and RFC-1. Majority of thiamine in the cytoplasm (approximately 90%) is phosphorylated by TPK1 to TDP
and used as a cofactor of cytosolic enzymes while the
rest remains unphosphorylated[3]. Most of the TDP (approximately 90%) is transported into mitochondria via
thiamine transporter from the solute carrier family of
proteins encoded by the SLC25A19 gene[6]. Two mutations in the SLC25A19 cause Amish lethal microcephaly,
an autosomal recessive disorder characterized by severe
microcephaly, delayed brain development, -ketoglutaric
aciduria and premature death[7]. Overview of intracellular
thiamine metabolism is presented in Figure 1. Thiamine
also crosses blood-brain barrier[8] and placenta[9].
Thiamine is excreted by kidneys and its rate depends
on glomerular filtration, tubular reabsorption and also
on plasma thiamine concentration[10]. Normally, thiamine
filtered in glomerulus is effectively reabsorbed in the
proximal tubule through thiamine/H+ antiport[11]. Longterm diuretic therapy is known to produce thiamine
deficiency[10]. As thiamine deficiency develops, thiamine
urinary excretion falls rapidly[12].

PHYSIOLOGICAL ROLE OF THIAMINE

IN GLUCOSE METABOLISM, THIAMINE
METABOLISM AND CONSEQUENCES OF
ITS DEFICIENCY

Thiamine deficiency
Thiamine reserves are low, limited amount (up to 30
mg) is stored in skeletal muscle, brain, heart and kidneys.
Thiamine stores may become depleted within weeks of

Role of thiamine in energy metabolism

Thiamine (vitamin B1) is a water soluble vitamin that be-

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Thiamine
THTR1

called Wernicke-Korsakoff syndrome[16].

Intracellular thiamine deficit due to mutations in the
gene SLC19A2 encoding for THTR1 causes thiamineresponsive megaloblastic anaemia syndrome (TRMA)[17].
TRMA is an autosomal recessive disorder that typically
manifests as megaloblastic anaemia, hearing loss and
diabetes[18].
Supplementation in case of proven thiamine deficiency can be achieved by free thiamine that was shown
to increase plasma thiamine levels as well as intracellular
TDP although the rate of thiamine transport through the
plasma membrane is quite slow[19]. Several lipophilic thiamine derivatives have been synthesized (e.g., fursultiamine
and sulbutiamine) which are able to diffuse through plasma membrane independent of transporters thus being
more effective than free thiamine. Within the cell they are
converted to thiamine. Benfotiamine (S-benzoylthiamine
O-monophosphate) is another derivative with better
availability than thiamine (reflected by higher plasma
thiamine levels). However benfotiamine must be dephosphorylated to S-benzoylthiamine by ecto-alkaline phosphatase to become lipophilic prior crossing plasma membrane. No adverse effects of either high-dose thiamine
or benfotiamine supplementation have been reported so
far probably due to an efficient renal excretion or rapid
uptake by hepatocytes with subsequent transformation to
thiamine and release into the blood, respectively[19].

TMP
THTR2

RFC1
Plasma
membrane

TPK
Mitochondrion

Glucose
TDP
Glucose-6-P
GLUT

TKT

Fructose-5-P

Pentose phosphate pathway

Cytosol

Figure 1 The overview of intracellular thiamine metabolism. GLUT: Glucose transporter; THTR1: Thiamine transporter 1; THTR2: Thiamine transporter
2; TKT: Transketolase; TPK: Thiamine pyrophosphokinase; RFC1: Reduced
folate carrier 1; TDP: Thiamine diphosphate.

a deficient diet since the biological half-life of thiamine

is 9 to 18 d[13]. Thiamine deficiency can result from decreased intake (most often due to its low content in diet
or compromised absorption), increased demands (e.g., in
pregnancy) or increased renal loss. In developed countries
overt thiamine deficiency due to a malnutrition is rare,
however, occurs in various health conditions with alcohol
abuse and chronic diseases (e.g., cancer) being the most
common causes. Secondary thiamine deficiency can also
accompany heart failure, severe infections or long-term
diuretic use.
Although all cell types utilize thiamine, the nervous
system is particularly sensitive to thiamine deficiency
due to its role in the synthesis of acetylcholine and
-aminobutyric acid in the brain. Also the heart is strongly sensitive to thiamine limitation due to the high level
of oxidative metabolism. Early symptoms of thiamine
deficiency are in general nonspecific including fatigue,
anorexia, nausea, weight loss and depression. Serious
thiamine deficiency can clinically manifest as beriberi,
Wernickes encephalopathy or Korsakoff s psychosis[14].
Beriberi, classically categorized as dry or wet, is present
in populations relying on diet constituting predominantly
of polished rice (very low thiamine content). Wet beriberi
(also known as thiamine deficiency with cardiopathy) affects primarily heart and can lead to a congestive heart
failure with peripheral oedemas, tachycardia, dyspnoea
and weakness[15]. Patients with dry form usually suffer
from peripheral neuropathy leading to paralysis, weakness, leg paraesthesia, wasting of muscle and various
other symptoms.
Thiamine deficiency is common in alcoholics as alcohol
negatively affects thiamine uptake and intracellular phosphorylation, thus contributing to a marked thiamine deficiency. Central nervous system manifestations of thiamine
deficiency in alcoholics are known as Wernicke-Korsakoff
syndrome. The symptoms include changes of mental status (e.g., confusion), ocular signs (nystagmus) and ataxia.
Thiamine deficiency in alcoholics can also be accompanied
by severe loss of memory denoted as Korsakoff psychosis.
Both symptoms commonly occurs together constituting so

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Laboratory test used for estimation of thiamine status

The two main tests routinely used for the assessment of
thiamine status are the measurement of erythrocyte TKT
activity and the so called thiamine effect. The former is
measured by a kinetic reaction without adding thiamine.
Thiamine effect expresses the increase of TKT activity
after addition of saturating amount of thiamine to the
reaction. The increase up to 15% is considered as normal
thiamine status, higher increase is an indicator of mild
(up to 25%) or severe (more than 25%) thiamine deficiency[15]. Plasma thiamine levels can also be measured although they predominantly reflect thiamine intake rather
than cellular levels. Combination of erythrocyte TKT
activity and thiamine effect measurement is considered as
the most reliable indicator of thiamine status in clinical
settings.

DIABETES AS A STATE OF INCREASED

DEMAND FOR THIAMINE AND THE
EVIDENCE FOR THE ALTERED THIAMINE
METABOLISM IN DIABETES
Consequences of hyperglycemia for thiamine availability
Diabetes of all types is ex definitione characterised by hyperglycemia. Contribution of fasting and postprandial
glucose elevation is variable though in various degrees of
abnormal glucose tolerance and most likely also interindividually. Increased glucose supply stimulates its intracellular metabolism (glycolysis) with subsequent increase in

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the production of reactive oxygen species (ROS) in mitochondria[20,21]. Overproduction of ROS in mitochondria
links- via inhibition of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase-hyperglycemia with
activation of several biochemical pathways involved in
the development of microvascular complications of diabetes incl. hexosamine and polyol pathways, production
of advanced glycation end products (AGEs) and activation of protein kinase C[22]. However, cells in general are
capable of either decreasing overproduction of ROS by
enzymatic and non-enzymatic antioxidant mechanisms
and/or eliminating of damaging metabolites and their
substrates (generated by overloaded glycolysis) that accumulate within cells. Pentose phosphate pathway (PPP)
is an example of the latter mechanism. PPP represents an
alternative pathway for glucose oxidation fulfilling three
important functions: (1) production of reducing equivalent NADPH necessary for reduction of oxidized glutathione thus supporting intracellular antioxidant defence;
(2) production of ribose-5-phosphate required for the
synthesis of nucleotides; and (3) metabolic use of pentoses obtained from the diet. PPP consists of two branches:
(1) irreversible oxidative branch necessary for NADPH
and pentose phosphates production; and (2) reversible
non-oxidative branch in which interconversion of three
to seven carbons containing sugars occurs. TKT (EC
2.2.1.1), one of the key enzymes of non-oxidative branch
of PPP, can limit the activation of damaging pathways
through lowering availability of their precursors. TKT
transports two-carbon units and catalyses formation of
ribose-5-phosphate from glycolytic intermediates. As a
cofactor of TKT, thiamine may have a profound effect
on glucose metabolism through the regulation of PPP
and indeed, TKT activation by benfotiamine (see below)
in endothelial cells blocked several pathways responsible
for hyperglycemic damage and prevented development
and progression of diabetic complications in animal
models[23]. The mechanism responsible for the observed
effect upon activation of non-oxidative reversible branch
of PPP by thiamine or its derivative benfotiamine was
the diminished accumulation of triosephosphates and
fructose-6-phosphate induced by hyperglycemia[2].

cells in high glucose conditions (26 mmol/L) decreases

both mRNA and protein expression of THTR1 and
THTR2 compared to 5 mmol/L glucose[25]. Renal clearance of thiamine is increased by 8-fold in experimental
model of diabetes. Interestingly, increased clearance was
prevented by high-dose thiamine supplementation[26].
Thiamine renal clearance is also increased in subjects with
T1DM (by 24-fold) and T2DM (by 16-fold)[24].
Further changes of thiamine metabolism probably occur with the development of chronic diabetic microvascular complications namely diabetic nephropathy together with chronic kidney disease (CKD). While in diabetics
with preserved renal function plasma thiamine levels tend
to be lower most likely on account of increased renal
clearance, in subjects with CKD stages corresponding
with renal insufficiency and failure the situation dramatically changes. We have previously comprehensively studied plasma and intracellular parameters of thiamine metabolism in diabetics with the aim to dissect the complex
relationships between the effect of diabetes and renal
function[27]. We reported that plasma levels of thiamine
and its esters and TKT activity in RBCs increased with
severity of diabetic nephropathy (and CKD respectively)
being highest in subjects with end-stage renal disease,
however, levels of TDP in RBCs did not show proportional trend. Since the effectiveness of intracellular TDP
production depends on substrate availability (i.e., the rate
of transmembrane transport via thiamine transporters)
and TPK activity we therefore hypothesized that these
could be the processes diminished by hyperglycemia and
the causal reasons for the failure of protective action
of PPP under hyperglycemia. While T1DM and T2DM
patients with normal renal function have been shown
to have a higher expression of THTR1 and THTR2 in
mononuclear cells compared to healthy subjects by one
study[28], data on TPK activity and THTR2 expression in
diabetes are missing at all. Obviously, there is still a large
gap in our understanding of the precise molecular mechanisms of thiamine deficiency and the problem definitely
warrants further study.

OVERVIEW OF IN VITRO, ANIMAL AND

HUMAN STUDIES WITH THIAMINE OR
BENFOTIAMINE SUPPLEMENTATION IN
DIABETIC CONDITIONS

Thiamine mishandling in diabetes

Little is known about the precise mechanisms how diabetes affects thiamine metabolism. Patients with type 1 and
2 diabetes mellitus (T1DM and T2DM) do not have a
marked thiamine deficiency [conventionally defined as an
increase of TKT activity in red blood cells (RBC) higher
than 15% after addition of saturating amount of TDP].
However, plasma thiamine levels in diabetics are decreased by 75% compared to healthy subjects[24]. RFC-1
and THTR1 protein expression in RBCs obtained from
diabetic patients (both T1DM and T2DM) is higher than
in healthy subjects[24].
Experimental evidence suggests abnormal thiamine
handling in the kidneys in diabetes that might be one
of the reasons for decreased plasma thiamine levels in
diabetics. Incubation of human primary proximal tubule

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In vitro studies
Several studies explored the effect of thiamine and/or
benfotiamine on pathways implicated in the pathogenesis
of hyperglycemia-induced damage in vitro. Cultivation
of RBC in hyperglycemia with addition of thiamine increased activity of TKT, decreased production of triose
phosphates and methylglyoxal and increased concentrations of sedoheptulose-7-phosphate and ribose-5phosphate[29]. Benfotiamine as well as thiamine have been
shown to correct defective replication of human umbilical vein endothelial cells (HUVEC) and to decrease their

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production of AGEs induced by hyperglycemia[30]. Thiamine also suppressed markers of endothelial cell damage
(inhibited cell migration and increased von Willebrand
factor secretion) induced by hyperglycemia in bovine aortic endothelial cells[31]. Both thiamine and benfotiamine
decreased activation of polyol pathway (aldose reductase
mRNA expression, enzyme activity and intracellular levels of sorbitol) while increasing expression and activity
of TKT in HUVEC and bovine retinal pericytes cultured
in hyperglycemia[32]. Notably, benfotiamine restored impairment of endothelial progenitor cells differentiation
caused by hyperglycemia[33]. Possible benfotiamine antioxidant properties and protective effect on DNA have
also been investigated. Benfotiamine prevented oxidative
stress (probably through direct antioxidant effect) and
also DNA damage[34]. The same study also confirmed
that benfotiamine increased TKT expression and activity.
Intermittent exposure of human retinal pericytes to fluctuating glucose levels induced their apoptosis, the effect
was however prevented by thiamine and benfotiamine[35].
It has also been studied whether thiamine and/or benfotiamine affect glucose and lipid metabolism in human
skeletal muscle cells. Benfotiamine but not thiamine
increased glucose oxidation while lipid oxidation and
metabolism was influenced by neither of the two. Benfotiamine also down-regulated NADPH oxidase 4 expression[36].

shown to normalize AGEs derived from methylglyoxal

and glyoxal. On the contrary, carboxy methyl lysine and
N-epsilon(1-carboxyethyl)lysine residues have been normalized by thiamine only[40]. Finally, they quantified protein damage caused by glycation, oxidation and nitration
in diabetic rats and found increased AGEs content in the
diabetic kidney, eye, nerve and plasma that was reversed
by thiamine and benfotiamine therapy. Thiamine itself
also reversed increase of plasma glycation free adducts.
Both therapies reversed increased urinary excretion of
glycation, oxidation and nitration free adducts[41]. Several
studies evaluated the effect of thiamine/benfotiamine
treatment with respect to heart function in diabetes
animal model. Benfotiamine alleviated abnormalities in
parameters related to the contractile dysfunction in diabetic mouse. It also reduced oxidative stress induced by
diabetes however production of AGEs was unchanged[42].
High-dose thiamine therapy prevented diabetes-induced
cardiac fibrosis through increased expression of genes
with pro-fibrotic effect and decreased matrix metalloproteinase activity in hearts of diabetic rats[43]. Another study
revealed that benfotiamine therapy protected diabetic
mice from heart failure with several pathogenic mechanism suggested including improved cardiac perfusion,
reduced fibrosis and cardiomyocyte apoptosis[44]. Same
authors found that benfotiamine improved prognosis of
diabetic mice after myocardial infarction in terms of survival, functional recovery, reduced cardiomyocyte apoptosis and neurohormonal activation[45]. The same was true
for control non-diabetic mice probably due to increased
activity of pyruvate dehydrogenase in hearts of diabetic
rats by thiamine treatment. Subsequent in vitro experiment
revealed that responsible molecular mechanism may be
suppression of O-glycosylated protein[46]. Both in vitro and
in vivo benfotiamine supplementation had positive effect
on cardiac progenitor cells in terms of their proliferation, abundance, functionality and TKT activity (all listed
parameters being compromised by hyperglycemia)[47]. In
mouse diabetes model of limb ischemia benfotiamine
increased TKT activity, prevented toe necrosis, improved
perfusion and restored vasodilation. Moreover, benfotiamine prevented accumulation of AGEs in vessels and
inhibited pro-apoptotic caspase-3 in muscles[48]. Another
work assessed cerebral oxidative stress in diabetic mice.
Benfotiamine was found to lower oxidative stress (estimated as reduced/oxidized glutathione) however levels
of AGEs, protein carbonyl and tumor necrosis factor-
were unchanged[49]. Administration of benfotiamine and
fenofibrate alone or in combination attenuated endothelial dysfunction and nephropathy in diabetic rats. Lipid
profile however was normalized only by fenofibrate not
by benfotiamine[50].

Animal models
The first published study exploring the effect of thiamine
and benfotiamine supplementation on peripheral nerve
function and production of AGEs in diabetic rats found
that benfotiamine but not thiamine had protective effect
with respect to both processes[37]. Already mentioned key
study provided evidence for the role of PPP in diabetes
showing that benfotiamine (activating TKT) inhibited
three harmful pathways and NF- signalling activated by
hyperglycemia and prevented development of diabetic
retinopathy in experimental rats[23]. The group of Thornalley published a series of papers investigating the effect
of thiamine and/or benfotiamine supplementation on
the development of diabetic microvascular complications, predominantly diabetic nephropathy. They found
that thiamine and benfotiamine were able to suppress
the accumulation of AGEs in the kidney, eye, nerves and
plasma of diabetic rats[38]. Furthermore, they reported
that high-dose thiamine and benfotiamine therapy prevented diabetic nephropathy through increased TKT expression, decreased level of triosephosphates a decreased
protein kinase C activation. Importantly, since no changes
in fasting plasma glucose and HbA1c were observed
this effect is independent of diabetes compensation[26].
Furthermore, high-dose thiamine therapy had positive
effect on diabetes-induced dyslipidaemia (preventing the
increase of plasma cholesterol and triglycerides but not
high-density lipoprotein decrease). Benfotiamine and lowdose thiamine failed to achieve the same effect[39]. They
also quantified AGEs in plasma of diabetic rats. Both
thiamine and benfotiamine supplementation have been

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Human studies
Only few studies in diabetic patients have been published
so far that explored the effect of thiamine or benfotiamine treatment on hard endpoints, i.e., development or
progression of clinically manifest diabetic complications,
namely kidney disease and neuropathy. In the pilot study,

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Table 1 The effect of thiamine or benfotiamine supplementation on surrogate markers related to hyperglycemia in human studies
Ref.

Treatment

Arora et al[56]

Thiamine

Du et al[57]
Gonzlez-Ortiz et al[58]
Polizzi et al[59]
Riaz et al[60]
Schupp et al[61]
Stirban et al[62]
Stirban et al[63]

Results

Improved endothelial-dependent vasodilation in subjects with impaired glucose tolerance and

in T2DM patients
Benfotiamine + -lipoic acid Normalization of AGEs production and prostacyclin synthase activity and decreases hexosamine-modified protein in monocytes without changing glycaemic control in T1DM
Thiamine
Lower blood glucose and leptin in T2DM patients
Thiamine + vitamin B6
Administration of vitamin B6 together with thiamine but not B6 itself decreases DNA glycation
in T2DM
Thiamine
Decreased albumin in urine in T2DM patients
Benfotiamine
Decreased genomic damage in peripheral lymphocytes in haemodialysis patients
Benfotiamine
No effect on skin autofluorescence in T2DM patients
Benfotiamine
No effect on flow-mediated dilation in T2DM patients

T1DM: Type 1 diabetes mellitus; AGEs: Advanced glycation end products; T2DM: Type 2 diabetes mellitus.

high-dose thiamine therapy for 3 mo significantly decreased urinary albumin excretion (UAE) without affecting glycaemic control, lipids and blood pressure in T2DM
patients[51]. In another study however, 3 mo of benfotiamine therapy improved thiamine status (assessed as a
TKT activity and the whole blood thiamine concentration) but did not change UAE and/or kidney marker of
tubular damage in T2DM patients[52]. The same authors
also determined AGEs production and markers of endothelial dysfunction and low-grade inflammation in the
same cohort. Benfotiamine did not affect any of the ascertained markers[53]. In patients with diabetic neuropathy,
short-term benfotiamine therapy was found to improve
neuropathy score and to decrease the pain perception[54].
In the recent study, long-term (1 year) benfotiamine therapy did not affect peripheral nerve function and soluble
inflammatory markers (e.g., interleukin-6 or E-selectin)
despite significantly increasing the whole blood levels of
thiamine and TDP in T1DM patients[55]. This study was
however criticized for inappropriate study design and
definition of end-points[55]. Several other studies in human diabetics explored various surrogate markers related
to pathologic processes occurring in hyperglycemia, the
results are summarized in Table 1.

mine most. Based on the data presented boosting solely

plasma levels might not be the right way to go since
intracellular TDP levels are not a mere reflection of the
plasma levels of their precursor. Apparently experimental
studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before giving clear
answer to diabetes community.

REFERENCES
1

4
5

CONCLUSION
Since glucose metabolism depends on thiamine as an
enzyme cofactor, it is biologically feasible to suppose that
adequate thiamine supplementation in diabetics might
have a profound effect on metabolic compensation and
thus development of vascular complications. It could
also possibly influence earlier stages of abnormal glucose
tolerance such as components of metabolic syndrome.
Data on surrogate markers of endothelial dysfunction
and cardiovascular disease indicate that thiamine could
be of interest also for the broader spectrum of diseases
apart from diabetes. While experimental studies mostly
resulted in beneficial effects clinical studies of appropriate size and duration focusing on the effect of thiamine
supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which
mechanisms contribute to the deficient action of thia-

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P- Reviewers: Li W, Gao C, Ozdemir S S- Editor: Wen LL
L- Editor: A E- Editor: Liu SQ

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