Fluoride toxicity and new-onset diabetes in Finland: A hypothesis

Abstract

The incidence of type 1 diabetes has increased substantially in Finland, but the exact trigger for the onset of T1D is still unknown. We know that use of amoxicillin and anti-cariogenic fluoride tablets is a common practice for children in Finland. It seems that beta-cell destruction is initiated by modification of the proinsulin by combined effects of fluoride (F2) and amoxicillin. Amoxicillin especially when used together with clavulanic acid results in an acid environment around the beta cells that promotes the conversion of F2 to hydrogen fluoride (HF). Unlike F2, HF can diffuse easily into the beta cell cytosol. Because the cytosol has a neutral pH, virtually all HF reverts to F2 in the cytosol and F2 cannot easily diffuse out of the cell. Exposure to excess F2 promotes proinsulin covalent dimerization and simultaneously hyperexpression of MHC Class I molecules. Proinsulin dimers then migrate to the cell membrane with MHC class I molecules, accumulate at the beta-cell membrane and produces a powerful immunogenic stimulus for the cytotoxic T-cells. Production of cytotoxic cytokines from the infiltrating T cells initiates the destruction of beta cells. In Finnish children, this might be helped along by a higher beta-cell activity and by a reactive thymus-dependent immune system induced by higher levels of thyroid hormones and calcitonin respectively. After repeated similar attacks, more and more effector T cells are raised and more and more beta cells are destroyed, and clinical diabetes occurs.

Full text

J Exp Integr Med 2014; 4(1):3-8 ISSN: 1309-4572
http://www.jeim.org 3
HYPOTHESIS
Fluoride toxicity and new-onset diabetes in Finland:
a hypothesis
M. Kemal Irmak1, Ilknur Senver Ozcelik2, Abdullah Kaya3
1High Council of Science, Gulhane Military Medical Academy, Etlik, Ankara;
2The Scientific and Technological Research Council of Turkey, Kavaklidere, Ankara;
3Service for Ophtalmology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul; Turkey
Received July 29, 2013
Accepted November 1, 2013
Published Online December 13, 2013
DOI 10.5455/jeim.011113.hp.007
Corresponding Author
M.Kemal Irmak
Gulhane Askeri Tip Akademisi
Yuksek Bilim Konseyi
06010 Etlik, Ankara, Turkey.
mkirmak@gata.edu.tr
Key Words
Amoxicillin; Diabetes; Fluoride
Abstract
The incidence of type 1 diabetes (T1D) has increased substantially in Finland, but the exact
trigger for the onset of T1D is still unknown. We know that use of amoxicillin and anti-cariogenic
fluoride tablets is a common practice for children in Finland. It seems that beta-cell destruction is
initiated by modification of the proinsulin by combined effects of fluoride (F2) and amoxicillin.
Amoxicillin especially when used together with clavulanic acid results in an acid environment
around the beta-cells that promotes the conversion of F2 to hydrogen fluoride (HF). Unlike F2,
HF can diffuse easily into the beta-cell cytosol. Because the cytosol has a neutral pH, virtually all
HF reverts to F2 in the cytosol and F2 cannot easily diffuse out of the cell. Exposure to excess F2
promotes proinsulin covalent dimerization and simultaneously hyperexpression of MHC Class I
molecules. Proinsulin dimers then migrate to the cell membrane with MHC class I molecules,
accumulate at the beta-cell membrane and produces a powerful immunogenic stimulus for the
cytotoxic T-cells. Production of cytotoxic cytokines from the infiltrating T-cells initiates the
destruction of beta-cells. In Finnish children, this might be helped along by a higher beta-cell
activity and by a reactive thymus-dependent immune system induced by higher levels of thyroid
hormones and calcitonin respectively. After repeated similar attacks, more and more effector T-
cells are raised and more and more beta-cells are destroyed, and clinical diabetes occurs.
© 2013 GESDAV
INTRODUCTION
Type 1 diabetes (T1D) is an autoimmune disease
wherein insulin-producing pancreatic beta (β)-cells are
attacked and destroyed by T lymphocytes [1]. During
the natural history of T1D, T-cell activity develops
against more and more β-cell epitopes, which is often
referred to as antigen spreading [2]. The presence of
both effector T-cell reactions and autoantibodies can be
detected, however the β-cell destruction is mediated
largely by T-lymphocytes [2, 3]. Resting β-cells display
less antigenicity and are less sensitive to immune
destruction. Growing evidence suggests that the
functional state of the β-cells plays a role in the
pathogenesis of T1D [4, 5]. They might be especially
sensitive to autoimmune diseases due to the fact that
these cells open themselves up during the insulin
secretion. It might well be imagined that not every
single molecule out of several billions produced is
totally correct, and therefore could elicit an antigenic
reaction. The possible mechanisms behind the β-cell
sensitivity as a function of their activity are: increased
susceptibility to the toxicity of diabetogenic agents and
increased antigen expression in β-cells with high
activity which could activate the destruction caused by
the immune system [6].
AUTOANTIGEN PRESENTATION TO CYTO-
TOXIC T LYMPHOCYTES
The destruction of the β-cells is mediated by cellular
immune responses [7]. But, the detailed mechanisms of
how the autoimmune response is initiated remain
unclear. The major cell type that destroys β-cells in
T1D is the CD8+ cytotoxic T lymphocyte (CTL) that
directly recognizes peptide antigens presented by
class I major histocompatibility complex (MHC)
proteins on the surface of β-cells [8]. T lymphocytes
have the unique property of recognizing and
responding only to peptide antigens that are present on
the surfaces of other cells. Although the expression
levels vary, all nucleated cells within the body use
class I MHC molecules to present antigen to CTLs.
Such antigens are derived from peptides produced by
intracellular degradation of target molecules and, by
this way, a cell can present to the immune system any
marker indicative of abnormal function [9]. In contrast,
CD4+ T cells recognize antigen only in the context of
class II MHC, which is normally expressed exclusively
on antigen-presenting cells (APCs). In this case, the
antigen is usually derived from the breakdown of
proteins that the APCs have endocytosed from their
environment [9]. Hyperexpression of MHC class I
molecules by β-cells is a feature unique to T1D

Irmak et al: Fluoride toxicity and diabetes
4 DOI 10.5455/jeim.011113.hp.007
whereas increased expression of MHC II molecules
have not been seen consistently on β-cells [10]. The
hyperexpression of class I MHC by islet endocrine cells
in human T1D appears to precede insulitis [10-13] and
insulitis is never observed in the absence of class I
MHC hyperexpression [14]. Hyperexpression of MHC
class I molecules on islet cells renders them more
susceptible to CTL killing as a result of the increased
surface density of autoantigenic peptide with MHC
molecules [14]. It has been argued that β-cells might,
themselves, represent the source of the signal that
results in the hyperexpression of class I MHC antigens
within islets [11, 15]. Some class I MHC-binding
peptides may be generated by proteolytic enzymes
resident in the endoplasmic reticulum (ER) and MHC
class I binding to self-peptides occurs within the
endoplasmic reticulum [16]. For example, peptides
from secretory proteins with hydrophobic signal
sequences are often found associated with class I MHC
molecules. These proteins bind directly to class I MHC
complex in the ER [16]. Class II MHC antigens have
been shown to be aberrantly expressed in the pancreas
in T1D [10-12, 17] and it occurs after hyperexpression
of MHC class I within a given islet [12], but the signal
that initiates the aberrant class II MHC expression in
β-cells has yet to be determined [18].
PROINSULIN DIMER AS AUTOANTIGEN
We thought that post-translational modifications of
β-cell peptides could contribute to the interaction
between peptides, MHC molecules and the autoreactive
T-cells. In this respect, a conformationally altered form
of native proinsulin may play such a role in the T1D
process [19-22]. It was suggested that disulfide cross-
linked dimers of proinsulin could provide the
autoantigenic stimulus, since their abnormal tertiary
structure would not be recognized as self by the
immune system [23]. Proinsulin is present in a soluble
aggregate state in the ER but may form dimers due to
abnormalities of microenvironment induced by toxic
compounds. Exposure of proinsulin monomers to
halogens such as iodine and chlorine was reported to
result in disulfide cross-linked dimers [24, 25].
Dimerization, being post-translational and not under
direct enzymatic control, would then result in
autoantigenity by virtue of the altered tertiary structure.
Dimeric proinsulin would then migrate to pancreatic
β-cell membranes together with MHC class I molecules
to be presented to cytotoxic T lymphocytes. This
abnormal dimer would not be recognized as self by the
immune system, triggering a selective destruction of
pancreatic β-cells, resulting in T1D [26].
T1D is a complicated disease that is difficult to
understand; the question of what causes T1D is still not
fully answered [2]. Environmental factors, such as diet,
and toxic compounds may potentially trigger the onset
of autoimmune diabetes [9]. It is in good accordance
with the partially un-inherited nature of T1D that the
incidence of the disease during the last 3-4 decades has
increased substantially in Finland; T1D is seen in up to
2% of all individuals during their life-time [2]. This is
an unusually high incidence for a potentially deadly
disease. However, for the vast majority of T1D patients
no direct β-cell toxic compound has been identified yet.
In the present study, we present a hypothesis in which
multiple pathogenetic factors related to fluoride,
amoxicillin, calcitonin, thyroid hormones, β-cell
activity and T-cells, act in concert for the development
of T1D.
FLUORIDE TOXICITY
Fluoride (F2) is another halogen like iodine and
chlorine and it is used as anti-cariogenic in drinking
water, oral tablets and dentifrices [27]. However,
chronic exposure to high dose F2 can result in dental
fluorosis [28]. Fluorosis is found in cities with a
fluoridated water supply and higher incidence of T1D
was reported in a number of these countries [29, 30].
However, in Finland children have fluorosis despite the
absence of fluoridated water supply [30]. Use of
fluoride tablets is the only significant contributory
factor for fluorosis in Finland [30] and fluorosis is
more common among children who take amoxicillin
during the first 2 years of life [31]. It seems that dental
ameloblasts are exposed to an acid environment with
the use of amoxicillin [27]. The low extracellular pH
surrounding the maturation stage ameloblasts promotes
the conversion of F2 to hydrogen fluoride (HF). Unlike
F2, HF can diffuse easily into the cell cytosol. Because
the cytosol has a neutral pH, virtually all HF reverts to
F2 in cytosol and F2 cannot easily diffuse out of the
cell. Over the course of months, the F2 concentration
within an ameloblast could rise to many times that
present in the extracellular matrix. Excess F2 can then
compromise the protein synthesis [32, 33], disrupt the
export of secretory granules from the ER, and lead to
the formation of autophagosomes in cytosol thus
generating the clinical manifestations of dental
fluorosis [34]. Fluoride was also reported to alter the
activity and morphology of pancreatic cells [35-38],
resulting in the decrease in insulin secretion and
hyperglycemia, thus indicating the diabetogenic effect
of fluoride [36].
CONTRIBUTION OF THYROID HORMONES
AND CALCITONIN
Increased linear growth, as measured by attained
childhood height, is associated with an increased risk
for T1D, especially at young ages [39-41]. Rapid

Journal of Experimental and Integrative Medicine 2014; 4(1):3-8
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growth observed in infants and young children [42] is
partly a continuation of the fetal growth under the
effect of thyroid hormones [43]. Growth becomes
thyroid hormone dependent immediately after birth
[44], and excessive thyroid hormone in this period was
reported to enhance body height in humans [45].
Growth velocity in this period is different between
populations [46, 47], and Finnish infants showed
significantly higher growth rate and higher thyroid
hormone serum levels than all other ethnic groups [48],
but the differences do not seem to correlate with
thyrotropin levels [49, 50]. The control of the thyroid
hormone secretion in this period was suggested to come
from parafollicular (C) cells which were reported to
stimulate the follicular cells in a paracrine way [51],
and calcitonin was suggested to be responsible for the
population differences in thyroid physiology [52].
Therefore, thyroid hormone dependent rapid growth
observed after birth is controlled by calcitonin; and
higher thyroid hormone levels and higher growth rate
in the early postnatal period seem to result from
elevated calcitonin levels in this period [53].
Thyroid hormones increase the rate of absorption of
carbohydrate from the gastrointestinal tract and they
also accelerate the degradation of insulin [54]. With
elevated levels of thyroid hormones, therefore, the
blood glucose level rises rapidly after a carbohydrate
meal, sometimes exceeding the renal threshold [55].
Higher thyroid hormone levels and higher growth
velocity observed in Finnish children may thus result in
greater insulin secretion which may increase demands
on the beta cells and make the beta cells vulnerable to
autoimmune attack. This view supports the overload
hypothesis for the onset of diabetes in Finland.
High levels of calcitonin receptor are expressed by
normal human T lymphocytes and binding of the
receptor with calcitonin leads to proliferation and
cytokine production in lymphocytes [56-59]. Serum
calcitonin concentration is significantly elevated in the
patients with T1D indicating a role of calcitonin in the
pathogenesis of diabetes [60-65]. The link between
calcitonin and T1D may involve increased numbers of
T-cells and higher levels of cytokines secreted by
lymphocytes in the pancreatic islets [66].
Previous considerations has led us to suggest that
childhood rapid growth in Finland trigger the
autoimmunity under the combined effect of thyroid
hormone and calcitonin by inducing higher insulin
production from the pancreas, which may make the
β-cell more active and more visible to the immune
system and by inducing proliferation and cytokine
production in T-cells already performing autoimmune
attack in the islets.
A SCENARIO FOR THE DEVELOPMENT OF
TYPE 1 DIABETES IN FINNISH CHILDREN
We suggest that β-cell destruction in T1D progresses
through a number of stages:
-Stage 1 is initiated by modification of the proinsulin
(dimer formation) by combined effects of fluoride and
amoxicillin. Amoxicillin especially when used together
with clavulanic acid results in an acid environment
around the β-cells that can dip below pH 6. The low
extracellular pH surrounding the β-cells promotes the
conversion of F2 to HF. Concentration of HF increases
as the pH falls. After the pH of the extracellular matrix
gets lower than that of the cell cytoplasm, an
intracellular-extracellular pH gradient is maintained
that continuously drives HF into the cell. Unlike F2,
HF can diffuse easily into the β-cell cytosol. Because
the cytosol has a neutral pH, virtually all HF reverts to
F2 and F2 cannot easily diffuse out of the cell. Over the
course of months, the F2 concentration within a β-cell
rises to many times that present in the extracellular
matrix. Exposure to excess F2 promotes disulfide bond
instability thereby allowing the formation of novel
disulfide cross-links between two proinsulin molecules
in the ER, thus leading proinsulin dimers and
simultaneously hyperexpression of MHC class I
molecules. The abnormal products of proinsulin then
migrate to the cell membrane with MHC class I
molecules, and immunoreactivity due to the changed
conformation of proinsulin molecules initiates a
destructive autoimmune process against the islets.
Shedding dimeric proinsulin molecules from beta cells
in combination with hyperexpression of MHC
molecules is a powerful immunogenic stimulus for the
cytotoxic T-cells.
-Stage 2 commences with infiltration of the islets by
the activated T-cells. Production of cytokines from the
infiltrating cells induces further upregulation of MHC
molecules in β-cells. The final stage encompasses
autoimmune-mediated destruction of the β-cells by the
targeted delivery of cytotoxic cytokines and other
mediators. In Finnish children, this might be helped
along by high β-cell activity and by a reactive thymus-
dependent immune system induced by thyroid
hormones and calcitonin respectively. Once the islets
have become infiltrated and highly populated with T-
cells and macrophages, they communicate via antigen
presentation and can, in turn, activate each other via
cytokines and direct cell communication through
surface receptors. With such a high population of
immune cells centered in one distinct area, activation
signals can travel fast, initiating a destructive cascade
easily. CTLs (CD8+) can directly kill β-cells, whereas
CD4+ effector T-cells activated possibly by β-cells
initiates the activation of B lymphocytes, thus
prompting autoantibody production. At this stage,
various amounts of β-cell antibodies are present, but

Irmak et al: Fluoride toxicity and diabetes
6 DOI 10.5455/jeim.011113.hp.007
the process may still be reversible. However, after
repeated similar attacks more and more effector T-cells
are raised and more and more β-cells are destroyed, and
a point of no return is passed. The insulitis process
perpetuates by itself and clinical diabetes will occur.
Consequently, Finnish children will have healthy teeth
at the expense of T1D.
FUTURE CONSIDERATIONS
T1D seems to develop if all the pathogenetic factors
related to fluoride, amoxicillin, thyroid hormones,
calcitonin, beta-cell activity and T-cells act in concert
to some degree, and that if any of the factors are
neutralized, inhibited, or acted against, T1D would not
occur. The fluoride compounds in drinking water are
completely absorbed from the gastrointestinal tract [67]
and while 60% of the absorbed fluoride is retained in
adults, this level rises to 80-90% in infants [35]. As a
result, drinking water should also be considered as the
potential source of fluoride that causes T1D in children.
In addition, dental products are other common sources
of overexposures today, particularly dentifrices,
because of their relatively high fluoride concentrations,
pleasant flavors, and their presence in non-secure
locations in most homes [68]. Therefore, it should be
kept in mind that ingestion of a little standard
fluoridated dentifrice by a child delivers enough
fluoride to reach the toxic dose.
ACKNOWLEDGEMENT
This work is dedicated to the parents of children with T1D.
COMPETING INTERESTS
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors
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