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Effect of fluoride intake on carbohydrate metabolism, glucose tolerance, and insulin signaling
Abstract
Fluoride is known to cause both local and systemic alterations in animals and humans, such as dental fluorosis and disturbances in glucose homeostasis. The effects of fluoride are dose dependent and can produce decreased insulin secretion, inhibition of glycolysis, glycogen depletion, hyperglycemia, and insulin resistance. Because excessive ingestion of fluoride during tooth brushing can lead to deterioration in health, the use of low-fluoride dentifrices is recommended for young children with diabetes.
... Besides influencing bone metabolism, fluoride can also alter glucose homeostasis [9,10]. Studies with castrated male rats demonstrated that chronic treatment with NaF promoted insulin resistance and decreased insulin signaling [11][12][13]. In addition, chronic treatment with fluoride in castrated rats also increased the IRS-1 serine phosphorylation status in adipose tissue, resulting in the attenuation of insulin signal transduction [11,13]. ...
... Studies with castrated male rats demonstrated that chronic treatment with NaF promoted insulin resistance and decreased insulin signaling [11][12][13]. In addition, chronic treatment with fluoride in castrated rats also increased the IRS-1 serine phosphorylation status in adipose tissue, resulting in the attenuation of insulin signal transduction [11,13]. ...
... There is no consensus about the effectiveness of NaF in promoting the formation of healthy bone [14], and, depending on the dosage, fluoride can promote changes in glycemic homeostasis [11,13,15] and insulin sensitivity [16]. Therefore, the aim of this study was to examine the effect of chronic treatment with NaF (50 mg/L in drinking water) on the insulin sensitivity, insulin signal transduction, and biomechanical and histomorphometric parameters in the bone of ovariectomized (OVX) rats. ...
Osteoporosis is a systemic disease characterized by bone degradation and decreased bone mass that promotes increased bone fragility and eventual fracture risk. Studies have investigated the use of sodium fluoride (NaF) for the treatment of osteoporosis. However, fluoride can alter glucose homeostasis. The aim of this study was to evaluate the effects of NaF intake (50 mg/L) from water on the following parameters of ovariectomized (OVX) rats: (1) tyrosine phosphorylation status of insulin receptor substrate (pp185 (IRS-1/IRS-2)) in white adipose tissue; (2) insulin sensitivity; (3) plasma concentrations of glucose, insulin, total cholesterol, triglyceride, TNF-α, IL-6, osteocalcin, calcium, and fluoride; (4) bone density and biomechanical properties in the tibia; and (5) tibia histomorphometric analysis. Fifty-two Wistar rats (2 months old) were ovariectomized and distributed into two groups: control group (OVX-C) and NaF group (OVX-F), which was subjected to treatment with NaF (50 mg/L) administered in drinking water for 42 days. The chronic treatment with NaF promoted (1) a decrease in pp185 (IRS-1/IRS-2) tyrosine phosphorylation status after insulin infusion in white adipose tissue and in insulin sensitivity; (2) an increase in the plasma concentration of insulin, fluoride, osteocalcin, calcium, triglyceride, VLDL-cholesterol, TNF-α, and IL-6; (3) a reduction in the trabecular width, bone area, stiffness, maximum strength, and tenacity; (4) no changes in body weight, food and water intake, plasma glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, bone mineral content, and bone mineral density. It was concluded that chronic treatment with NaF (50 mg/L) in OVX rats causes a decrease in insulin sensitivity, insulin signaling transduction, and biochemical, biomechanical, and histomorphometric bone parameters.
... Conversely, glucagon induces hyperglycemia, stimulates fatty acid oxidation, and enhances gluconeogenesis [74]. Various studies have revealed that increased fluoride levels lead to decreased plasma insulin and serum glucagon levels, disrupting glucose homeostasis, reducing C-peptide levels, causing hyperglycemia, inhibiting glycolysis, and depleting glycogen stores [20,21,28,30,52,57,59,63,75,76]. Enhanced glucose homeostasis has been observed when plasma fluoride levels exceed 5 μmol/L. ...
... Enhanced glucose homeostasis has been observed when plasma fluoride levels exceed 5 μmol/L. Fluoride concentrations ranging from 5 to 20 μmol/L significantly inhibit both basal and glucose-stimulated insulin secretion in isolated islets of Langerhans [29,55,76]. Beta cells exposed to fluoride exhibit reduced insulin mRNA expression [22]. ...
This review explores the diverse effects of fluoride on pancreatic function, encompassing both in vitro and in vivo studies. Fluoride exposure induces notable alterations at the cellular and molecular levels, affecting pancreatic morphology, histology, and enzymatic activity. In vitro studies demonstrate significant inhibition of pancreatic α-amylase activity and apoptosis in pancreatic beta cells. In vivo investigations reveal structural abnormalities in pancreatic cells, including mitochondrial damage, vacuolation, and nuclear damage. Moreover, fluoride exposure disrupts antioxidant enzyme activity, exacerbating oxidative stress and lipid peroxidation. Changes in digestive enzyme activity, such as the inhibition of pancreatic lipase and α-amylase, further contribute to pancreatic dysfunction. Additionally, alterations in hormone secretion, notably insulin levels and disturbed glucose homeostasis, highlight the complex effects of fluoride on the pancreatic endocrine system. These findings underscore fluoride-induced pancreatic toxicity and highlight the need for a comprehensive understanding and mitigation strategies to safeguard pancreatic health.
... The consumption of the fluoride ion (F) must be controlled and maintained within the recommended parameters, because excessive F intake can promote toxic effects on the endocrine system, resulting in disorders and alterations in carbohydrate metabolism, glucose tolerance, and insulin signaling. 1,2 Lupo et al. demonstrated that plasma insulin levels increased as the F concentration of the drinking water increased, producing insulin resistance. 3 Another study showed that F can reduce insulin signaling. ...
... 3 Another study showed that F can reduce insulin signaling. 1 Chronic F intake promotes a decrease in the insulin receptor substrate (pp185 -IRS-1/2) tyrosine phosphorylation status of muscle and white adipose tissue and an increase in the IRS-1 serine phosphorylation status of white adipose tissue, resulting in insulin resistance. 4,5 Type 2 diabetic subjects normally show changes in lipid profile, and evidence suggests that insulin resistance plays a central role in the development of dyslipidemia, since it causes an increase in free fatty acid release by insulinresistant adipose cells. ...
Excessive fluoride ion (F) intake promotes systemic metabolic alterations, such as a decrease in insulin secretion, hyperglycemia, and insulin resistance, similar to those observed in diabetes. Cardiovascular disease is responsible for a large degree of morbidity and mortality in individuals with diabetes, and dyslipidemia is considered to be one of the most important risk factors for the development of cardiovascular disease. This study aimed to evaluate the chronic effect of NaF on insulin signal transduction in liver and in muscle, and to determine the plasma concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C). Seven-week-old castrated male Wistar rats were randomly distributed into a control group, which received 76.4 mg/ L NaCl in their drinking water, and a fluoride group, which received 54.9 mg/L NaF in their drinking water and F in their food pellets (estimated total F intake: 4.0 mg/kg body weight (bw)/day). After 42 days, the insulin receptor substrate-1 (IRS-1) serine phosphorylation status in the liver and muscle tissues and plasma concentrations of triglycerides, total cholesterol, HDL-C, LDL-C, VLDL-C and F were evaluated. The chronic treatment with F promoted an increase in the plasma concentrations of TG, TC, VLDL-C and F but no alteration in the plasma concentrations of HDL-C and LDLC or in the IRS-1 serine phosphorylation status in liver or muscle tissue. These results demonstrate that chronic treatment with NaF (4.0 mg/kg bw/day) promotes dyslipidemia in castrated rats but does not interfere with the IRS-1 serine phosphorylation status, one of the inhibitory pathways of the insulin signal in muscle and liver tissues.
... The presence of illness is directly attributable to an insufficient number of sperm in the semen. A major issue that affects persons living in dominating regions is a low level of testosterone in their blood [30,48]. ...
The fluoride contamination has developed into a significant risk for our society on a global scale. Chronic exposure to geogenically produced fluoride in high quantities in groundwater may have a detrimental effect on the health of millions of individuals throughout the globe. The fluorination in the water source is largely caused by fluoride-rich soil, volcanic activity and human factors. Due to the adverse health consequences such as dental discoloration and skeletal fluorosis, the World Health Organization recommends 1.5 mg/L of fluoride for drinking water to prevent dental mottling and skeletal fluorosis. Apart from skeletal and dental fluorosis, the presence of extreme fluoride in water may have several other health effects like arthritis, osteoarthritis, muscle damage, weariness, joint difficulties, and chronic disorders. In severe cases, it may harm the heart, veins, kidney, liver, sensory organs and nervous system of a living creature, as discussed in this paper. In addition, a worldwide scenario for the many nations struggling with excessively fluoridated water has been laid out. Ion-selective and colorimetric techniques are used in water applications to identify fluoride contamination. The study also emphasized the removal processes of several approaches for removing fluoride from water. The method's prospective usage in the nation's economy has also been investigated. The membrane method is seldom utilized in developing nations like India and Kenya, which use adsorption and coagulation-precipitation for the defluoridation of water. Defluoridation procedures vary according to the literature. Some important factors and mechanistic adjustments might advance defluoridation approaches.
Keywords
FluorinationFluorosisArthritisIon selectiveDefluoridationAdsorption
... Fluoride toxicity was found to be linked with increased insulin sensitivity, altered homeostasis, and insulin resistance based on animal studies (Lobo et al. 2015). Chronic exposure to fluoride imparts insulin resistance and results in T2DM (Trivedi et al. 1993;Chiba et al. 2012). In addition, water fluoride levels were also found to be significantly associated with the prevalence of hypertension (Amini et al. 2011;Ostovar et al. 2013). ...
Chronic exposure to fluoride through drinking water has been linked to insulin resistance and resulting type 2 diabetes mellitus (T2DM). Here, we aim to study the impact of water fluoride levels on blood glucose and vitamin D levels. A hospital-based study was conducted on diabetic patients (n = 303) at All India Institute of Medical Sciences (AIIMS), Raebareli outstation patient department (OPD). The relationship between vitamin D or fasting blood glucose levels (BGLs) with water fluoride levels was estimated through Spearman's rank correlation. We found a significant negative correlation between water fluoride and vitamin D levels [rs = −0.777, p-value < 0.001] and a positive correlation between water fluoride and fasting BGLs [rs = 0.178, p-value 1.5 mg/L) had higher odds of severe vitamin D deficiency (odds ratio: 5.07, 95% CI: 1.9–13.2, p-value = 0.0009). The results demonstrate that vitamin D deficiency and fasting BGLs are significantly associated with water fluoride levels. This study signifies the role of fluoride toxicity in poor glycemic control and derived vitamin D deficiency. Vitamin D supplementation and the application of standard household water purification devices are recommended to tackle vitamin D deficiency in fluoride-endemic areas.
HIGHLIGHTS
Water fluoride levels had a negative correlation with vitamin D deficiency and a positive correlation with blood glucose levels.;
Toxic levels of fluoride in drinking water appeared as a risk factor for developing vitamin D deficiency.;
Severe vitamin D deficiency and high blood glucose levels were observed in patients from fluoride-endemic areas compared to non-endemic areas.;
... Lack of testosterone in the blood of those in dominant areas is a common problem. Drinking water with more fluoride is consumed here (Chiba et al., 2012). ...
According to data from the Environmental Protection Agency, fluoride is an agent that favors contamination in public drinking water and may has an adversely effect on human health. The Water Conservation Agency and World Health Organization have set a limit (1.5 mg fluoride per liter) on the maximum pollution level of fluoride that has some adverse effect. Fluoride is known to be used for stimulating the formation of bone cells, for preventing tooth decay. Fluoride shows its presence naturally and artificially but drinking water, food, dental products, and pesticides are major sources of fluoride that affect the human body in many ways, such as metabolic and nutritional disorders. Dental effect, musculoskeletal effects such as skeletal fluorosis, bone fractures, reproductive and developmental effects, neurotoxicity, and neurobehavioral effects, endocrine effects, genotoxicity and carcinogenicity, and some other effects like gastrointestinal system, kidneys, liver, and immune system are the effects on human health due to fluoride.
... In the human body, the thyroid gland is the most sensitive tissue to the fluoride and exposure to fluoride raises TSH (thyroid stimulating hormone) concentration and decreases T 3 and T 4 concentration, thereby resulting in hypothyroidism 15,16 . In several studies, it has been pointed out that prolonged exposure of fluoride from drinking water does develop insulin resistance in human beings 17,18 . Excessive consumption of fluoride ultimately leads to hyperglycemia and impaired glucose tolerance 19,20 . ...
As drinking water is considered as a major pathway of exposure to fluoride in the human body, an endeavor has been made for the assessment of the non-carcinogenic health risk by using hazard quotient (HQ) of fluoride for males, females, and children separately in fluoride affected ground water areas of Indo-Gangetic Alluvial Plains. The study suggests that children groups are more prone to the non-carcinogenic risk of fluoride in the area as HQ for fluoride is more than unitary in 44% (Pre-monsoon) and 38% (Post-monsoon) samples respectively. Field survey conducted in fluoride-affected villagers of the study area portrays cases of mottling of teeth and bone deformities depending on the duration and dosage of fluoride consumption. Petrographic observations of host rocks coupled with molar ratios of chemical species studies exemplify that weathered material developed over the granite-gneiss, mica-schist, amphibolite, granitic intrusive and pegmatite veins due to weathering and extensive water-rock interaction resulting higher concentration of fluoride in groundwater. Likewise, the base exchange index (r1) and meteoric genesis index (r2) advocates that most of the samples belong to Na+-HCO3− type and meteoric origin respectively, and substantiate longer residence time of water along with solute acquisition processes are responsible for elevated fluoride in groundwater. It is, therefore, solar energy-driven electrolytic de-fluoridation technology ought to be provided on a priority basis to the affected inhabitants besides the implementation of rainwater harvesting schemes for mitigation/ dilution of elevated fluoride concentration.
... It is also established that F − increases the conversion of ATP to cAMP by stimulation of adenylyl cyclase [235,236]. Consistent with this, evidence from human and animal studies show that F − stimulates cAMP production [237][238][239][240][241][242][243][244][245][246][247][248] leading to increased concentrations of cAMP in plasma, saliva, urine, and tissues. Moreover, in vitro human tissue models have demonstrated that F − in micromolar concentrations of 1-10 µM significantly increases the synthesis of cAMP in a dose dependent manner [249]. ...
In this study, several lines of evidence are provided to show that Na + , K + -ATPase activity exerts vital roles in normal brain development and function and that loss of enzyme activity is implicated in neurodevelopmental, neuropsychiatric and neurodegenerative disorders, as well as increased risk of cancer, metabolic, pulmonary and cardiovascular disease. Evidence is presented to show that fluoride (F) inhibits Na + , K + -ATPase activity by altering biological pathways through modifying the expression of genes and the activity of glycolytic enzymes, metalloenzymes, hormones, proteins, neuropeptides and cytokines, as well as biological interface interactions that rely on the bioavailability of chemical elements magnesium and manganese to modulate ATP and Na + , K + -ATPase enzyme activity. Taken together, the findings of this study provide unprecedented insights into the molecular mechanisms and biological pathways by which F inhibits Na + , K + -ATPase activity and contributes to the etiology and pathophysiology of diseases associated with impairment of this essential enzyme. Moreover, the findings of this study further suggest that there are windows of susceptibility over the life course where chronic F exposure in pregnancy and early infancy may impair Na + , K + -ATPase activity with both short- and long-term implications for disease and inequalities in health. These findings would warrant considerable attention and potential intervention, not to mention additional research on the potential effects of F intake in contributing to chronic disease.
... Diabetes has been increasing in a number of countries since the 1940s in line with the roll out of Fluoridation. Insulin resistance in humans caused by chronic Fluoride exposure from drinking water is well known [Trivedi 1993, Stephen 1994, Cheoud 2008, Menoya 2008, Chiba 2010, Chiba 2012a, 2012bBergman 2013, Vandenberg 2012. ...
Experts in endocrinology have shown that Fluoride causes Diabetes and Obesity. This review assembles the wealth of science that shows how Fluoride damages the organs that generate or use Insulin to control Glucose metabolism and the crucial involvement of other hormone systems.
... Mechanistically, fluorine can decrease the secretion of insulin dose-dependently and caused insulin resistance [41]. In response to insulin insufficiency, the levels of osteocalcin can decrease [42] worsening bone lesions in patients suffering from skeletal fluorosis. ...
Accumulation of excess fluoride in the environment poses serious health risks to plants, animals, and humans. This endangers human health, affects organism growth and development, and negatively impacts the food chain, thereby affecting ecological balance. In recent years, numerous studies focused on the molecular mechanisms associated with fluoride toxicity. These studies have demonstrated that fluoride can induce oxidative stress, regulate intracellular redox homeostasis, and lead to mitochondrial damage, endoplasmic reticulum stress and alter gene expression. This paper reviews the present research on the potential adverse effects of overdose fluoride on various organisms and aims to improve our understanding of fluoride toxicity.
... Fluoride is a low-dose endocrine disruptor whose toxicity is greater in diabetic patients. Various researchers' study came to a point that insulin resistance in humans caused by chronic fluoride exposure from drinking water [29][30][31][32][33]. According to The US National Research Council [10], impaired glucose metabolism appears to be associated with serum or plasma fluoride concentrations of about 0.1 ppm or greater in both animals and humans. ...
Fluorine (F-) is a chemically reactive electronegative univalent gaseous halogen found in small amount in the
water, air, plants and animals. Fluorine is essential for the maintenance and solidification of our bones and to
prevent dental decay. It has beneficial effects on teeth and bones when it is present at low concentration in
drinking water, but excessive exposure to fluoride in drinking-water, or in combination with exposure to fluoride from other sources, can give rise to a number of adverse effects which include teeth decay, osteoporosis and harm to kidney, bones, reproductive organs, nerve and muscle. Fluoride, when in excess, is known to interfere with thyroid gland function causing TSH elevation and lessen T3/T4 hormones in some populations which may be due to its antagonistic properties towards iodine. As an endocrine disruptor, Finduces more toxic outcome in diabetic patients. Chronic F- exposure through drinking water may leads to insulin resistance in humans in addition to its hyperglycemic effect due to increased hepatic glycogenolysis. Fluoride also hinders glycolysis by inhibiting enolase enzyme and repressing insulin secretion from islets of Langerhans cells resulting in elevation of blood glucose level. High Fexposure is also associated with increased levels of FSH and LH, decreased estrogen and testosterone levels, disturbed androgen to estrogen ratios (A/E) and estrogen receptor to androgen receptor ratios (ER/AR). Decreased circulating testosterone concentrations were also reported in male skeletal fluorosis patients. The most significant consequences of fluoride exposures in male reproduction are: changes in the structure and functional activities of spermatozoa and disruption of spermatogenesis while in an experimental data involving female rats showed that high fluoride concentration lowers the pregnancy rate and the number of implantation. Most interestingly, recent research showed that exposure to high concentration of F- does have deleterious effect on the mental ability of children. A strong association between exposure to fluoride and low IQ was found and it was also noted that children who live in fluorosis prevalent areas have higher chances of developing a low IQ than those who live in normal areas. So it is clear that the severity of the above pathological conditions is dependent on the dose, duration and age of the individual. Therefore, to ensure whether people need any fluoride supplements or not, government should have to take initiative to prevent health problems due to deficiency or excess fluoride exposure. Evidence-wise further thorough research is essential based on scientific facts to enlighten best practices in the use of fluoride containing materials for the safety and security of public health.
Fluoride is abundant in the environment and exists mostly in combination with other elements as fluoride compounds. Several studies showed that exposing to irregular level of fluoride could impair the normal function of mitochondria that have major contribution for producing of reactive oxygen species (ROS). However, information about the exact mechanism behind the fluoride-induced mitochondrial damage has not been fully understood. In the present study, isolated rat liver mitochondria were exposed to different concentrations of sodium fluoride (NaF) for 30 min and their functionality was assessed at the presence of different concentrations of N-acetylcysteine (NAC) and IC50 concentration of NaF. Mitochondrial dehydrogenase activity, glutathione (GSH) content, lipid peroxidation, ROS production and mitochondrial membrane potential (MMP) assay in the presence of these two substances were evaluated. Our findings demonstrated that, NaF reduced the GSH content of mitochondria, increased ROS and lipid peroxidation which led to a decrease in the dehydrogenase activity (complex II) of mitochondria. NAC considerably inhibited those noxious effects of NaF on mitochondria and prevented NaF toxicity on mitochondria isolated from rat liver.
The effects of fluoride on endocrine tissues has not been sufficiently explored to date. The current body of knowledge suggest significant effects of that mineral on reducing sex hormone levels, which may consequently impair fertility and disrupt puberty. The majority of studies confirm that sodium fluoride increases TSH levels and decreases the concentrations of T3 and T4 produced by the thyroid. Moreover, a correlation was observed between NaF and increased secretion of PTH by the parathyroid glands, without a significant impact on body calcium levels. Probably, fluoride may exert adverse effects on insulin levels, impairing pancreatic function and resulting in abnormal glucose tolerance. Observations also include decreased levels of cortisol secreted by the adrenal glands. In light of the few existing studies, the mechanism of fluoride toxicity on the endocrine system has been described.
Fluoretação da água de abastecimento público é a adição de compostos de flúor nas estações de tratamento da água como uma das formas de prevenção da cárie dentária. Ainda que a fluoretação das águas seja reconhecidamente eficaz na prevenção da cárie dentária, e mesmo que a Organização Mundial da Saúde (OMS) siga recomendando-a como medida estratégica de saúde pública, há questionamentos quanto à sua efetividade em contextos em que as populações estão expostas a múltiplas fontes de flúor. O objetivo desta revisão foi apresentar alguns pontos sobre fluoretação da água no Brasil. Para além de saber se a fluoretação das águas de abastecimento público é eficaz ou não, é relevante seguir avaliando se essa tecnologia de saúde pública é ou não efetiva na prevenção da cárie, sobretudo em contextos socioeconômicos marcados por desigualdades, como é o caso do Brasil. Somente com a análise detalhada de todos os argumentos poder-se-á chegar a um posicionamento sólido em relação ao tema, com conclusões mais acuradas.
In 2017 the Australian National Health and Medical Research Council (NHMRC) released a draft information paper on the health effects of water Fluoridation that completely ignored thousands of peer-reviewed scientific publications regarding Fluoride toxicity, by using contrived exclusion criteria and time limits. Similar tactics were employed by the NHMRC in its Fluoridation review published in 2007. This submission, one of the 32 made public, formally records some of the science that has been deliberately ignored.
The aim of this study was to make a preliminary assessment of etiological factors related to dental fluorosis of permanent teeth among children in Poznan, Poland. Included were 19 resident children, aged 8-17 with symmetrical diffuse enamel opacities, along with 19 matched controls. Possible etiological factors of dental fluorosis were recorded by a detailed interview with the parents. Short-duration breastfeeding and the use of tap water for reconstitution of infant formula significantly increased the risk of developing fluoride (F) opacities (p = 0.02). There was no statistically significant difference in the distribution of medical problems that have been reported to cause enamel opacities in the study group and the control group.
This brief literature review and bibliography presents evidence that Fluoride, through fluoridation of public drinking water, causes Diabetes as well as injury to existing diabetics.
Forty seven-week-old male castrated Wistar rats were randomly divided evenly into a control group and a fluoride (F) group. The latter was given a single dose of NaF from a solution containing 1.0 mg F ion/kg bw, administered by gavage. After 30 min, the following experiments were performed: intravenous insulin tolerance test (0.75 U/kg bw) and determination of the insulin receptor substrate (pp 185-IRS-1/IRS/2) tyrosine phosphorylation status. The acute treatment with NaF promoted increased blood glycemia, but there were no significant changes in the insulin sensitivity and in the pp185 tyrosine phosphorylation status in the muscular or in the white adipose tissues.
The prevalence of obesity is increasing all over the world in the last decades. This is a concerning fact since the excess of body fat, especially abdominal fat, is directly related to the lipidic profile that is altered, to the increase of arterial pressure and hyperinsulinemia. All of these are considered risk factors to the onset of chronic-degenerative diseases such as type 2 diabetes and cardiovascular disease. High levels of leptin and the alterations of fibrinolytic factors have also been observed in obese individuals. These modifications are described as "metabolic syndrome" or "insulin resistance syndrome", since hyperinsulinemia has an important role in the development of other components of the metabolic syndrome. However, the question is if these alterations are already present in these children and adolescents. This paper describes the physiopathology of the metabolic syndrome components and aims at clarifying how this process takes place in youth.
The use of fluoridated products has significantly contributed to the reduction in rates of dental caries. However, excessive sodium fluoride (NaF) intake promotes inhibition of glycolysis, decrease in insulin secretion, hyperglycemia, and insulin resistance. Seven-week-old castrated male Wistar rats were used to evaluate the chronic effect of NaF on insulin sensitivity, insulin signal transduction in white adipose tissue (WAT), and plasma TNF-α and resistin concentrations. The animals were randomly divided into two groups: (1) control group (CN); (2) fluoride (F) group, which was treated with NaF in the drinking water and F in the food pellets (estimated total F intake: 4.0 mg/kg bw/day). After 42 days, an intravenous insulin tolerance test (0.75 U/kg), plasma TNF-α and resistin quantification analysis, and insulin receptor substrate (pp185 – IRS-1/IRS-2) tyrosine phosphorylation and IRS-1 serine phosphorylation status tests in WAT were performed. The chronic treatment with F promoted: (1) decrease in pp185 (IRS-1/IRS-2) tyrosine phosphorylation status in the WAT; (2) increase in IRS-1 serine phosphorylation status in the WAT; (3) increase in plasma concentrations of TNF-α and resistin; and (4) decrease in insulin sensitivity.
The prevalence of obesity is increasing all over the world in the last decades. This is a concerning fact since the excess of body fat, especially abdominal fat, is directly related to the lipidic profile that is altered, to the increase of arterial pressure and hyperinsulinemia. All of these are considered risk factors to the onset of chronic-degenerative diseases such as type 2 diabetes and cardiovascular disease. High levels of leptin and the alterations of fibrinolytic factors have also been observed in obese individuals. These modifications are described as "metabolic syndrome" or "insulin resistance syndrome", since hyperinsulinemia has an important role in the development of other components of the metabolic syndrome. However, the question is if these alterations are already present in these children and adolescents. This paper describes the physiopathology of the metabolic syndrome components and aims at clarifying how this process takes place in youth.
The aim of this paper is to collect, organize and offer a few national data on dental caries in permanent teeth of Brazilian schoolchildren at last decades of the XX Century. Studies that used DMF-T index as a tool to verify dental caries conditions and data from the Brazilian Ministry of Health at its site on Internet were examined. This analysis reveal a significant reduction in the DMF-T index value in the period 1980-1996. From a "very high" value (7,25) in 1980 at the 12-years-old index-age, DMF-T index shown a consistence falling tendency registering 3,1 in 1996. This is a "moderate" prevalence. There were an expressive decline around 58% at DMF-T value in the period 1980-1996. Increment on access to water fluoridation and dentifrice fluoridation and health system reform must be regarded to understand this situation.
: The insulinic response of rats challenged with glucose at different times after an oral dose of 40 µmol NaF/100 g bw revealed the concentration of the molecular species reacting with anti-insulin antibody was significantly lower after 3 hr, and the glucose levels were somewhat higher than in controls. At the 4 th and 5 th hr, plasma F levels were still higher than in the controls, at which times the response of β-cells toward glucose was assessed by a dose-response function. The concentration of glucose that produced 50% of the insulinic response was significantly higher in rats treated with NaF (6.3±0.2 g/L) compared with the control group (4.3±0.4 g/L), P<0.05. These results indicate that F-treated rats exhibit a significantly reduced sensitivity to glucose stimulus. Measurements of plasma insulin at the 5 th hr after F load by gel filtration of plasma, followed by measurement of insulin in the fractions containing 5–8 kDa peptides, revealed that only one-fifth of the species reacting against the antiserum corresponds to this hormone. The secretion of C-peptide did not exhibit the expected relationship with immunoreactive insulin-like species. The clearance of intravenously injected 125 I-insulin was not affected by the presence of fluoride. The incorporation of 3 H-leucine into β-cell proteins in the range of 5 to 13 kDa was higher in F-treated than in control slices, supporting the hypothesis that F does not interfere with the synthesis of insulin. This work provides further data on the dysfunction induced on pancreatic β-cell physiology by increased F in the extracellular fluid, a dysfunction that most probably involves disturbance of the enzymatic processing of insulin precursors.
: Fourteen-week-old male Wistar FL strain rats were administered sodium fluoride in a single intraperitoneal dose (35 mg NaF/kg bw) and after 90 min were fatally anesthetized. In a separate experiment, four-week-old male rats of the same strain were given fluoride in their drinking water (50 or 100 mg F – /L) for four months and then anesthetized. Both experiments produced hyperglycemia, accompanied by a statistically significant increase in the concentrations of fluoride in the blood serum. Hypertriacylglycerolemia also occurred in the long-term intoxication experiment, thereby indicating disturbances of lipid metabolism under the influence of NaF, which are similar to those observed in diabetes mellitus or in starvation.
This study measured the total daily fluoride (F) intake of 21 children, living in Bauru, a fluoridated community. F intake from diet (D) and dentifrice (B) was determined for 2 groups of children: A (4-5-year-old) and B (6-7-year-old). The method of 24-hour duplicate diet was used. F ingested from dentifrice was indirectly obtained, subtracting the amount expelled and the amount left on the toothbrush from the amount initially loaded onto the brush. F analysis was carried out with the ion specific electrode (Orion 9409), after hexamethyldisiloxane-facilitated diffusion. The amount of F intake from D and B was divided by the child weight and total intake (T) was calculated by adding D and B. Data were analyzed by Students "t" (p<0.05) test and by linear regression. Results (mean ± SD, mg F/Kg body weigh) of T, D and B were, respectively: 0.056±0.040; 0.018±0.12; 0.037±0.038 for all children; 0.055±0.026; 0.021±0.014; 0.034±0.027 for Group A and 0.057±0.052; 0.016±0.010; 0.041±0.046 for Group B. There was a strong positive correlation between the amount of dentifrice used and the amount of fluoride ingested (r = 0.92, p<0.0001). One-third of the children analyzed were exposed to a F dose above 0.07 mg / Kg body weight, which is recommended as the upper limit of daily F intake. Dentifrice was the main source of F ingested by children with percentages of 57.43 ± 29.02 for all children; 56.49 ± 31.82 for group A; and 58.29 ± 27.78 for group B. No significant differences were found between the 2 groups.
Breakfast cereals and snacks are foodstuffs highly appreciated by children, and the possibility that they contain substantial amounts of fluoride, associated with their widespread consume, may make them important contributors to the total daily fluoride intake. The aim of this study was to analyze the fluoride content on several breakfast cereals (A) and snacks (B) purchased in Brazil. The analysis were made after HMDS-facilitated diffusion (Taves) using the ion-specific electrode (9609). Mean fluoride concentrations ± SD (range, unit mg F/g) were: A= 0.76 ± 0.60 (0.08-1.86, n=15) and B= 0.32 ± 0.09 (0.22-0.55, n=18). Our results suggest that the total amount of fluoride available in some products may contribute to the total daily fluoride intake. The product labels should provide information on their fluoride content to prevent fluorosis at the age of risk.
Low-fluoride dentifrices have been suggested as alternatives to reduce dental fluorosis risk, but there is no consensus regarding their clinical effectiveness, which has been suggested to be increased when their pH is acidic.
This single-blind randomized clinical trial evaluated the caries increment during the use of a low-fluoride acidic liquid dentifrice.
Four-year-old schoolchildren (n = 1,402) living in a fluoridated area (0.6-0.8 ppm F) were randomly allocated to 4 groups differing according to the type of dentifrice used over a 20-month period. Group 1 (n = 345): liquid dentifrice, 1,100 ppm F, pH 4.5. Group 2 (n = 343): liquid dentifrice, 1,100 ppm F, pH 7.0. Group 3 (n = 354): liquid dentifrice, 550 ppm F, pH 4.5. Group 4 (n = 360): toothpaste, 1,100 ppm F, pH 7.0. At baseline and after 20 months, clinical examinations were conducted (dmfs index) and caries increment was calculated. Data were analysed by GLM procedure using classrooms (cluster) as unit of analysis (p < 0.05).
The mean ± SD (95% CI) net increments found were as follows. Group 1: 2.06 ± 2.38 (1.8-2.3); group 2: 2.08 ± 2.87 (1.7-2.4); group 3: 2.05 ± 2.79 (1.7-2.4), and group 4: 2.08 ± 2.34 (1.8-2.4). No significant differences were detected among the groups.
In a population with high caries risk living in a fluoridated area, as the selected sample, and according to the present protocol, the low-fluoride acidic liquid dentifrice seems to lead to similar caries progression rates as conventional 1,100 ppm F toothpaste.
A mortalidade dos pacientes com diabetes (DM) é maior do que a da população em geral e decorre especialmente das doenças cardiovasculares. Os prováveis mecanismos da aterosclerose acelerada nestes pacientes são os efeitos tóxicos diretos da glicose sobre a vasculatura, a resistência à insulina e a associação do DM a outros fatores de risco para doença cardiovascular. O principal determinante do dano tecidual causado pelo DM é a hiperglicemia, resultando em aumento de glicose intra-celular, aumento de diacilglicerol (DAG) e ativação da proteína quinase C (PKC). Esta revisão tem por objetivo compilar os efeitos da hiperglicemia sobre a via DAG-PKC, a disfunção vascular relacionada a ela, e, finalmente, as novas perspectivas de tratamento das complicações crônicas vasculares do DM baseadas na inibição desta via.
To examine trends in diabetes prevalence in the U.S.
This study was conducted via telephone surveys in states that participated in the Behavioral Risk Factor Surveillance System between 1990 and 1998. The participants consisted of noninstitutionalized adults aged 18 years or older. The main outcome measure was self-reported diabetes.
The prevalence of diabetes rose from 4.9% in 1990 to 6.5% in 1998--an increase of 33%. Increases were observed in both sexes, all ages, all ethnic groups, all education levels, and nearly all states. Changes in prevalence varied by state. The prevalence of diabetes was highly correlated with the prevalence of obesity (r = 0.64, P<0.001).
The prevalence of diabetes continues to increase rapidly in the U.S. Because the prevalence of obesity is also rising, diabetes will become even more common. Major efforts are needed to alter these trends.
To determine the total fluoride dose to which children were exposed during the critical age of developing dental fluorosis, in an optimally fluoridated region, having diet (liquids and solids) and dentifrice as fluoride sources.
For the pilot study, 39 children (aged 20 to 30 months) were selected from a day care center in Piracicaba, Brazil. They drank and ate food prepared with fluoridated water. To determine the total dose of fluoride exposure, duplicate-plate samples and products from tooth brushing were collected for two consecutive days, in four periods of the year. Fluoride was determined using an ion specific electrode. A 5% level of significance variance analysis (Anova) was carried out.
Children were exposed to a total fluoride dose of 0.090 mg/day/kg of body weight, of which 45% came from the diet and 55% from dentifrice.
Assuming 0.07 mg/kg as a threshold value of fluoride systemic exposure, children were exposed to a risk dose for dental fluorosis. Thus, measures to reduce fluoride intake at the studied age range would be recommended. Reducing the amount of dentifrice used for tooth brushing seems to be the best measure, given the risk/benefits of fluoride use from the public health perspective.
Diabetes mellitus is a common disease and costly public health concern and an expressive number of affected individuals have undiagnosed diabetes mellitus. In 2001, the Brazilian Ministry of Health conducted a national diabetes screening campaign. The purpose of this study was to estimate the yield and economic impact of this screening strategy.
Based on positive screenees (fasting glucose >100 mg/dL or nonfasting >140 mg/dL) probable new cases of diabetes were estimated and a decision analytic model was built up. Primary and secondary data were used to estimate screening cost (in Brazilian Reais, R89. The results were sensitive to percentage of confirmatory tests performed.
The costs of nationwide community screening in Brazil were significant, however, in absolute terms lower than those described by other countries.
Einfluß von Fluorid auf die Insulin-Sekretion bei Ratten
Natriumfuorid (CAS 7681-49-4) in Konzentrationen von 5–20 µmol/L im extrazelullären Raum hemmt die InsulinSekretion in isolierten, mit Glukose stimulierten Langerhansschen Inseln. Das Phänomen ist reversibel, die Insulin-Sekretion folgt einer negativen Exponentialfunktion der Fluorid-Konzentration.
Die Perfusion des pankreatischen Gewebes der Ratte in vivo mit Glukose-Konzentrationen, die die Insulin-Sekretion stimulieren, zeigte, daß Fluorid in einer Konzentration von 20 µmol/L in der Perfusionsflüssigkeit die anfängliche und die länger dauernde Phase der Insulin-Sekretion im Vergleich zur Kontrolle um 15 % hemmt.
Die stimulierende Wirkung von Ionophor A23187, Phorbol-Ester und Forskolin auf die Insulin-Sekretion in isolierten Langerhansschen Inseln der Ratte wurden durch 20 µmol/L Fluorid gehemmt. Diese Ergebnisse legen nahe, daß Fluorid Phasen der Insulin-Sekretion affiziert, die in der Kaskade unterhalb der Beteiligung von Calmodulin, Protein-Kinase C und zyklischem AMP liegen.
Chocolate bars and chocolate cookies are foodstuffs highly appreciated by children. The possibility of having fluorine (F) among their components, associated with an excessive consumption, may make them decisive contributors to the total daily F intake. Thus, they could participate in the establishment of dental fluorosis. The aim of this study was to analyze the fluorine concentration [F] of the chocolates bars (CB) Baton, Confeti, Garoto Ball, Kinder Ovo, M&M s, Milkybar, Nescau, Nescau Ball, Surpresa, Surpresa Bichos, Tortuguita; and of the chocolate cookies (CC) Danyt s, Hipop , Nescau, Passatempo, Pokémon, S tio do Pica-Pau Amarelo and Trakinas. Samples were purchased in Bauru, São Paulo, Brazil. Three grams of each product were previously ashed at 525 C (CB and cookies fillings) and at 550 C (cookies dough), during 4 hours. Fluorine was separated from the ash by hexamethyldisiloxane (HMDS)-facilitated diffusion. Fluorine analysis was carried out with the specific electrode. Mean [F]s SD and amplitude (unit mg/g) were: CB = 0.30 0.45 (0.07 - 1.60, n = 12) and CC = 1.08 2.64 (0.04 - 7.10, n = 7). It was concluded that some of the analyzed foods may be important contributors to the total daily F intake. As for the product that had the highest [F] (Danyt s), when only 3 units are consumed just once a day, they may supply up to 40% of the maximum recommended daily F intake (0.07 mg/kg body weight) for a 2-year-old child (12 kg). The [F] in these products should be informed on their labels.
Certain liver metabolic diseases point to the presence of disturbances in glycogen deposition. Epinephrine raises the cAMP level that activates protein kinase A leading to the activation of phosphorylase and glycogen breakdown. In the present report, we sought to investigate whether NO is produced during adrenoceptor agonist-induced glycogenolysis in rat hepatocytes in cultures. Isolated glycogen rich rat hepatocytes in cultures were used. NO production (NO(2)(-)) was assessed under the effect of adrenergic agonists and adrenergic agonist/antagonist pairs, dibutyryl cyclic AMP sodium-potassium salt (db-cAMP), NO synthase (NOS) inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and the NO donor S-nitroso-N-acetyl penicillamine (SNAP). The inducible NO synthase (iNOS) mRNA was examined by the reverse transcription-polymerase chain reaction (RT-PCR). Glycogenolysis was quantified by glucose levels released into medium. The amount of glucose and NO(2)(-) released by hepatocytes was increased as a result of epinephrine, phenylephrine or db-cAMP treatments. The increase in glucose and NO(2)(-) released by epinephrine or phenylephrine was blocked or reduced by prazosin pretreatment and by NOS inhibitors aminoguanidine and L-NAME. iNOS gene expression was up-regulated by epinephrine. It can be concluded that glycogenolysis occurs through -adrenoceptor stimulation and a signaling cascade may involve NO production.
Eight 14-week-old male Wistar FL strain rats were administered sodium fluoride in a single intraperitoneal dose (35 mg NaF/kg of bw). After 90 min the rats were fatally anesthetized with ether, and blood samples were taken. Compared to ten control rats, fluoride-treated rats developed hyperglycemia accompanied by a statistically significant increase in the concentration of fluoride, creatinine, and urea and a decrease in the level of protein and calcium in the blood serum. The results indicate disturbances in the filtrating function of kidneys in rats.
Endemic fluorosis is a condition resulting from prolonged ingestion of drinking water which contains excess fluoride. Studies on rats have suggested that fluoride toxicity may produce glucose intolerance and abnormalities in insulin secretion. We studied glucose and insulin profiles following an oral glucose load in patients with endemic fluorosis. Twenty-five young adults (age range, 15–30 years) with endemic fluorosis, and an equal number of matched healthy control subjects with normal fluoride intake were studied. Impaired glucose tolerance was demonstrated in 10 of 25 (40%) patients with endemic fluorosis. Patients with impaired glucose tolerance had significantly higher fasting serum immunoreactive insulin (p<0.05), higher fasting serum fluoride (p<0.001), and a significantly lower fasting glucose to insulin ratio than that in patients with normal glucose tolerance (p<0.001) or control subjects (p<0.05). The fasting serum fluoride levels correlated positively with the area under the glucose curve (r=0.80,p<0.01) in patients with impaired glucose tolerance. Interestingly these abnormalities could be reversed when the village was provided drinking water with fluoride levels within acceptable limits. The present study shows that chronic fluoride toxicity in humans could result in significant abnormalities in glucose tolerance which are reversible upon removal of the excess fluoride.
Glucose intolerance in fluorosis areas and when fluoride is administered for the treatment of osteoporosis has been reported. Controlled fluoridation of drinking water is regarded as a safe and effective measure to control dental caries. However, the effect on glucose homeostasis was not studied so far. The aim of this study was to evaluate the effect of the intake of fluoridated water supply on glucose metabolism in rats with normal and deficient renal function. Male Sprague-Dawley rats were divided into eight groups of four rats. Renal insufficiency was induced in four groups (NX) which received drinking water containing 0, 1, 5, and 15 ppm F (NaF) for 60 days. Four groups with simulated surgery acted as controls. There were no differences in plasma glucose concentration after a glucose tolerance test between controls and NX rats and among rats with different intakes of fluoride. However, plasma insulin level increased as a function of fluoride concentration in drinking water, both in controls and in NX rats. It is concluded that the consumption of fluoridated water from water supply did not affect plasma glucose levels even in cases of animals with renal disease. However, a resistance to insulin action was demonstrated.
The effect of milk products on the gastrointestinal absorption of fluoride from sodium fluoride tablets was studied in five healthy subjects. Two different diets were tested: (1) 250 ml standardized milk (3% fat) and (2) 500 ml of milk, 3 pieces of white bread with cheese and 150 ml of yoghurt. The 100% bioavailability of sodium fluoride tablets during fasting was greatly decreased by coadministration of milk products: with Diet 1 the absolute bioavailability calculated from combined plasma and urine data was in the range 50--79% and with Diet 2 it ranged from 50--71%. It is suggested that the decreased bioavailability produced by dairy products should be taken into account when establishing flouride dosage regimens for prophylaxis of caries.
Acute fluoride toxicity in the rat is accompanied by a marked hyperglycemia, the magnitude of which is dose-dependent. Muscle and liver glycogen contribute to the increased blood glucose, but no direct effect of fluoride on liver glycogen phosphorylase was detected. Adrenalectomy prevented the fluoride response and plasma epinephrine assays (intact animals) revealed a fourto fivefold rise after fluoride treatment. Fluoride-induced hyperglycemia thus appears to be mediated by epinephrine secreted by the adrenal medulla.
Intravenous infusion of 6 mg of fluoride/kg/hr for 3 hr caused a sharp decrease in formation of respiratory 14CO2 from [14C]glucose, regardless of position of the label. Oxidation of [1-14C]fructose was not impaired, indicating that triose metabolism was not hindered; this information, along with the similarity in depression of metabolism of all labels indicated that glycolysis was not impaired. Glycogen deposition was decreased. The data suggest that the interference caused by fluoride at the observed concentrations is located at or prior to phosphorylation of glucose.
Fluorosis prevalence has increased in North America since the 1930's-1940's. It may also have increased since 1970, though the evidence for that is less clear. Continued monitoring will help determine whether increased fluorosis prevalence in children in the United States is a cohort effect from the 1970's. This review considers the evidence for an increase in fluoride ingestion from all sources since the 1970's. If an increase has occurred, the most likely sources are fluoride dietary supplements, inadvertent swallowing of fluoride toothpastes, and increased fluoride in food and beverages. For adults, there is no evidence from dietary surveys to show that fluoride intake has increased over the last generation. Dietary surveys for children aged six months to two years are similarly inconclusive, though the great variation in fluoride content of various infant foods might be obscuring real effects. The data on fluoride intake by children from food and beverages, infant foods included, are not strong enough to conclude that an increase in fluoride ingestion has occurred since the 1970's. However, the suggested upper limit of fluoride intake is substantially being reached in many children by ingestion of fluoride from food and drink (0.2-0.3 mg per day) and from fluoride toothpaste (0.2-0.3 mg per day). Two public health issues that arise from this review are: (a) the need for a downward revision in the schedule for fluoride supplementation, and (b) education on the potential for high fluoride concentration of soft drinks and processed fruit juices.
The oral administration of sodium fluoride (NaF) (40 mumol/100 body weight [bw]) to fasting rats produced an immediate fall in insulin levels and the consequent increase in glycemia. These phenomena were observed with plasma fluoride concentrations 5-15 microM. Glycemia and insulin returned to normal levels within 4-5 hours, together with the washing out of fluoride from plasma and soft tissues. The insulin secretion of isolated Langerhans islets, perifused with solutions containing 5, 10, or 20 microM fluoride, was found to be significantly inhibited as a function of fluoride levels, both with basal and stimulatory concentrations of glucose. One hour after the intake of 60 mg of NaF, fasting human volunteers showed increased fluoride (5-15 microM) together with a significant fall of plasma insulin levels.
The metabolism and toxicity of fluoride are discussed with emphasis on new scientific findings. The gastric absorption, tissue distribution, and renal excretion of the ion are all influenced by the magnitude and direction of the pH gradient between adjacent body fluid compartments. This mechanism explains the asymmetric distribution of fluoride across cell membranes, and the manipulation of transmembrane pH gradients has proven efficacious in acute fluoride toxicity. The comparative metabolism and relative toxicities of ionic fluoride and monofluorophosphate are discussed. It is no longer certain that there is a difference between the acute toxic potentials of sodium fluoride and those of MFP. It is concluded that the "probably toxic dose" or PTD of fluoride--the dose which should trigger therapeutic intervention and hospitalization--is 5 mg/kg of body weight. As currently packaged, many dental products contain sufficient fluoride to exceed the PTD for young children. There is a need for additional research into the sources, effects, and fate of strongly bound or organic fluoride compounds. Attention is drawn to the fact that, while the metabolic characteristics and effects of fluoride in young and middle-aged adults have received considerable research attention, there is a paucity of such information for young children and the elderly. The increasing prevalence of dental fluorosis is addressed. It is concluded that nondietary sources of fluoride, mainly fluoride-containing dental products, are a major source of ingested fluoride. The article concludes with 12 recommendations for future research.
This investigation demonstrates that intraperitoneal injections of NaF (15 mg F/kg) results in hyperglycemia, inhibition of glycolysis, and an increase in tissue cAMP concentrations. Sodium fluoride significantly increases the cAMP concentration in liver, submaxillary gland, lung, heart, and kidney within 60 minutes following the injection.
Plasma fluoride (F) concentration and urinary F excretion were studied in 8 children and 5 adults following topical application of three different types of F gel, (Luride® 1.23% F, Gel II® 1.23% F, Fluor gel 0.1% F). The amount of F gel applied to each child was 3.33 ± 0.05 g (mean ± SD). The amount of F ingested was 31.2 ± 6.4 mg. The fraction of ingested F not recovered in the urine was 26.4 ± 4.2 mg. After 1 h the plasma F concentration in the children ranged from 300 to 1,443 ng/ml (16–76 μM/l) and remained high after 2h. The adults received 5 g gel (61.5 mg F) resulting in plasma F levels ranging from 300 to 950 ng/ml (16–50 μM/l). When individual trays were used, the plasma F concentration never exceeded 230 ng/ml (12 μM/l). The bioavailability of F from one F gel was tested in 1 subject and found to be complete. The results show that topical application of 1.23% F gels may result in plasma F levels high enough to cause a decrease in urinary concentration ability. Consequently, F gels with a high F concentration should not be used excessively and not be encouraged as home care treatment especially in children.Copyright © 1981 S. Karger AG, Basel
Cultured human lymphocytes and rat hepatoma cells were labeled with [32P]orthophosphate and the insulin receptor subunits identified by immunoprecipitation and sodium dodecyl sulfate-gel electrophoreses. In both cell types the 95,000-dalton (beta) subunit of the insulin receptor was selectively phosphorylated. Phosphorylation was specifically stimulated by insulin in a dose-dependent fashion after 1 and 15 minutes of hormone treatment, whereas human growth hormone was without effect. This phosphorylation may be a very early event in insulin action.
Acute exposure of rats to strontium or fluoride by i.p. injection of sodium fluoride or strontium chloride resulted in a systemic response in which changes occurred in the plasma electrolytes and metabolites. Strontium resulted in a rapid but temporary hypercalcaemia while fluoride produced a temporary hypocalcaemia. There was no significant hypophosphataemia after fluoride and only a transient hypophosphataemia with strontium. There was some indication of kidney damage and a general stress response following fluoride injection. These results do not support the hypothesis that interglobular dentine is associated with hypophosphataemia or hypoplastic enamel with hypocalcaemia and are in conflict with the observation that the formation of interglobular dentine following the injection of lead acetate is associated with hyperphosphataemia and hypercalcaemia.
The effect of acute and chronic administration of sodium fluoride (NaF) or sodium monofluorophosphate (MFP) on the glucose homeostasis of the rat are compared. The oral administration of a single dose of 40 mumol/100 g b.w. of either compound produced similar increases in plasma glucose (up to 1.8 g/l) and diffusible fluoride (up to 130 mumol/l). In long-term experiments (three months of duration), treatment with NaF (a 5 mmol/l solution as the water supply) produced, in the first month of experiment, abnormal glucose tolerance tests and increased plasma diffusible fluoride levels (range: 2-12 mumol/l). Treatment with MFP, on the other hand, did not affect glucose homeostasis; plasma diffusible fluoride was always below 2 mumol/l. The results of these experiments indicate that glucose homeostasis is affected when plasma diffusible fluoride exceeds 5 mumol/l. The basal and glucose-stimulated insulin secretion of isolated Langerhans rat islets (incubated with solutions containing 2, 5, 10 and 20 mumol/l NaF) was significantly inhibited by 5 to 20 mumol/l fluoride. No effect was observed under similar conditions with MFP at concentrations of 2, 5, 10, 20 and 50 mumol/l.
Aluminum, responsible of dialysis encephalopathy, is suspected to be involved in other neurological disorders such as Alzheimer disease. Absorption of aluminum from the digestive tract can be enhanced by the concommittant intake of substances such as citrate. We studied in rats and mice the interactions between fluoride and aluminum for their digestive absorption and showed that fluoride increased the levels of aluminum in plasma as much as citrate whereas aluminum decreased the absorption of fluoride. This result could be the consequence of the high affinity between aluminum and fluoride which form complexes able to increase the absorption of aluminum and to decrease the absorption of fluoride.
We have recently reported that fluoride interacts directly with the insulin receptor, which causes inhibition of its phosphotransferase activity. The inhibitory effect of fluoride on phosphotransferase activity is not due to the formation of complexes with aluminium and occurs in the absence of alterations to the binding of ATP or insulin. In this report we substantiate that the tyrosine kinase activity of insulin receptors partially purified from rat skeletal muscle shows a strict requirement of Mg2+ ions (Ka near 11 mM). This effect of Mg2+ was inhibited in a competitive manner by Mn2+, which is compatible with competition of both divalent ions for binding sites. The inhibition of tyrosine kinase activity caused by fluoride was dependent on the concentration of Mg2+ in the medium and no inhibitory effect was detected at low concentrations of Mg2+. Moreover, the addition of increasing concentrations of Mn2+ in the presence of a constant high concentration of Mg2+, led to a gradual decrease in the inhibitory effect of fluoride. These results indicate that the Mg-insulin receptor complex is the major fluoride-susceptible form. Based on the characteristics of the inhibition of tyrosine kinase shown by fluoride it might be proposed that its action is exerted by the formation of multi-ionic MgF complexes analogous to Pi, which bind to the insulin receptor kinase.
This paper reports metabolic data of 24 women and two men, 44-66 years old, ex-residents in an area of endemic fluorosis close to Bahía Blanca city. Fasting fluoremias of these subjects (0.5 to 9.2 microM) and daily urinary fluoride excretion (> 60 mumoles/day) are characteristics of zones with endemic fluorosis. Bone mineral density (BMD) at the lumbar spine (L2-4 1330 +/- 41 mg/cm2) and femoral neck (1045 +/- 10 mg/cm2) were significantly above average of normal subjects of the same age and sex. A significant correlation was observed between the daily excretion of fluoride and BMD L2-4 (r = 0.43, P < 0.05). The Area Under the Curve of insulin during a standard glucose tolerance test showed an inverse relationship with fluoremia. This observation coincides with experiments published elsewhere indicating that fluoride intake at concentrations 5 microM or greater, inhibits the secretion of insulin.
This paper compares fluoride pharmacokinetics (plasma, renal, and extrarenal clearances) and metabolic balances in healthy infants or children with those in young or middle-aged adults. Regardless of age, the removal of fluoride from the intra- and extracellular body fluids occurs almost exclusively by uptake in calcified tissues and excretion in the urine. While there can be considerable differences among individuals, the rates at which fluoride is cleared from plasma by calcified tissues and the kidneys in adults are approximately equal. The calcified tissue clearance of fluoride from plasma in children is substantially higher than that by the kidneys. This is due to the greater surface area of the loosely organized crystallites in the developing calcified tissues during growth. Thus, the balance of fluoride (total intake minus total excretion) is typically higher in children than in adults, but it can be positive or negative at any age. Positive balance occurs when chronic fluoride intake is sufficient to prevent plasma concentrations from declining. When positive, the fluoride content of the calcified tissues, which contain more than 99 percent of the body's fluoride, tends to gradually increase. Negative balance, which indicates net mobilization of fluoride from calcified tissues, can occur when plasma concentrations decline due to a reduction in the level of fluoride intake.
Intestinale Resorption von Fluorid beihoher Fluorid Konzentration im DarmLumen
In der vorliegenden Arbeit wird darüber berichtet, daßhohe Fluorid Konzentrationen im DarmLumen die Resorption dieses Anions behindern. Diese Schlußfolgerung wurde anhand von drei verschiedenen Versuchsmodellen verifiziert.
Pharmakokinetische Untersuchungen bei menschlichen Probanden ergaben, daß die Bioverfügbarkeit von Fluorid aus Natriumfluorid (NaF, CAS 7681-49-4) in Form von magensaftresistenten Tabletten 33 % von der Bioverfügbarkeit bei normalen (sofortlöslichen) Tabletten betrug.
Diese Ergebnisse wurden im Tierver-such mit Ratten bestätigt, die 1 ml NaF-Lösung (40, 80 oder 160 mmol) über eine Sonde erhielten. Die größte AUC (Fläche unter der Kurve der Fluorämie als Funktion der Zeit) wurde bei oraler Verabrei -chungvon 80 µmol NaF erzielt. Dieser Parameter war bei 80 µmol NaF signifikant größer (p < 0,01) als bei 40 µmol, aber ähnlich wie bei 160 µmol. Die Fluorid Ausscheidung in den Fäzes (innerhalb von 24 h nach einmaliger Gabe von NaF) under Fluoridgehalt in den Knochen (nach 30tägiger Behandlung mit 40, 80 oder 160 µmol NaF/Tag) entsprachen den AUC- Werten.
Die Geschwindigkeit der Fluorid Resorption (v, µmol/10 min) durch die Darmwand wurde anhand von perfundiertem isoliertem Ratten Duodenum in vivo untersucht. Die Fluorid Resorption nahm bei 0 bis 10 mmol Fluorid im Lumen zu und ging bei höheren Konzentrationen zurück.
Der Sauerstoffverbrauch des Duodenalgewebes nahm zwischen 0 mmol (1,12 µmol 02 min⁻¹ g⁻¹) und 10 mmol Fluorid (0,45 µmol O2 min⁻¹ g⁻¹) exponentiell ab.
Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents.
All subjects underwent a two-hour oral glucose-tolerance test (1.75 g [DOSAGE ERROR CORRECTED] of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose.
Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance.
Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.
Fluoride toothpastes are a risk factor for the development of dental fluorosis. Products with low fluoride content offer a higher security, but their effectiveness must be proven. The aim of this in vitro study was to compare two acidified toothpastes with low fluoride concentration (412 and 550 microg F/g) with neutral toothpastes. Bovine enamel blocks were selected by surface microhardness (SMH) and randomized to twelve groups of 13, according to the fluoride concentration in toothpaste (placebo, 275, 412, 550 or 1,100 microg F/g) and pH (7.0 or 5.5). Two commercially available toothpastes were also studied: a 1,100-microg F/g, pH 7.0 paste (positive control) and a children's paste (500 microg F/g, pH 7.0). The blocks were subjected to pH cycling for 7 days. The toothpaste treatment was done twice daily. Surface and cross-sectional microhardnesses were assessed to calculate the percentage change of SMH (%SMH) and the mineral loss (DeltaZ). The amount of fluoride, calcium and phosphorus in the solutions after the pH cycling was also analyzed. Compared to neutral toothpastes, the acidified toothpastes reduced the %SMH in all F concentrations. Higher F and lower Ca and P concentrations were found in solutions for the acidified toothpastes. Regarding DeltaZ, only the positive control, 1,100-microg F/g (acidified and neutral) groups were not statistically different. The acidified toothpastes showed a dose-response relationship with all variables. For the low-fluoride toothpastes evaluated, only the 550-microg F/g acidified paste had the same anticariogenic action as the 1,100-microg F/g neutral paste.
This study evaluated the effectiveness of acidic low-fluoride dentifrices compared to conventional neutral dentifrices. Enamel blocks were submitted to pH cycling and treatment with slurries of dentifrices containing 0, 275, 412, 550 and 1,100 microg F/g (pH 4.5 or 7.0), and also a commercial dentifrice (1,100 microg F/g) and a commercial children's dentifrice (500 mug F/g). Variations in surface microhardness and in the mineral content in enamel after pH cycling were calculated. Enamel blocks treated with acidic dentifrices exhibited less mineral loss compared to neutral dentifrices (ANOVA; p < 0.05). The acidic dentifrices with 412 and 550 microg F/g had the same effectiveness as the neutral 1,100-microg F/g dentifrice and commercial 1,100-microg F/g dentifrice.