Mercedes Lombarte

Physical exercise ameliorates the toxic effect of fluoride on the insulin–glucose system

Daily intake of water with fluoride concentrations >1.5 mg/l produces insulin resistance (IR). On the other hand, physical activity increases insulin sensitivity in the muscle. Therefore, the aim of this study was to evaluate the effect of physical activity on IR in rats treated with sodium fluoride (NaF) in drinking water. Sprague-Dawley rats were divided into three groups (n=10/group): Control (drinking water without NaF), NaF (drinking water with NaF 15 mg/l for 30 days), and Exercise (daily running on a treadmill for 60 min at 2.25 m/min and drinking water with NaF 15 mg/l for 30 days). IR was evaluated with the homeostasis model assessment-IR (HOMA-IR) index using fasting plasma levels of glucose and insulin. IR increased in rats treated with 15 mg/l NaF in drinking water. A decrease in IR was observed in rats that performed physical activity and drank water with 15 mg/l NaF; the Exercise group also showed an increase in the amounts of bone fluoride. The variation in the HOMA-IR values could be the consequence of variation in the sensitivity of tissues to insulin or decrease in plasma fluoride levels due to bone fluoride intake. These findings indicate that the performance of daily physical activity could reduce the negative effects of the chronic ingestion of NaF on glucose homeostasis.

Fluoride increases superoxide production and impairs the respiratory chain in ROS 17/2.8 osteoblastic cells.

It is known that fluoride produces oxidative stress. Inflammation in bone tissue and an impairment of the respiratory chain of liver have been described in treatments with fluoride. Whether the impairment of the respiratory chain and oxidative stress are related is not known. The aim of this work was to study the effects of fluoride on the production of superoxide radical, the function of the respiratory chain and the increase in oxidative stress in ROS 17/2.8 osteoblastic cells. We measured the effect of fluoride (100 µM) on superoxide production, oxygen consumption, lipid peroxidation and antioxidant enzymes activities of cultured cells following the treatment with fluoride. Fluoride decreased oxygen consumption and increased superoxide production immediately after its addition. Furthermore, chronic treatment with fluoride increased oxidative stress status in osteoblastic cells. These results indicate that fluoride could damage bone tissue by inhibiting the respiratory chain, increasing the production of superoxide radicals and thus of the others reactive oxygen species.

Extended adaptive predictive controller with robust filter to enhance blood glucose regulation in type I diabetic subjects

Abstract In this paper, an improved adaptive predictive control with robust filter is developed to be applied in an artificial pancreas. Several problems inherent to endocrine systems for diabetic persons have to be tackled such as nonlinearities, long time delays or daily variations of parameters. Three Finite Impulse Response models for insulin input and the same for meal intake (perturbations) corresponding to normal, hyper-hypoglycaemia levels to implement three zones control are taken into account. The glycaemia reference trajectory is shaped from a healthy person response. A variable weighting factor in the cost function is included to prevent dangerous glycaemia excursions out of the allowed limits. Additionally, a noisy blood glucose subcutaneous sensor model is used. This control strategy is tested on 30 virtual subjects from the UVa – Padova Simulator. Simultaneous meals and physiological disturbances are taken into account and the main conclusions are drawn from Control Variability Grid Analysis.

Mathematical model of glucose-insulin homeostasis in healthy rats

According to the World Health Organization there are over 220 million people in the world with diabetes and 3.4 million people died in 2004 as a consequence of this pathology. Development of an artificial pancreas would allow to restore control of blood glucose by coupling an infusion pump to a continuous glucose sensor in the blood. The design of such a device requires the development and application of mathematical models which represent the gluco-regulatory system. Models developed by other research groups describe very well the gluco-regulatory system but have a large number of mathematical equations and require complex methodologies for the estimation of its parameters. In this work we propose a mathematical model to study the homeostasis of glucose and insulin in healthy rats. The proposed model consists of three differential equations and 8 parameters that describe the variation of: blood glucose concentration, blood insulin concentration and amount of glucose in the intestine. All parameters were obtained by setting functions to the values of glucose and insulin in blood obtained after oral glucose administration. In vivo and in silico validations were performed. Additionally, a qualitative analysis has been done to verify the aforementioned model. We have shown that this model has a single, biologically consistent equilibrium point. This model is a first step in the development of a mathematical model for the type I diabetic rat.

Regulation of intestinal calcium absorption by luminal calcium content: Role of intestinal alkaline phosphatase

SCOPE Intestinal alkaline phosphatase is a brush border enzyme that is stimulated by calcium. Inhibition of intestinal alkaline phosphatase increases intestinal calcium absorption. We hypothesized that intestinal alkaline phosphatase acts as a minute-to-minute regulatory mechanism of calcium entry. The aim of this study was to evaluate the mechanism by which intestinal luminal calcium controls intestinal calcium absorption. METHODS AND RESULTS We performed kinetic studies with purified intestinal alkaline phosphatase and everted duodenal sacs and showed that intestinal alkaline phosphatase modifies the luminal pH as a function of enzyme concentration and calcium luminal content. A decrease in pH occurred simultaneously with a decrease in calcium absorption. The inhibition of intestinal alkaline phosphatase by l-phenylalanine caused an increase in calcium absorption. This effect was also confirmed in calcium uptake experiments with isolated duodenal cells. CONCLUSION Changes in luminal pH arising from intestinal alkaline phosphatase activity induced by luminal calcium concentration modulate intestinal calcium absorption.

Comparison of fluoride effects on germination and growth of Zea mays, Glycine max and Sorghum vulgare.

BACKGROUND Fluorosis is a disease caused by over-exposure to fluoride (F). Argentinas rural lands have higher fluorine content than urban lands. Evidence confirms that plants grown in fluoridated areas could have higher F content. We compared F uptake and growth of crops grown in different F concentrations. The effect of 0-8 ppm F concentrations on maize, soybeans and sorghum germination and growth was compared. After 6 days seeding, the germination was determined, the roots and aerial parts lengths were measured, and vigor index was calculated. F content was measured in each part of the plants. Controls with equal concentrations of NaCl were carried out. RESULTS Significant decrease in roots and aerial parts lengths, and in vigor index of maize and soybeans plants was observed with F concentrations greater than 2 ppm. This was not observed in sorghum seedlings. Also, the amount of F in all crops augmented as F increases, being higher in roots and ungerminated seeds. Sorghum was the crop with the highest F content. CONCLUSION Fluoride decreased the germination and growth of maize and soybeans and therefore could influence on their production. Conversely, sorghum seems to be resistant to the action of F.

A rat–human scale-up procedure for the endocrine system

Abstract The main contribution of this work is to present a detailed scale-up procedure between human and rats models to more accurately predict what would happen in human beings, based on the experimental results obtained from rats. This procedure begins using the human model, given by Sorensen (1985) . The proposed scale-up technique required to establish some assumptions, to do an intensive search in the literature about organs volumes and flow rates of body rats and a dedicated experimental work in the laboratory with these animals. Even though it is mainly focused on studying the endocrine system behavior to obtain a proper in in silico healthy rat it can be extended to study another body regions. Several simulation results with the obtained rat model are included and confronted with experimental data of ten healthy rats. The analogy between human and rat dynamic behavior after equivalent meal intakes are also discussed.

CHAPTER 17:Effect of Fluoride on the Sensitivity and Secretion of Insulin

Fluoride has been used in the treatment of osteoporosis and in the prevention of dental caries. However, excessive fluoride intake causes significant systemic alterations in animals and human beings. In this chapter disturbances induced in glucose homeostasis are discussed: hyperglycemia, impaired glucose tolerance and modification of metabolic pathways of glucose and glycogen. These changes are the consequence of an inhibition of insulin secretion and/or a reduction in insulin sensitivity.

Scaling the Endocrine System from Rats to Humans

Abstract As a common laboratory practice rats are studied as biological models for understanding several human’s diseases. This work is focused on studying the endocrine behavior to obtain a proper in silico healthy and diabetic rat which would be able to compare well with the experimental data. After this, the expectations are to get valuable insight to quantify the analogies with humans and to determine a realistic scale-up between both, humans and rats. With this purpose the scale-up procedure proposed in Hall et al. [2012] is taken into account. In this context, the well-known model of healthy subject given by Sorensen [1985] was proper to implement the scale-up methodology. Therefore, the main contribution of this work is to present the preliminary procedure of the scale-up focused on the specific problem of diabetes Mellitus. An intensive search in the literature had to be done to perform the simulations. Hence, several results are included and confronted with experimental data. These results will be useful to the pre-clinical testing of control algorithms with rats to be extrapolated to human beings.

In vivo measurement of the rate constant of liver handling of glucose and glucose uptake by insulin-dependent tissues, using a mathematical model for glucose homeostasis in diabetic rats

Diabetes mellitus is a disease that affects glucose homeostasis. The World Health Organization informs that there are over 347 million people in the world with diabetes. The diagnosis and characterization of glucose homeostasis in different metabolic conditions are subjects of great importance with high clinical impact. There are many mathematical models that describe the glucoregulatory system in detail. However, the use of these models is limited because they have a large number of mathematical equations and parameters and they require complex methodologies to estimate of them. This forced to work with average values that decrease the validity of results and the applicability of the models. In this study two mathematical models for rats with diabetes mellitus were developed. The difference between these models and others lies in the possibility of obtaining all parameters for each animal from simple measurements (glucose and insulin plasma levels). Moreover, the models allow to measure in vivo the different physiological processes involved in glucose homeostasis in animals: insulin secretion and its plasma clearance, absorption of insulin from a subcutaneous injection, the liver handling of glucose, intestine absorption of glucose, glucose uptake rate of insulin-independent tissues, glucose uptake rate of insulin-dependent tissues, and renal glucose excretion.