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Therapeutic effect of rosiglitazone has been reported to result from an improvement of insulin sensitivity and inhibition of glucose synthesis. As the latter process occurs in both liver and kidney cortex the aim of this study was to elucidate the rosiglitazone action on glucose formation in both tissues. Primary cultured cells of both liver and kidney cortex grown in defined medium were use throughout. To identify the mechanism responsible for drug-induced changes, intracellular gluconeogenic intermediates and enzyme activities were determined. In contrast to hepatocytes, the administration of a 10 mmol/L concentration of rosiglitazone to renal tubules resulted in about a 70% decrease in the rate of gluconeogenesis, accompanied by an ~75% decrease in alanine utilization and a 35% increase in lactate synthesis. The effect of rosiglitazone was not abolished by GW9662, the PPAR-γ irreversible antagonist, indicating that this action is not dependent on PPAR-γ activation. In view of rosiglitazone-induced changes in gluconeogenic intermediates and a diminished incorporation of [sup.14][CO.sub.2] into pyruvate, it is likely that the drug causes a decline in flux through pyruvate carboxylase and (or) phosphoenolpyruvate carboxykinase. It is likely that the hypoglycemic action of rosiglitazone is PPAR-γ independent and results mainly from its inhibitory effects on renal gluconeogenesis. Key words: diabetes, rosiglitazone, glucose synthesis, PPAR-γ, primary cultures. L'effet therapeutique de la rosiglitazone semble resulter d'une amelioration de la sensibilite a l'insuline et de l'inhibition de la synthese de glucose. Puisque ce dernier processus se produit dans le foie et le cortex renal, le but de cette etude etait d'elucider l'action de la rosiglitazone sur la formation de glucose dans ces deux tissus. Des cultures primaires de foie et de cellules du cortex renal cultivees dans un milieu defini ont ete utilisees pour toutes les experiences. Afin d'identifier le mecanisme responsable des changements induits par le medicament, les intermediaires intracellulaires et l'activite des enzymes de la neoglucogenese ont ete determines. Contrairement aux hepatocytes, l'administration de 10 mmol/L de rosiglitazone aux tubules renaux a resulte en une diminution d'environ 70 % du taux de neoglucogenese, accompagne e par une diminution de 75 % de l'utilisation de l'alanine et d'une augmentation de 35 % de la synthese du lactate. L'effet de la rosiglitazone n'etait pas aboli par le GW9662, un antagoniste reversible du PPAR-γ, indiquant que cette action etait independante de l'activation du PPAR-γ. Considerant les changements induits par la rosiglitazone chez les interme diaires de la neoglucogenese et la diminution de l'incorporation de [sup.14][CO.sub.2] dans le pyruvate, il est probable que le medicament cause un declin du flux via la pyruvate carboxylase et (ou) la phosphoenolpyruvate carboxykinase. Il est aussi probable que l'action hypoglycemiante de la rosiglitazone soit independante du PPAR-γ et qu'elle resulte principalement de ses effets inhibiteurs de le neoglucogenese renale. Mots-cles : diabete, rosiglitazone, synthese de glucose, PPAR-γ, cultures primaires. [Traduit par la Redaction], Introduction Diabetic hyperglycemia results from β-cell dysfunction, insulin resistance of the liver and peripheral tissues, including skeletal muscle and adipose tissue, and glucose overproduction because of an acceleration of gluconeogenesis [...]

For many years the spectrum of gluten-related disorders had been limited only to celiac disease and its typical gastrointestinal symptoms. In the last few years, not only new disorders like non-celiac gluten sensitivity have been described, but also pathogeneses of celiac disease and wheat allergy have been better understood. It is also known that impaired gluten tolerance in many cases leads to appearance of extraintestinal symptoms that may affect any organ or system of the human body including the nervous system that may be the cause of some neurological disorders such as ataxia, neuropathy, autism spectrum disorder (ASD) or schizophrenia. In this paper we present the spectrum of neurological disorders, whose pathogeneses may depend on gluten ingestion and some proposed mechanisms elucidating those pathogeneses. [ABSTRACT FROM AUTHOR]

In developed countries, we can observe an increasing number of people with obesity, type 2 diabetes, dyslipidemia, hypertension and arteriosclerosis. The main reason for this phenomenon is the abnormal energy balance due to sedentary lifestyles. Cardiovascular diseases are the leading cause of death in many countries around the world, nowadays. In this paper, the impact of physical activity on the effectiveness of treatment and prevention of metabolic diseases and cancer is considered. Exercise is one of the factors activating 5'AMP-activated protein kinase (AMPK). This enzyme is crucial in maintaining the energy balance of the cell and the entire organism, and its activation results in excluding the anabolic and switching on the catabolic processes. It is believed that the activation of AMPK is responsible for most of the positive effects resulting from physical exercise. Although there are pharmacological methods of activation of this enzyme, they seem to be not as effective as physical exercise. Therefore, physical activity should be the most important form of prevention and treatment of metabolic diseases. [ABSTRACT FROM AUTHOR]

Aging is one of the most extensively studied biological process and yet still some of its aspects remain elusive. It appears that AMP - activated protein kinase (AMPK) plays an important role in many processes of aging, but this fact is often neglected in the studies on aging. This work summarizes the information about AMPK participation in the aging process. AMPK participation in the regulation of aging was indicated in the mechanisms dependent on: caloric restriction, mTOR, p53, sirtuins, autophagy, inflammation and the effects caused by polyphenols.

A novel function of ATP as a signal molecule was described nearly 50 years ago. Since then many receptors that could be activated via ATP, ADP, UTP, UDP and adenozine binding were discovered. The mechanism of signal transduction as well as quite complicated regulation of changes of extracellular nucleotides concentration is currently studied. Purinergic signaling in blood vessels is mostly engaged in vascular tone regulation thus maintaining proper blood pressure. ATP coreleased with noradrenaline from perivascular sympathetic nerves cause vasoconstriction whereas ATP in blood vessel lumen stimulate endothelial cells to release endothelium derived relaxing factor. Nucleotides and nucleosides contributes also to growth and differention of new blood vessels. Changes in purinergic signaling is commonly observed in cardiovascular diseases that plague our times, that is why nucleotide receptors seems to be good pharmacological target.

Glucose is one of the most important sources of energy in human metabolizm. Cells absorb it by active transport (with SGLT transporters) or by facilitated diffusion (with GLUT transporters). GLUT family consists of 14 proteins grouped in 3 subclasses based on similarities in their architecture. They differ from one another in affinity to glucose, tissue distribution and type of signals that cause their translocaton to the cell membrane what results in different levels of sugar transport into the tissues. SGLT proteins cotransport glucose with Na+ ions. Energy required to this transport is acquired from gradient of Na+ ions that is maintained by Na+/K(+)-ATPase. SGLT family consists of 12 proteins which include sugar cotransporters of anions, vitamins and short-chain fatty acids. Some of them also have a function of glucose sensors as well as water and urea channels.

AMP-activated kinase is an evolutionarily conserved enzyme found in every eukaryotic organism examined for its presence. It plays a critical role in the shift between catabolic and anabolic metabolism. Its activity is under the control of many factors, but basically it integrates the level of intracellular AMP with signals transduced by upstream kinases. It acts through the control of the activities of other enzymes, mitochondrial biogenesis, vesicular transport, and gene expression. From a physiological point of view its effects are pleiotropic and tissue dependent. In 2004, the control of food intake in hypothalamic neurons was added to the long list of its varied functions. Since then, its crucial role in transmitting signals from all important factors that inform the brain about the body's energy level, including leptin, insulin, glucose, ghrelin, and adiponectin, has been well established. Much attention was also paid to the molecular basis of this regulation. It seems that the main targets of hypothalamic AMPK are acetyl-CoA carboxylase and mTOR and the main candidate for upstream kinase is CaMKKbeta. These discoveries seem interesting not only due to their cognitive value, but because they may also carry significant practical aspects, both in the context of AMPK activators, such as the use of metformin in diabetes mellitus therapy, and in the recent trend to look for new ways to deal with the increase in obesity in well-developed countries. A better understanding of the role of AMPK in the control of food intake may create the possibility for new therapeutic approaches in this disease.

Therapeutic effect of rosiglitazone has been reported to result from an improvement of insulin sensitivity and inhibition of glucose synthesis. As the latter process occurs in both liver and kidney cortex the aim of this study was to elucidate the rosiglitazone action on glucose formation in both tissues. Primary cultured cells of both liver and kidney cortex grown in defined medium were use throughout. To identify the mechanism responsible for drug-induced changes, intracellular gluconeogenic intermediates and enzyme activities were determined. In contrast to hepatocytes, the administration of a 10 micromol/L concentration of rosiglitazone to renal tubules resulted in about a 70% decrease in the rate of gluconeogenesis, accompanied by an approximately 75% decrease in alanine utilization and a 35% increase in lactate synthesis. The effect of rosiglitazone was not abolished by GW9662, the PPAR-gamma irreversible antagonist, indicating that this action is not dependent on PPAR-gamma activation. In view of rosiglitazone-induced changes in gluconeogenic intermediates and a diminished incorporation of 14CO2 into pyruvate, it is likely that the drug causes a decline in flux through pyruvate carboxylase and (or) phosphoenolpyruvate carboxykinase. It is likely that the hypoglycemic action of rosiglitazone is PPAR-gamma independent and results mainly from its inhibitory effects on renal gluconeogenesis.

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that acts as an energy sensor maintaining the energy balance at the cellular as well as at the whole body level. Within the healthy cell, metabolic stress leading to an increase in AMP concentration results in AMPK activation. Once activated, AMPK "switches off" many anabolic pathways e.g. fatty acid and protein synthesis while "switches on" catabolic pathways such as fatty acid oxidation or glycolysis which serve to restore intracellular ATP level. Adipocyte derived hormones leptin and adiponectin activate AMPK in peripheral tissues increasing energy expenditure. AMPK also regulates food intake due to response to hormonal and nutrient signals in hypothalamus. Antidiabetic drugs that mimic the action of insulin activate the AMPK signaling pathways. Further studies are needed to clarify the importance of the AMPK activation for therapeutic effects of this drugs.

Chloroquine is a drug with over 60 years of safe clinical use in the treatment of malaria. The multiple mechanisms of chloroquine action have appeared to be useful in the therapy of many miscellaneous disorders well beyond its original antimalarial purposes. This paper is focused on the application of chloroquine for the treatment of malaria, porphyria cutanea tarda, rheumatoid arthritis, palindromic rheumatism and lupus. The possibility of the use of chloroquine in the therapy of other disorders such as diabetes mellitus, AIDS, hyperlipidemia, sarcoidosis, hypercalcemia, and melanoma is reviewed. Mechanisms of action of the drug as well as side effects on metabolism are discussed in view of recent discoveries.