Changes in Cells Associated with Insulin Resistance.

Insulin is a polypeptide hormone synthesized and secreted by pancreatic ß-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance.

Insulin Resistance: The Increased Risk of Cancers.

Insulin resistance, also known as impaired insulin sensitivity, is the result of a decreased reaction of insulin signaling to blood glucose levels. This state is observed when muscle cells, adipose tissue, and liver cells, improperly respond to a particular concentration of insulin. Insulin resistance and related increased plasma insulin levels (hyperinsulinemia) may cause metabolic impairments, which are pathological states observed in obesity and type 2 diabetes mellitus. Observations of cancer patients confirm that hyperinsulinemia is a major factor influencing obesity, type 2 diabetes, and cancer. Obesity and diabetes have been reported as risks of the initiation, progression, and metastasis of several cancers. However, both of the aforementioned pathologies may independently and additionally increase the cancer risk. The state of metabolic disorders observed in cancer patients is associated with poor outcomes of cancer treatment. For example, patients suffering from metabolic disorders have higher cancer recurrence rates and their overall survival is reduced. In these associations between insulin resistance and cancer risk, an overview of the various pathogenic mechanisms that play a role in the development of cancer is discussed.

Glucose transporters as markers of diagnosis and prognosis in cancer diseases.

The primary metabolic substrate for cells is glucose, which acts as both a source of energy and a substrate in several processes. However, being lipophilic, the cell membrane is impermeable to glucose and specific carrier proteins are needed to allow transport. In contrast to normal cells, cancer cells are more likely to generate energy by glycolysis; as this process generates fewer molecules of adenosine triphosphate (ATP) than complete oxidative breakdown, more glucose molecules are needed. The increased demand for glucose in cancer cells is satisfied by overexpression of a number of glucose transporters, and decreased levels of others. As specific correlations have been observed between the occurrence of cancer and the expression of glucose carrier proteins, the presence of changes in expression of glucose transporters may be treated as a marker of diagnosis and/or prognosis for cancer patients.

Human Gut Microbiota in Health and Selected Cancers.

The majority of the epithelial surfaces of our body, and the digestive tract, respiratory and urogenital systems, are colonized by a vast number of bacteria, archaea, fungi, protozoans, and viruses. These microbiota, particularly those of the intestines, play an important, beneficial role in digestion, metabolism, and the synthesis of vitamins. Their metabolites stimulate cytokine production by the human host, which are used against potential pathogens. The composition of the microbiota is influenced by several internal and external factors, including diet, age, disease, and lifestyle. Such changes, called dysbiosis, may be involved in the development of various conditions, such as metabolic diseases, including metabolic syndrome, type 2 diabetes mellitus, Hashimoto's thyroidis and Graves' disease; they can also play a role in nervous system disturbances, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and depression. An association has also been found between gut microbiota dysbiosis and cancer. Our health is closely associated with the state of our microbiota, and their homeostasis. The aim of this review is to describe the associations between human gut microbiota and cancer, and examine the potential role of gut microbiota in anticancer therapy.

Human Glucose Transporters in Renal Glucose Homeostasis.

The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration and subsequent reabsorption or excretion of glucose. As glucose is hydrophilic and soluble in water, it is unable to pass through the lipid bilayer on its own; therefore, transport takes place using carrier proteins localized to the plasma membrane. Both sodium-independent glucose transporters (GLUT proteins) and sodium-dependent glucose transporters (SGLT proteins) are expressed in kidney tissue, and mutations of the genes coding for these glucose transporters lead to renal disorders and diseases, including renal cancers. In addition, several diseases may disturb the expression and/or function of renal glucose transporters. The aim of this review is to describe the role of the kidney in glucose homeostasis and the contribution of glucose transporters in renal physiology and renal diseases.

Insulin and Insulin Resistance in Alzheimer's Disease.

Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses hepatic glucose production. Insulin influences cell growth, differentiation and protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis and proteolysis. Insulin and insulin-like growth factor-1 receptors are expressed on all cell types in the central nervous system. Widespread distribution in the brain confirms that insulin signaling plays important and diverse roles in this organ. Insulin is known to regulate glucose metabolism, support cognition, enhance the outgrowth of neurons, modulate the release and uptake of catecholamine, and regulate the expression and localization of gamma-aminobutyric acid (GABA). Insulin is also able to freely cross the blood-brain barrier from the circulation. In addition, changes in insulin signaling, caused inter alia insulin resistance, may accelerate brain aging, and affect plasticity and possibly neurodegeneration. There are two significant insulin signal transduction pathways: the PBK/AKT pathway which is responsible for metabolic effects, and the MAPK pathway which influences cell growth, survival and gene expression. The aim of this study is to describe the role played by insulin in the CNS, in both healthy people and those with pathologies such as insulin resistance and Alzheimer's disease.

Glucose Transporters as a Target for Anticancer Therapy.

Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP. Therefore, cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by these cells is due to overexpression of glucose transporters, especially GLUT1 and GLUT3, that are hypoxia responsive, as well as other glucose transport proteins. Increased expression of these carrier proteins may be used in anticancer therapy. This phenomenon is used in diagnostic techniques such as FDG-PET. It is also suggested, and there are observations, that therapeutic inhibition of glucose transporters may be a method in treatment of cancer patients. On the other hand, there are described cases, in which upregulation of glucose transporters, as, for example, NIS, which is used in radioiodine therapy, can help patients with cancer. The aim of this review is the presentation of possibilities, and how glucose transporters can be used in anticancer therapy.

Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer's Disease.

The most common cause of dementia, especially in elderly people, is Alzheimer's disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer's disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.

Expression of glucose transporters in human neurodegenerative diseases.

The central nervous system (CNS) plays an important role in the human body. It is involved in the receive, store and participation in information retrieval. It can use several substrates as a source of energy, however, the main source of energy is glucose. Cells of the central nervous system need a continuous supply of energy, therefore, transport of glucose into these cells is very important. There are three distinct families of glucose transporters: sodium-independent glucose transporters (GLUTs), sodium-dependent glucose cotransporters (SGLTs), and uniporter, SWEET protein. In the human brain only GLUTs and SGLTs were detected. In neurodegenerative diseases was observed hypometabolism of glucose due to decreased expression of glucose transporters, in particular GLUT1 and GLUT3. On the other hand, animal studies revealed, that increased levels of these glucose transporters, due to for example by the increased copy number of SLC2A genes, may have a beneficial effect and may be a targeted therapy in the treatment of patients with AD, HD and PD.

Human Gut Microbiota in Health and Alzheimer's Disease.

Gut microbiota plays a crucial role in human health and disease. The alterations in the composition of gut microbiota may cause the onset of certain human pathologies. One of these is Alzheimer's disease (AD). High-fat diets, administration of antibiotics, lack of probiotics and/or prebiotics in diet increase the risk of AD. On the other hand, modulation of the composition of gut microbiota may decrease the risk of AD and be able to slow down the progression of AD.

Distribution of glucose transporters in renal diseases.

Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney.Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three families of glucose transporters: GLUT proteins, sodium-dependent glucose transporters (SGLTs) and SWEET. In kidney, only GLUTs and SGLTs protein are expressed. Mutations within genes that code these proteins lead to different renal disorders and diseases. However, diseases, not only renal, such as diabetes, may damage expression and function of renal glucose transporters.

Glucose transporters in healthy heart and in cardiac disease.

Heart consumes more energy than any other organ. It can utilize various metabolic substrates as a source of energy. The primary substrates are free fatty acids, especially long-chain fatty acids and glucose. The lipid bilayer of plasmalemma is impermeable for glucose. Therefore, glucose transport across the plasma membrane is mediated via glucose transporters. In human, cardiac cells are expressed as 2 families of glucose transporters: GLUTs and SGLTs. These transport proteins are GLUT1, GLUT3, GLUT8, GLUT10, GLUT11, GLUT12 and SGLT1. In human heart, GLUT4 is the major isoform that represents approximately 70% of the total glucose transporters. The changes observed in diabetic heart showed that type 1 diabetes mellitus alters the expression and translocation of GLUT4 and GLUT8 in the atria. In diabetic atria, the content in cell surface of these glucose transporters is downregulated. Expression of SGLT1, is increased in patients with end-stage cardiomyopathy secondary to type 2 diabetes. Increased expression of SGLT1 is a compensatory mechanism to the reduction in cardiac GLUT1 and GLUT4 expression. In animal model of type 1 diabetes, the expression of Sglt1 transporter is significantly decreased, and in the animal model of type 2 diabetes it is significantly increased. In heart diseases, such as cardiac hypertrophy (that is similar to fetal heart), heart failure and myocardial ischemia different perturbations in expression of glucose transporters are observed, especially in GLUT1 and GLUT4, due to changes in heart glucose metabolism. In this article, the functions of glucose transporters in healthy heart and in cardiac diseases are reviewed.

Glucose Transporters in Brain: In Health and in Alzheimer's Disease.

Neurons need a continuous supply of glucose, the major source of energy for mammalian brain metabolism. The central nervous system is protected by three main physiological cell barriers. Cell membranes are impermeable for glucose, therefore glucose is transferred across the cell membranes by specific transport proteins: sodium-independent glucose transporters (GLUTs), encoded by SLC2 genes, and sodium-dependent glucose transporters (for example SGLTs), encoded by SLC5 genes. Human brain expresses 10 GLUT proteins and 10 proteins encoded by SLC5 genes. In patients with brain diseases, particularly Alzheimer's (AD) and Huntington's diseases, abnormalities in neuronal glucose metabolism have been showed. The levels of GLUT1 and GLUT3, the major brain glucose transporters, are decreased, especially in the cerebral cortex. Therefore, in AD, hypometabolism of glucose and deficits in energy are observed. Production of ATP from glucose metabolism in sporadic AD declines to 50% and the tendency to decline continues throughout the progression of the disease. This decrease is correlated with O-GlcAcetylation and tau hyperphosphorylation, as the compensatory mechanisms in AD are the utilization of endogenous brain substances and drastic increase in GLUT2 levels. The present review focuses on the changes in the expression of glucose transporters due to AD.

The structural and functional changes of blood cells and molecular components in diabetes mellitus.

It is known fact that diabetes mellitus (DM) affects blood cells. Changes in the erythrocyte membrane, disorder in hemoglobin oxygen-binding and modification in mechanical characteristics, are effects of hyperglycemia on red blood cells. Altered susceptibility infection of patients with diabetes has been ascribed to a depression in the function of polymorphonuclear leukocytes. Neutrophil function in patients with diabetes with good glucose control is slightly different than in healthy ones. DM causes significant changes in lymphocytes metabolism and their functions. Patients with diabetes, presenting with acute coronary syndrome, are at higher risk of cardiovascular complications and recurrent ischemic events in comparison to non-diabetic counterparts. Various mechanisms, including endothelial dysfunction, platelet hyperactivity, and abnormalities in coagulation and fibrynolysis have been implicated for this increased atherothrombotic risk. There are many other alterations of blood cells due to DM. In the present review we focused on modifications of blood cells due to DM. Then, as a second point, we explored how the changes affect functions of red blood cells, white blood cells and platelets.

Leptin at gender-specific concentrations does not affect glucose transport, expression of glucose transporters and leptin receptors in human lymphocytes.

Leptin shows pleiotropic effects in organisms including an important role in the regulation of glucose homeostasis. Elevated serum leptin, particularly in obese individuals, is a warning sign of energy imbalance, hyperinsulinemia, insulin resistance and other metabolic risk factors that are strongly associated with type 2 diabetes. Obesity is also related to a higher rate of infections and immune function deterioration may in part ensue from decreased glucose uptake as the main energy source for lymphocytes. The aim of this study was to investigate the effect of physiologic and low pathophysiologic gender-specific leptin concentration found in lean and obese subjects on glucose transport, the expression of glucose transporters and leptin receptors in human peripheral blood lymphocytes. Isolated lymphocytes were incubated with human leptin at gender-specific concentrations observed in normal weight and obese subjects. Glucose uptake in lymphocytes was determined using nonmetabolizable radiolabeled deoxy-D-glucose. The expression of GLUT1, 3, 4 and leptin receptors was investigated using methods of immunocytochemistry and flow cytometry. Leptin at concentrations used in the study does not change glucose transport into lymphocytes and seems to have no influence on the expression of glucose transporters and leptin receptors. Further studies are necessary to address the relationship between leptin, glucose transport and the lymphocytes' function in obesity.

Statins impair glucose uptake in human cells.

OBJECTIVE: Considering the increasing number of clinical observations indicating hyperglycemic effects of statins, this study was designed to measure the influence of statins on the uptake of glucose analogs by human cells derived from liver, adipose tissue, and skeletal muscle. DESIGN: Flow cytometry and scintillation counting were used to measure the uptake of fluorescently labeled or tritiated glucose analogs by differentiated visceral preadipocytes, skeletal muscle cells, skeletal muscle myoblasts, and contact-inhibited human hepatocellular carcinoma cells. A bioinformatics approach was used to predict the structure of human glucose transporter 1 (GLUT1) and to identify the presence of putative cholesterol-binding (cholesterol recognition/interaction amino acid consensus (CRAC)) motifs within this transporter. Mutagenesis of CRAC motifs in SLC2A1 gene and limited proteolysis of membrane GLUT1 were used to determine the molecular effects of statins. RESULTS: Statins significantly inhibit the uptake of glucose analogs in all cell types. Similar effects are induced by methyl-ß-cyclodextrin, which removes membrane cholesterol. Statin effects can be rescued by addition of mevalonic acid, or supplementation with exogenous cholesterol. Limited proteolysis of GLUT1 and mutagenesis of CRAC motifs revealed that statins induce conformational changes in GLUTs. CONCLUSIONS: Statins impair glucose uptake by cells involved in regulation of glucose homeostasis by inducing cholesterol-dependent conformational changes in GLUTs. This molecular mechanism might explain hyperglycemic effects of statins observed in clinical trials.

Diabetes mellitus: influences on cancer risk.

Diabetes mellitus and cancer are common conditions, and their co-diagnosis in the same individual is not infrequent. The relative risks associated with type 2 diabetes are greater than twofold for hepatic, pancreatic, and endometrial cancers. The relative risk is somewhat lower, at 1.2-1.5-fold for colorectal, breast, and bladder cancers. In comparison, the relative risk of lung cancer is less than 1. The evidence for other malignancies (e.g. kidney, non-Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in male patients with diabetes. The potential biologic links between the two diseases are incompletely understood. Evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti-diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre-existing diabetes. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Obtained results showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes.

Role of immune system in type 1 diabetes mellitus pathogenesis.

The immune system is the body's natural defense system against invading pathogens. It protects the body from infection and works to communicate an individual's well-being through a complex network of interconnected cells and cytokines. This system is an associated host defense. An uncontrolled immune system has the potential to trigger negative complications in the host. Type 1 diabetes results from the destruction of pancreatic ß-cells by a ß-cell-specific autoimmune process. Examples of ß-cell autoantigens are insulin, glutamic acid decarboxylase, tyrosine phosphatase, and insulinoma antigen. There are many autoimmune diseases, but type 1 diabetes mellitus is one of the well-characterized autoimmune diseases. The mechanisms involved in the ß-cell destruction are still not clear; it is generally believed that ß-cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes are involved in the ß-cell-specific autoimmune process. It is necessary to determine what exact factors are causing the immune system to become unregulated in such a manner as to promote an autoimmune response.

Transport of deoxy-D-glucose into lymphocytes of patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is linked to increased risk of insulin resistance and diabetes mellitus in patients' later life. The aim of this study was to investigate uptake of deoxy-D-glucose by peripheral blood lymphocytes of PCOS patients with normal fasting plasma glucose and normal glucose tolerance test. The study involved 20 patients with PCOS with normal fasting plasma glucose and normal glucose in 60 and 120 min of oral glucose tolerance test, aged 18-32 (mean 23), BMI between 20 and 30 (mean 26). A control group consisted of 20 healthy women matched for glucose level (normoglycemia), aged 18-28 years (mean 23), BMI 20-25 (mean 23). Blood for the studies was collected in fasting conditions onto heparin. Lymphocytes were isolated within 2 h from collection by centrifuging. The intracellular transport into lymphocytes was studied using tritium-labeled deoxy-D-glucose and measured with a liquid scintillation counter. Radioactivity in curie per minute (cpm) was evaluated after 24 h. An initial examination was performed to check the presence of GLUT4 in peripheral blood lymphocytes of PCOS women. In all of the studied time points, the value of cpm for lymphocytes of PCOS patients was statistically significantly lower in comparison with the value obtained for lymphocytes of healthy women. However, the profile of deoxy-D-glucose uptake (d cpm) was the same for lymphocytes in both studied groups without statistically significant differences. In lymphocytes of PCOS patients, GLUT4 was detected. The obtained results indicate that PCOS affects the intracellular transport of deoxy-D-glucose into lymphocytes of PCOS patients with normal glucose level.

Expression of glucose transporters in cancers.

It has been known for 80 years that cancer cell growth in an energy-related process supported by an increased glucose metabolism. This phenomenon suggests a need for a corresponding increased uptake of glucose across the plasma membrane through an enhancement in the glucose transporter proteins, SGLT proteins as well as GLUT proteins. The results of many studies have demonstrated that the expression of glucose transporters, especially GLUT1, is increased in a variety of malignancies. GLUT1 overexpression has been found to be associated with tumor progression. It was found that GLUT1 overexpression is associated with poor overall survival in various malignant tumors.