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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bed rest is an integral part of treatment of numerous diseases. Typical examples are bone fractures of lower extremities and pelvis. Temporary immobilization is necessary also, e.g., in heart diseases (stroke), backbone and imminent abortion. The sick organism spares energy during the bed rest wich is beneficial. However, bed rest results in many alterations which are disadavantageous. They concern the function of almost all organs and systems but affect most significantly the locomotor and ciruclatory systems. Bed rest brings also about changes in the composition of peripheral blood and functions of the morphotic elements of blood. Red blood cells are subjected to the action of large amounts of reactive oxygen species (ROS). During oxidation of hemoglobin to methemoglobin superoxide radical anion (O2-) is formed: HbFe2+ + O2 --> MetHbFe3+ + O2- (1) Ferrous and ferric ions present in the cytoplasm of red blood cells may be catalysts of the Fenton reaction leading to the production of the hydroxyl radical: O2- + Fe3+ --> O2- + Fe2+ (2) Fe2+ + H2O2 --> Fe3+ + OH + HO- (3) OH shows a tremendous reactivity. It may react with lipids, proteins, nucleic acids and carbohydrates. The process of lipid peroxidation is best understood. It concerns mainly polyunsaturated fatty acids present in cell membranes. Peroxidation of membrane lipids decreases membrane fluidity and impairs its barrier function. The lowered membrane fluidity compromises erythrocyte deormability which in turn disturbs oxygen delivery to the tissues. End productions of lipid peroxidation are low-molecular wieght compounds, among them carbohydrates (ethane and pentane) and aldehydes, e.g. malondialdehyde (MDA). MDA concentration is an acknowldeged marker of the intensity of lipid peroxidation. Erythrocytes contain a complex system of protection against the action of ROS. It includes various enzymatic and non-enzymatic mechanism. The most important antioxidative enzymes of the red blood cells are superoxide dismutase (Cu,Zn-SOD, EC 1.15.1.1) catalase (CAT, EC 1.11.1.6) and glutathione peroxidase (GSH-Px, EC 1.11.1.9). Cu,Zn-SOD catalyzes the dismuation of O2- to hydrogen peroxide (H2O2). Catalase and peroxidase remove H2O2 and, moreover, GSH-Px can reduce lipid peroxides. Under normal conditions an equilibrium exists between the formation and removal ROS. If ROS are formed in excess or the defensive antioxidative mechanism are inefficient, oxidative stress develops. Derangement of the equilibrium between the formation and removal of ROS is important in the pathosgenesis of many diseases, e.g. atherosclerosis, diabetes, Down syndrome and Alzheimer disease. There are literature data on disturbances of enzymatic antioxidant defense mechanism of blood plateless during bed rest. This study was aimed at an examination of the post-traumatic bed rest on the enzymatic antioxidative defense mechanisms and lipid peroxidation in erythrocytes.
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PMID:Effect of long term bed rest in men on enzymatic antioxidative defence and lipid peroxidation in erythrocytes. 1154 39

Oxidative stress is suspected to intervene in certain chronic diseases. Much research has been devoted to the relationship between vitamin E, a major lipid-soluble antioxidant, and certain widespread diseases. Experimental and epidemiological proof supports a protective effect of vitamin E in a number of pathological processes such as coronary heart disease, cancer, cataract, diabetes mellitus, and Alzheimer disease. Randomized clinical trials have not confirmed a beneficial effect of vitamin E supplementation on the progression of these diseases. Certain methodological biases could however have affected these studies, explaining conflicting results. These biases include inaccuracy of vitamin E intake estimates and changes in eating habits during the course of the survey. An insufficient supplementation period using an insufficient dose and inclusion of aged and high-risk patients are the main limitations of the reported clinical trials. Large scale randomized clinical trials including healthy and low-risk subjects, along with prolonged administration of high-dose natural vitamin E, associated with synergetic compounds, and testing on morphological or biological features, will allow a better understanding of the relationship between vitamin E and chronic diseases.
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PMID:[Vitamin E deficiency: risk factor in human disease?]. 1190 53

Nosologically, Alzheimer disease may not be considered to be a single disorder in spite of a common clinical phenotype. Only a small proportion of about 5% to 10% of all Alzheimer cases is due to genetic mutations (type I) whereas the great majority of patients was found to be sporadic in origin. It may be assumed that susceptibility genes along with lifestyle risk factors contribute to the causation of the age-related sporadic Alzheimer disease (type II). In this context, the desensitization of the neuronal insulin receptor similar to not-insulin dependent diabetes mellitus may be of pivotal significance. This abnormality along with a reduction in brain insulin concentration is assumed to induce a cascade-like process of disturbances including cellular glucose, acetylcholine, cholesterol, and ATP associated with abnormalities in membrane pathology and the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein. Sporadic Alzheimer disease may, thus, be considered to be the brain type of diabetes mellitus II. Experimental evidence is provided and discussed.
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PMID:The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. 1195 56

The recent development of acetylcholinesterase inhibitors to treat patients with Alzheimer's disease has increased interest in the use of biochemical markers for the early detection and diagnosis of dementia, but only the measurement of the protein 14-3-3 in cerebrospinal fluid (CSF) to help diagnose sporadic Creutzfeldt-Jakob disease has become accepted clinical practice. CSF concentrations of tau protein and beta-amyloid peptide 42 have been widely investigated as potential diagnostic tests for Alzheimer's disease, but neither has shown sufficient sensitivity and specificity for clinical use. Preliminary investigations suggest that beta-amyloid peptide 42 may be useful in monitoring disease progression, but this needs to be verified. In addition, biochemical investigations may help to identify the small number of patients with treatable causes of dementia such as hypothyroidism and vitamin B12 deficiency, as well as any other compounding condition such as anaemia or diabetes mellitus that increase morbidity.
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PMID:Biochemical investigations in patients with dementia. 1203 95

Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE --). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
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PMID:Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. 1263 21

Carnitine is an ammo acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, the liver and the suprarenal glands). It is essential for the intermediary metabolism of fatty acids. Carnitine is indispensable for beta-oxidation of long-chain fatty acids in the mitochondria but also regulates CoA concentration and removal of the produced acyl groups. AcylCoAs act as restraining factor for several enzymes participating in intermediary metabolism. Transformation of AcylCoA into acylcarnitine is an important system for removing the toxic acyl groups. Although primary deficiency is unusual, depletion due to secondary causes, such as a disease or a medication side effect, can occur. Primary carnitine deficiency is caused by a defect in plasma membrane carnitine transporter in muscle and kidneys. Secondary carnitine deficiency is associated with several inborn errors of metabolism and acquired medical or iatrogenic conditions, for example in patients under valproate and zidovuline treatment. In cirrhosis and chronic renal failure, carnitine biosynthesis is impaired or carnitine is lost during hemodialysis. Other chronic conditions like diabetes mellitus, heart failure, Alzheimer disease may cause carnitine deficiency also observed in conditions with increased catabolism as in critical illness. Preterm neonates develop carnitine deficiency due to impaired proximal renal tubule carnitine re-absorption and immature carnitine biosynthesis. Carnitine stabilizes the cellular membrane and raises red blood cell osmotic resistance but has no metabolic influence on lipids in dialysis patients. L-Carnitine has been administered in senile dementia, metabolic nerve diseases, in HIV infection, tuberculosis, myopathies, cardiomyopathies, renal failure anemia and included in baby foods and milk.
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PMID:Carnitine metabolism and deficit--when supplementation is necessary? 1276 64

Advanced glycation end-products (AGEs) are formed during non-enzymatic glycation--the process occurring in vitro and in the organism. The glycation products accumulate in tissues and interact with specific receptors, what induces various cellular responses. Some enzymes important in metabolism can be also glycated. The disturbances of homeostasis, related to the glycation products, are the reason for complications observed in diabetes and aging processes. There are presented in this paper: mechanism of the formation of AGEs, their cellular receptor (RAGE), as well as the effects of glycation in aging, diabetes and Alzheimer disease. Finally, there are described the compounds which could be useful as inhibitors of glycation in clinical practice.
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PMID:[Biochemical properties and clinical significance of protein glycation products]. 1286 52

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
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PMID:Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. 1292 38

The receptor for advanced glycation end products (RAGE) is known to be causally involved in a variety of pathophysiological processes, e.g. immune/inflammatory disorders, Alzheimer disease, tumors, and abnormalities associated with diabetes as arteriosclerosis or disordered wound healing. So far, human cDNAs have been characterized encoding for the RAGE receptor and a truncated soluble form lacking the transmembrane and the cytosolic domain. The latter form represents a naturally occurring competitive inhibitor of signalling pathways induced by the membrane-standing RAGE receptor. In order to perform a relative expression analysis of both RAGE forms, an RT-PCR experiment was designed allowing the simultaneous amplification of corresponding transcripts. We were able to identify three novel human RAGE transcripts all encoding truncated soluble forms of RAGE. The relative expression ratios for the full-length RAGE transcript to the sum of its splice-variants encoding the soluble variants varied strongly among the tissues tested. Therefore, the pre-mRNA of RAGE must be subject to regulated alternative splicing activated by extracellular cues of yet unknown cellular signalling pathways. Thus, as deduced from the occurrence at the RNA level, it can be hypothesized that there is a complex RAGE regulation network involving isoforms competing for the binding of ligands.
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PMID:Tissue-specific expression patterns of the RAGE receptor and its soluble forms--a result of regulated alternative splicing? 1458 Jun 73

The term myofibrillar myopathy (MFM) was proposed in 1996 as a non-committal term for a pathological pattern of myofibrillar dissolution associated with accumulation of myofibrillar degradation products and ectopic expression of multiple proteins that include desmin, alphaB-crystallin (alphaBC), dystrophin and congophilic amyloid material. Subsequent studies revealed dominant mutations in desmin and alphaBC in some MFM patients, and clinical differences between kinships. We here review the clinical, structural and genetic features of 63 unrelated patients diagnosed as having MFM at the Mayo Clinic between 1977 and 2003. The age of onset was 54 +/- 16 years (mean +/- SD). Weakness was both proximal and distal in 77% and proximal only in 13%. Cardiomyopathy was diagnosed in 16%. Electro myography revealed a myopathic pattern associated with abnormal electrical irritability; 13 patients had abnormal nerve conduction studies but four of these had long-standing diabetes. The abnormal muscle fibres are best identified in trichrome-stained sections as harbouring amorphous, granular or pleomorphic hyaline structures, and vacuoles containing membranous material. The hyaline structures are strongly congophilic. Semiquantitative analysis in each case indicates that among the abnormal fibres, an average of 90, 75, 75, 70 and 70% abnormally express myotilin, desmin, alphaBC, dystrophin and beta-amyloid precursor protein, respectively. Therefore, immunostains for these proteins, and especially for myotilin, are useful adjuncts in the diagnosis of MFM. Electron microscopy shows progressive myofibrillar degeneration commencing at the Z-disk, accumulation of degraded filamentous material and entrapment of dislocated membranous organelles in autophagic vacuoles. In all patients, we searched for mutations in desmin and alphaBC, as well as in telethonin, a Z-disk-associated protein, or in syncoilin, which together with plectin links desmin to the Z-disk. Two of the 63 patients carry truncation mutations in the C-terminal domain of alphaBC, four carry missense mutations in the head or tail region of desmin, and none carries a mutation in syncoilin or telethonin. Thus, MFM is morphologically distinct but genetically heterogeneous. Further advances in defining the molecular causes of MFM will probably come from linkage studies of informative kinships or from systematic search for mutations in proteins participating in the intricate network supporting the Z-disk.
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PMID:Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. 1471 82


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