Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cerebellum, frontal cortex, hippocampal and parahippocampal regions of 100 patients older than 80 years, most of whom had died of stroke, were examined. Eighteen percent were diagnosed as clinically demented. On the specimens labeled previously with Thioflavin S and Bielschowsky method, immunohistochemical studies were performed with Fab (antigen-binding fragment) of the anti beta-amyloid antibody 4G8. Positive amyloid immunoreactivity was observed in the cerebrum in 71 of 100 cases, Cerebella of 31 subjects of 71 with cerebral amyloidosis also revealed amyloid deposits. They appeared in various morphological forms, such as diffuse plaques and focal subpial deposits, as well as classical and primitive neuritic plaques. Cases with amyloid in the cerebellum alone were not observed. Beta-amyloid deposits in the cerebellum were associated with a significant number of beta-amyloid plaques in the cerebrum, which showed other Alzheimer-type pathology, also in individuals without clinical symptoms of dementia. There was no correlation either between cerebellar amyloid deposits and clinical cerebellar symptoms or between the presence of diabetes mellitus, arterial hypertension, and neuropathological changes. A clear association of microglial cells with amyloid deposits in the cerebellum was demonstrated. In our experience, LN-1 and RCA-1 were not as suitable for formalin-fixed paraffin-embedded tissue, as was anti-ferritin. Negative staining for tau-1 and positive staining for anti-ubiquitin characterized neurites within primitive and classical plaques. No neurofibrillary pathology was detected in the cytoplasm of cerebellar neurons when we used anti tau-1 labeling.
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PMID:beta-Amyloid deposits within the cerebellum of persons older than 80 years of age. 134 Sep 21

1. Proteins in eukaryotic cells are continually degraded and replaced under precise control mechanisms. Although this continual proteolysis may seem wasteful, it serves several important functions: cells selectively degrade proteins with abnormal sequences or conformations, the accumulation of which could be harmful; the rapid degradation of regulatory peptides and enzymes is essential for the control of metabolic pathways and the cell cycle; and the breakdown of proteins in starvation provides amino acids for gluconeogenesis and energy metabolism. 2. Protein breakdown in eukaryotic cells occurs through distinct pathways: A) lysosomal (involves cathepsins B, H, L, etc.); B) Ca(2+)-dependent (involves Ca(2+)-dependent proteases calpains I and II); C) ATP-dependent, that require or not ubiquitin (comprises at least two large cytosolic proteases, UCDEN and proteasome), and D) ATP-independent (it is not known which proteases are involved in this degradative system). Despite recent dramatic progress, the relative contributions of these pathways to the accelerated proteolysis occurring in normal and pathological states is still largely unknown. 3. In order to identify the cellular mechanisms of skeletal muscle atrophy during fasting and diabetes mellitus, we have studied protein turnover in soleus and EDL muscles from control and fasted (for 24 h) or diabetic rats (1, 3, 5 and 10 days after streptozotocin injection). 4. The increase in muscle proteolysis during fasting seems to be attributable to an enhancement of the energy-requiring process. An increase in the ATP-dependent proteolytic pathway was evident 1 day after food restriction and probably accounted for all of the increased proteolysis demonstrated in the EDL muscles. In parallel with the alterations in the ATP-dependent process, an increase in the ubiquitin-mRNA and proteasome subunit-mRNA was detected. 5. In the acute phase of diabetes (1-3 days) there was an activation of Ca(2+)-dependent (soleus and EDL) and ATP-dependent (EDL) pathways. However, after 5 and 10 days of diabetes the activity of these two pathways fell to values even below control ones. No changes in the lysosomal proteolytic system were observed during diabetes. 6. Although appreciable progress has been made in this research, a large number of important questions remain to be answered, and some of them are discussed in the present paper.
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PMID:Regulation of different proteolytic pathways in skeletal muscle in fasting and diabetes mellitus. 808 98

To clarify whether ubiquitin is expressed in atherosclerotic lesions, and, if so, the expression is influenced by diabetes mellitus, we examined atherosclerotic (AS) lesions from Wistar fatty (WF) and Wistar lean (WL) rats immunohistochemically using an antibody against ubiquitin (AUb). Ten-week-old male WF and WL rats were treated to cannulize a silicon tube from the left carotid artery (LCA) to the descending aorta under chloral hydrate anesthesia and the tube was fixed. Age-matched WF and WL rats without cannulization were served as controls. Eight weeks after operation, 1 ml of 0.1% Evans blue solution was injected to all rats from the tail vein. 15 min latter, the aortae were removed, fixed with 4% paraformaldehyde and embedded in paraffin. Immunohistochemical staining with AUb by the ABC method, hematoxylin and eosin (HE) and elastica-Goldner (EG) stains were performed. In the cannulized group, focal areas of the luminal surface of the aorta were stained blue with Evans blue and these areas were microscopically confirmed as AS lesions in all WF and WL rats. In the control group, no Evans blue staining or AS lesions were observed. The destruction of the internal elastic lamina in AS lesions were seen with EG stain in the cannulized aorta of both WF and WL rats. No significant difference of the area ratio of intima/media was present between WF and WL rats in the cannulized group. Ubiquitin immunoreactivity was observed in the nucleus and cytoplasm of cells in AS lesions of both WF and WL rats. The present study suggests that ubiquitin plays a role in the formation of AS, and the condition of diabetes mellitus has little influence on ubiquitin expression and AS formation in this experimental model.
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PMID:Ubiquitin expression in atherosclerotic lesions of wistar fatty and wistar lean rats. 882 96

The daily turnover of protein amounts to 280 g in an adult weighing 70 kg but the metabolic processes responsible for protein turnover are only just beginning to be understood. In cells, the major pathway of protein degradation is the ubiquitin-proteasome pathway and protein flux through this pathway is precisely regulated. In catabolic conditions such as uremia, activity of the ubiquitin-proteasome pathway increases, resulting in degradation of muscle protein. In addition to increased protein degradation, gene transcription is activated, resulting in higher levels of the mRNAs encoding ubiquitin and proteasome subunits. The signals activating this pathway include metabolic acidosis and glucocorticoids but must be more diverse since the pathway is also activated in response to starvation, sepsis, cancer, muscle denervation, thermal injury, and acute diabetes. Understanding how the pathway is controlled could lead to the prevention of muscle loss in uremia and other conditions.
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PMID:Cellular mechanisms controlling protein degradation in catabolic states. 938 15

In chronic renal failure (CRF), the ATP-dependent, ubiquitin-proteasome proteolytic pathway is activated with concurrent increases in the transcription of genes encoding proteins of this pathway in muscle. We have shown that the stimuli for these responses include acidosis and glucocorticoids, but other endocrine abnormalities in CRF (e.g., insulin resistance) could contribute to these responses. In fact, a major effect of insulin in muscle is to suppress protein degradation. To examine whether insulin influences the ubiquitin-proteasome pathway, we measured protein degradation in incubated epitrochlearis muscles of diabetic and pair-fed control rats. Muscle proteolysis was increased in pathways that do not involve lysosomes or Ca(2+)-dependent proteases; but MG132, a protease inhibitor that blocks ATP synthesis, eliminated the accelerated rate of protein degradation in diabetic rat muscles. Diabetes mellitus also increased levels of mRNAs encoding ubiquitin (334%), E2 ubiquitin-conjugating enzyme (247%), and the C3 (320%), C5 (349%), and C9 (216%) proteasome subunits in muscle. Finally, transcription of the ubiquitin gene in diabetic rat muscles was increased. Diabetic rats were acidotic, but eliminating acidemia by giving NaHCO3 did not block the increase in muscle proteolysis. Giving diabetic rats insulin prevented the excessive muscle proteolysis, suggesting that insulin acts as a suppressor of the ubiquitin-proteasome pathway. Thus, the insulin resistance of uremia could contribute to muscle protein wasting in CRF.
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PMID:Signals regulating accelerated muscle protein catabolism in uremia. 938 16

Loss of lean body mass is common in patients with acute or chronic renal failure but the mechanisms causing this loss are only beginning to be understood. One mechanism involves an inability of uremic patients to activate the critical metabolic responses that maintain protein balance when dietary protein is limited. Metabolic responses to dietary protein restriction include a sharp reduction in the degradation of essential amino acids and protein; changes in protein synthesis are less reliable. If uremia prevents suppression of essential amino acid or protein degradation when dietary protein is reduced by anorexia, negative nitrogen balance and loss of lean body mass will ensue. One complication of uremia, metabolic acidosis, stimulates the degradation of branched-chain amino acids and proteins and therefore blocks the ability of the patient to respond to a low-protein diet. The mechanisms require glucocorticoids and involve increased activity of branched-chain keto acid dehydrogenase and the ubiquitin-proteasome proteolytic pathway; there also is increased transcription of genes encoding components of enzymes involved in the pathways. Besides acidosis, a low insulin concentration and cytokines activate the ubiquitin-proteasome proteolytic pathway. Understanding how proteolysis is activated, including how these genes are stimulated, is important because the same pathways are activated in diabetes, cancer, sepsis, burns, starvation, and muscle denervation. Activation of the ubiquitin-proteasome pathway leads to reduced lean body mass.
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PMID:Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease. 949 77

Induction of experimental insulin-deficiency by a single administration of streptozotocin to rats resulted in substantial changes in heart and skeletal muscle size and protein content. This was accompanied by a marked loss of total body (carcass) nitrogen and raised concentrations of circulating branched-chain amino acids. These changes were related to alterations in protein turnover in skeletal muscle. Thus, the diabetic animals showed changes in both the fractional protein rates of synthesis (decreased by 37%) and degradation (increased by 141%). The increased protein degradation observed in the muscle of the diabetic animals was associated only with an increase in the expression of the genes controlling ubiquitin-dependent proteolysis. It may be suggested that the hormonal changes associated with the diabetic state play an important role in the regulation of the activity of the ubiquitin-dependent proteolytic system in skeletal muscle, highlighting the major role of this system in the diabetes-related cachexia.
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PMID:Protein turnover in skeletal muscle of the diabetic rat: activation of ubiquitin-dependent proteolysis. 985 33

Insulin plays a major role in the regulation of skeletal muscle protein turnover but its mechanism of action is not fully understood, especially in vivo during catabolic states. These aspects are presently reviewed. Insulin inhibits the ATP-ubiquitin proteasome proteolytic pathway which is presumably the predominant pathway involved in the breakdown of muscle protein. Evidence of the ability of insulin to stimulate muscle protein synthesis in vivo was also presented. Many catabolic states in rats, e.g. streptozotocin diabetes, glucocorticoid excess or sepsis-induced cytokines, resulted in a decrease in insulin action on protein synthesis or degradation. The effect of catabolic factors would therefore be facilitated. In contrast, the antiproteolytic action of insulin was improved during hyperthyroidism in man and early lactation in goats. Excessive muscle protein breakdown should therefore be prevented. In other words, the anabolic hormone insulin partly controlled the 'catabolic drive'. Advances in the understanding of insulin signalling pathways and targets should provide information on the interactions between insulin action, muscle protein turnover and catabolic factors.
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PMID:Insulin action on skeletal muscle protein metabolism during catabolic states. 1022

During the last years many investigations have shown that a major catalyst within the mechanism of skeletal muscle wasting occurring under conditions like sepsis, injuries, trauma, cancer cachexia, chronic acidosis, fasting, glucocorticoid treatment, and insulinopenia is the ubiquitin-proteasome system. Evidence for this was obtained by findings that the rate of ATP-dependent protein degradation is increased, that m-RNA concentrations of several proteasome subunits and ubiquitin are increased and the amount of ubiquitin-protein conjugates is elevated under these conditions. Additionally, the enhanced protein breakdown was shown to be suppressed by proteasome inhibitors. In the present report we show that most but not all of the proteolytic activities of partially purified 20S/26S proteasomes from skeletal muscle of rats increase after induction of Diabetes mellitus. This finding suggests that part of the mechanism of acceleration of muscle protein breakdown is due to changes in proteasome activities.
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PMID:Alterations of proteasome activities in skeletal muscle tissue of diabetic rats. 1036 52

Insulin deficiency (e.g., in acute diabetes or fasting) is associated with enhanced protein breakdown in skeletal muscle leading to muscle wasting. Because recent studies have suggested that this increased proteolysis is due to activation of the ubiquitin-proteasome (Ub-proteasome) pathway, we investigated whether diabetes is associated with an increased rate of Ub conjugation to muscle protein. Muscle extracts from streptozotocin-induced insulin-deficient rats contained greater amounts of Ub-conjugated proteins than extracts from control animals and also 40-50% greater rates of conjugation of (125)I-Ub to endogenous muscle proteins. This enhanced Ub-conjugation occurred mainly through the N-end rule pathway that involves E2(14k) and E3alpha. A specific substrate of this pathway, alpha-lactalbumin, was ubiquitinated faster in the diabetic extracts, and a dominant negative form of E2(14k) inhibited this increase in ubiquitination rates. Both E2(14k) and E3alpha were shown to be rate-limiting for Ub conjugation because adding small amounts of either to extracts stimulated Ub conjugation. Furthermore, mRNA for E2(14k) and E3alpha (but not E1) were elevated 2-fold in muscles from diabetic rats, although no significant increase in E2(14k) and E3alpha content could be detected by immunoblot or activity assays. The simplest interpretation of these results is that small increases in both E2(14k) and E3alpha in muscles of insulin-deficient animals together accelerate Ub conjugation and protein degradation by the N-end rule pathway, the same pathway activated in cancer cachexia, sepsis, and hyperthyroidism.
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PMID:Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats. 1056 3


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