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)

A retrospective analysis of 812 patients admitted to the Ross Tilley Burn Centre between 1984 and 1992 resulted in 37 cases of burn injuries which were directly related to premorbid disabilities. The majority of these burns (83.8 per cent) occurred in the patient's home, most commonly as scald injuries in the bath tub, the shower, or following hot water spills. Nineteen patients were male, 17 were female. The median age was 58 years. Six patients had spinal cord disorders: four had traumatic cord damage, two had spina bifida. Six patients had seizure disorders. Five of these patients had been taking anti-seizure medications, but all had subtherapeutic blood levels on admission to hospital. Two patients had diabetes mellitus with peripheral neuropathies. Thirteen patients had four miscellaneous neurological disorders, including: tardive dyskinesia (two), CVA (four), Parkinson's disease (two), Alzheimer's disease (two), cerebral palsy (one), multiple sclerosis (one) and blindness (one). Three patients had a diagnosis of syncope. Two patients had emphysema, and four were morbidly obese. The average length of stay (LOS) for the disabled patients was 27.6 days for a median burn size of 10 per cent body surface area (BSA), compared to an average LOS for the general population of 25.7 days for a larger median burn size of 21 per cent BSA. The mortality rate was also much higher in the disabled population (22.2 per cent vs. 6.0 per cent). Most of these burn injuries were preventable. A series of burn prevention guidelines is presented, in an attempt to reduce the incidence of these burn injuries in disabled patients.
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PMID:Burns in the disabled. 850 62

Factors that modify onset of Alzheimer's disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.
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PMID:Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. 854 1

Oxidant stress secondary to dopamine metabolism has been proposed as a pathogenic factor in the development of Parkinson's disease. Biochemical abnormalities extending beyond the central nervous system have been identified in patients with this condition. Previous investigators have found abnormally elevated concentrations of the lipid peroxidation product, malondialdehyde, in the plasma and serum of patients with Parkinson's disease. We attempted to replicate these findings but controlled for other factors that could influence malondialdehyde levels. We detected no significant elevations in mean serum malondialdehyde concentrations in either levodopa-treated or untreated patients with Parkinson's disease, compared to normal controls; similarly, no elevation was found in a group of patients with dementia of Alzheimer's type. On the other hand, a group of subjects with diabetes mellitus but no neurodegenerative disease had significantly elevated mean serum malondialdehyde levels, consistent with previous studies of diabetic patients. Autoxidation is one of the two major routes by which dopamine and dopa metabolism may generate oxygen free radicals. We analyzed the autoxidation product of dopa, 5-S-cysteinyl-dopa, in the plasma of these same groups of patients with neurodegenerative disease and normal controls; no significant differences were identified. Serum concentrations of two other antioxidant substances, alpha-tocopherol and uric acid, were also statistically similar in these groups. In conclusion, analysis of several blood products relevant to oxidant stress, including malondialdehyde, 5-S-cysteinyl-dopa, alpha-tocopherol, and uric acid, failed to distinguish patients with Parkinson's disease or dementia of Alzheimer's type from controls.
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PMID:No evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease. 855 7

Nonenzymatic glycation of proteins by glucose leading to the formation of toxic and immunogenic advanced glycation end products (AGEs) may be a major contributor to the pathological manifestations of diabetes mellitus, aging, and, possibly, neurodegenerative diseases such as Alzheimer's. We tested the in vitro inhibition of antigenic AGE formation on bovine serum albumin, ribonuclease A, and human hemoglobin by various vitamin B1 and B6 derivatives. Among the inhibitors, pyridoxamine and thiamine pyrophosphate potently inhibited AGE formation and were more effective than aminoguanidine, suggesting that these two compounds may have novel therapeutic potential in preventing vascular complications of diabetes. An unexpected finding was that aminoguanidine inhibited the late kinetic stages of glycation much more weakly than the early phase.
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PMID:Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine. 860 28

Several lines of evidence suggest that amyloid deposition in the brain contributes to neuronal degeneration in Alzheimer's disease (AD). In the AD brain, diffuse plaques composed mostly of amorphous beta amyloid (Am-beta A) are inert, whereas compact plaques composed of beta amyloid fibrils (Fib-beta A) are associated with neurodegenerative changes. The effects of these two types of amyloid were tested on primary rat hippocampal neurons. Fib-beta A induced the formation of dystrophic neurites and caused neuronal cell death, whereas Am-beta A was not toxic. In addition, Fib-beta A caused synapse loss in the remaining viable neurons, whereas Am-beta A did not significantly affect synapse number. We also examined the effects of amylin, the primary constituent of the amyloid fibrils that form in the pancreas in adult-onset diabetes. Amylin was toxic to rat and human insulin-producing islet cells in the concentration range of fibril formation. The relative toxic potencies of amylin peptides of different species correlated with their fibril-forming capacity. Soluble amylin was not toxic. The amyloid fibril-binding dye Congo red inhibited the toxicity of both beta A and amylin. Congo red afforded protection against toxicity by a dual mechanism. When present during the phase of fibril polymerization, Congo red could inhibit fibril formation from some peptides. When added to preformed fibrils, Congo red bound to fibrils rendering them nontoxic. These results suggest that fibril formation is necessary for both beta A and amylin toxicity. Congo red appears to be a general inhibitor of amyloid fibril toxicity and may therefore be a useful prototype for drugs targeted to the amyloid pathology of AD and adult-onset diabetes.
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PMID:Amyloid fibril toxicity in Alzheimer's disease and diabetes. 862 32

Nonenzymatic glycation (Maillard reaction) of long-lived proteins is a major contributor to the pathology of diabetes and possibly aging and Alzheimer's disease. We report here kinetic studies of the glycation of the model protein ribonuclease A by glucose and ribose leading to the formation of antigenic advanced glycation end products ("AGEs"), detectable by AGE-specific polyclonal antibodies, and pentosidine, an acid-stable fluorescent AGE. As anticipated, the kinetics of glycation by ribose were considerably faster than by glucose, and the rate of AGE formation initially increased with increasing sugar concentrations. However, ribose above 0.15 M appeared to paradoxically slow the kinetics of AGE formation, suggesting ribose inhibits the conversion of "early" Amadori rearrangement products to "late" AGEs and thus favors the accumulation of reactive Amadori intermediates. The facile isolation of such protein intermediates was achieved by an "interrupted glycation" protocol which free and reversibly bound (Schiff base) ribose was removed following a short (24h) initial incubation of 0.5 M ribose at 37 degrees C. The kinetics of buildup of the Amadori intermediates and the kinetics of their post-Amadori conversion to antigenic AGEs were independently studied. A rapid and reversible inhibition of the post-Amadori kinetics by free ribose was verified by direct re-addition of ribose to the isolated, sugar-free intermediate. The pH dependence of the kinetics of antigenic AGE formation from such intermediates was measured and exhibited an unusual bell-shaped profile over the pH range of 5.0-9.5 with a maximum near pH 8.0. Aminoguanidine, a pharmacological AGE inhibitor, was found to moderately or weakly inhibit antigenic AGE formation in such post- Amadori steps. The isolation of the glycated ribonuclease intermediate thus simplifies kinetic and mechanistic studies of AGE formation, permits AGE studies in the absence of complications arising from free or Schiff base bound sugar, and provides a novel methodology for evaluating the mechanism and efficacy of therapeutic agents that may inhibit AGE formation.
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PMID:Kinetics of nonenzymatic glycation of ribonuclease A leading to advanced glycation end products. Paradoxical inhibition by ribose leads to facile isolation of protein intermediate for rapid post-Amadori studies. 866 53

Glucose and other reducing sugars react with proteins by a nonenzymatic, post-translational modification process called nonenzymatic glycosylation or glycation. The sugar-derived carbonyl group adds to a free amine, forming a reversible adduct which over time rearranges to produce a class of products termed advanced-glycation end-products (AGEs). These remain irreversibly bound to macromolecules and can covalently crosslink proximate amino groups. The formation of AGEs on long-lived connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal ageing and which occurs at an accelerated rate in diabetes. AGEs can activate cellular receptors and initiate a variety of pathophysiological responses. They modify an appreciable fraction of circulating low-density lipoproteins preventing uptake of these particles by their high-affinity tissue receptors. Advanced glycation has also been implicated in the pathology of Alzheimer's disease. Because AGEs may form by a pathway involving reactive alpha-dicarbonyl intermediates, we investigated a potential pharmacological strategy for selectively cleaving the resultant glucose-derived protein crosslinks. We now describe a prototypic AGE crosslink 'breaker', N-phenacylthiazolium bromide (PTB), which reacts with and cleaves covalent, AGE-derived protein crosslinks. The ability of PTB to break AGE crosslinks in vivo points to the importance of an alpha-dicarbonyl intermediate in the advanced glycation pathway and offers a potential therapeutic approach for the removal of established AGE crosslinks.
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PMID:An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. 871 35

Advanced glycation endproducts (AGEs), structural components of beta-amyloid plaques and neurofibrillary tangels, have been implicated in the pathogenesis of Alzheimer's disease. AGE levels, measured by fluorescence, and their precursor molecules such as glucose and its Amadori product, fructosylamine, were measured to examine the question whether the reported increased level of AGEs in the brain is reflected in an increase in AGE-associated parameters in peripheral blood. Lactoferrin, proposed to play an important role in the interaction of AGEs with their receptors, was determined by ELISA. All AGE-associated parameters showed trends to lower values in patients with Alzheimer's disease compared with non-demented controls. Albumin and total iron were not significantly different between the groups. In contrast to diabetes and renal failure, where high levels of AGEs and their precursors are present in tissue as well as in peripheral blood, elevated CNS AGE levels in patients with Alzheimer's disease are manifested without detectable peripheral changes.
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PMID:Advanced glycation endproducts-associated parameters in the peripheral blood of patients with Alzheimer's disease. 876 Oct 18

Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. In addition, the hippocampus, hypothalamus and olfactory bulb--the three areas where the insulin receptors are most dense--are also subject to neurodegeneration. The exact cause of the beta-amyloid deposits and NFTs is unknown. However, it is our intention to explicate the various pathogenic pathways through which Alzheimer disease arises. Fundamentally, the structural and metabolic damage found in Alzheimer disease is due to sustained elevation of interleukin-1 beta, a feature which is also found in insulin-dependent diabetes mellitus. Similarly, the beta-AP deposits found in the Alzheimer brain share the same molecular structure as the amylin deposits found in the pancreatic beta-cells in non-insulin-dependent diabetes mellitus (NIDDM), and are equally neurotoxic. These, and other pathophysiological parallels, afford some insight into the probably cause of Alzheimer disease and, as such, forms the basis of the causal hypothesis advanced in this paper.
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PMID:Interleukin-1 beta: a common cause of Alzheimer's disease and diabetes mellitus. 877 Oct 51

Acetyl-CoA provision to the synaptoplasmic compartment of cholinergic nerve terminals plays a regulatory role in the synthesis of acetylcholine. The disturbances in glucose utilization and in decarboxylation of the end product of its metabolism pyruvate, are considered to be significant factors causing cholinergic deficits in several diseases of the central nervous system. In this article we review data concerning role of acetyl-CoA in patomechanisms of disturbances of cholinergic metabolism in Alzheimers disease, thiamine deficiency, inherited defects of pyruvate dehydrogenase and diabetes.
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PMID:Disturbances of acetyl-CoA, energy and acetylcholine metabolism in some encephalopathies. 878 93


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