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)

Neuronal apoptosis has been demonstrated to be a significant factor in neurological deficiencies associated with diabetes, and these deficiencies are exaggerated following ischemia. Diabetic rats have an increased basal level of apoptosis compared to non-diabetics and it has been previously demonstrated that infarct volumes were greater in diabetic animals following middle cerebral artery occlusion (MCAO) when compared to non-diabetics. In this study, we evaluated both the acute and chronic effects of insulin and/or C-peptide on CNS necrosis and apoptosis in non-diabetic and streptozotocin-induced diabetic rats following MCAO with reperfusion. Two brain areas, the sensori-motor cortex (layers-5 and 6) and the CA1 and CA3 sectors (pyramidal cell layers) of the hippocampus, were analyzed for apoptosis using TUNEL and Caspase-3 immunoreactivity. The chronic administration of a low maintenance concentration of insulin (2 U/kg), or the acute administration of insulin (2 U/kg) with or without C-peptide, did not alter the lesion volume or basal levels of apoptosis or the apoptotic levels in animals subjected to 2-h MCAO followed by 24-h reperfusion. However, both the acute or chronic administration of a high concentration of insulin (12 U/kg) significantly decreased lesion volume and apoptosis subsequent to 2-h MCAO followed by 24-h reperfusion. High dose insulin treatment also decreased the basal level of apoptosis. We conclude that in diabetic rats subjected to ischemia and reperfusion chronic insulin treatment decreased the basal apoptotic level, and both acute and chronic insulin decreased the MCAO-induced lesion volume and apoptosis. Maintenance insulin concentrations with or without C-peptide were without effect.
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PMID:Cerebral ischemia-induced apoptosis and necrosis in normal and diabetic rats: effects of insulin and C-peptide. 1672 87

Type 2 diabetes (T2D) and Alzheimer disease are degenerative diseases that may share common pathophysiologic mechanisms. Neuronal dysfunction in Alzheimer patients has been linked to overactivity of the cyclin-dependent kinase 5 (CDK5) and its activator p35. Both of these proteins are expressed in the insulin-producing beta cells of the pancreas. Further, glucose enhances p35 gene expression, promoting the formation of active p35/CDK5 complexes that regulate the expression of the insulin gene. In T2D, chronic elevations of glucose, glucotoxicity, impair beta cell function. We therefore postulated that CDK5 and p35 may be responsible for this beta cell impairment and that inhibition of CDK5 might have a beneficial effect. To test this hypothesis, the pancreatic cell line INS-1 was selected as a known in vitro model of glucotoxicity, and roscovitine (10 mum) was used as a CDK5 inhibitor. Chronic exposure of INS-1 cells to high glucose (20-30 mm) reduced both insulin mRNA levels and the activity of an insulin promoter reporter gene. Inhibition of CDK5 prevented this decrease of insulin gene expression. We used DNA binding (gel shift) assays and Western immunoblots to demonstrate that cellular levels of the transcription factor PDX-1, normally decreased by glucotoxicity, were preserved with CDK5 inhibition, as was the binding of PDX-1 to the insulin promoter. Analyses of nuclear and cytoplasmic PDX-1 protein levels revealed that CDK5 inhibition restores nuclear PDX-1, without affecting its cytoplasmic concentration, suggesting that CDK5 regulates the nuclear/cytoplasm partitioning of PDX-1. Using a Myc-tagged PDX-1 construct, we showed that the translocation of PDX-1 from the nucleus to the cytoplasm during glucotoxic conditions was prevented when CDK5 was inhibited. These studies indicate that CDK5 plays a role in the loss of beta cell function under glucotoxic conditions and that CDK5 inhibitors could have therapeutic value for T2D.
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PMID:Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. 1688 99

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step.
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PMID:Molecular misreading: the occurrence of frameshift proteins in different diseases. 1705 86

Retinal ischemic injury is common in patients with diabetes, atherosclerosis, hypertension, transient ischemia attack and amaurosis fugax. Previously, signs of ischemic stress, such as pericyte loss, blood-retinal barrier breakdown and neovascularization, which can lead to occlusion of retinal vessels, have been prevented in diabetic db/db mice with aldose reductase (AR) null mutation. To determine the role in retinal ischemic injury of AR and sorbitol dehydrogenase (SDH), the first and second enzymes in the polyol pathway, mice with deletion of AR (AR(-/-)) or SDH-mutation (SDH(-/-)), or C57BL/6N mice treated with AR or SDH inhibitors were subjected to transient retinal artery occlusion (2h of occlusion and 22h of reperfusion) by the intraluminal suture method. Neuronal loss and edema observed in wildtype (AR(+/+)) retinas after transient ischemia were prevented in the retinas of AR(-/-) mice or C57BL/6N mice treated with an AR inhibitor, Fidarestat. Fewer TUNEL-positive cells and smaller accumulations of nitrotyrosine and poly(ADP-ribose) were also observed in the retinas of AR(-/-) mice. However, SDH(-/-) mice and C57BL/6N mice treated with SDH inhibitor, CP-470,711, were not protected against ischemia-induced retinal damage. Taken together, AR contributes to retinal ischemic injury through increased edema and free radical accumulation. Therefore, AR inhibition should be considered for the treatment of retinal ischemic injury often observed in diabetic patients.
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PMID:Gene deletion and pharmacological inhibition of aldose reductase protect against retinal ischemic injury. 1772 43

The effect of vitamin E (1 g/kg body weight) supplementation on myosin-V and neuronal nitric oxide synthase (nNOS) immunoreactive myenteric neurons from the ileum of diabetic rats was investigated in the present study. Forty animals were divided into the following groups: normoglycemics (N), normoglycemics treated with vitamin E (NE), diabetics (D), and diabetics treated with vitamin E (DE). Quantitative and morphometric analyses were performed. The area of the tertiary plexus was also determined. Diabetes produced a 24% reduction in the number of myosin-V neurons in group D compared with group N, an effect that was accompanied by an increase in the tertiary plexus area (P < 0.05). Neuronal density was 27% higher in group NE than group N (P < 0.05). Nitrergic neuronal density was not altered as a consequence of either diabetes or vitamin E treatment. Myosin-V and nNOS immunoreactive neuronal cell body area increased significantly in group NE. The area of myosin-V and nNOS myenteric neurons also increased in group D. Vitamin E treatment (group DE) increased only the size of nitrergic neurons. The present results suggest that vitamin E elicited a neuroprotective and neurotrophic effect on the natural aging process, but with regard to diabetes, vitamin E supplementation exerted a neurotrophic effect only on nitrergic neurons.
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PMID:Vitamin E supplementation in rats with experimental diabetes mellitus: analysis of myosin-V and nNOS immunoreactive myenteric neurons from terminal ileum. 1895 59

The molecular mechanism of fatty acid uptake and utilization is of high medical relevance for the treatment of obesity, diabetes, and cardiovascular disease. Neuronal processes, hormones, and transcription factors are master regulators of these essential processes while their fine-tuning is achieved by modulating the activity and amount of enzymes. Proteins involved in fatty acid uptake and metabolism are important pharmaceutical targets. Only basic research on these molecules will lead to new strategies for therapy. Conceptionally, the intracellular utilization of long chain fatty acids may be subdivided into three steps: uptake across the plasma membrane, activation by esterification with coenzyme A, and subsequent metabolism. Long chain acyl-CoA synthetases (ACSLs) activate fatty acids for intracellular metabolism but are also involved in the regulation of uptake. The predominant pathways for fatty acids are their storage, membrane biosynthesis, and conversion to energy. How activated fatty acids are channeled toward one particular metabolic pathway is not well understood on the molecular level. We have previously shown that ACSLs localized to either the endoplasmic reticulum or to mitochondria can regulate the extent of fatty acid uptake. Multiple different long chain ACSLs are expressed simultaneously in the same cell type but differ in their subcellular localization. The hypothesis we put forward here implies that the spatial organization of ACSL activity is a key factor in channeling fatty acids toward a particular metabolic fate.
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PMID:Acyl-CoA synthetases: fatty acid uptake and metabolic channeling. 1911 50

Neuronal malfunction is a characteristic feature of diabetic mellitus. Hence, the present study therefore sought to evaluate the effect of diphenyl diselenide (DPDS) on the antioxidant status, sodium pump, cholinergic and glutamatergic system in the rat brain of streptozotocin (STZ) induced diabetes. The results show that although STZ evoke a significant diminution on the antioxidant status and activity of Na(+)/K(+)-ATPase, the activity of acetylcholinesterase and glutamate uptake and release was not altered. However, DPDS was able to markedly restore the observed imbalance in cerebral antioxidant status and also relieve the inhibition of Na(+)/K(+)-ATPase caused by streptozotocin. Hence, we conclude that DPDS is a potential candidate in the management of neuronal dysfunction that often accompanied complications associated with diabetic hyperglycemia.
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PMID:Diphenyl diselenide and streptozotocin did not alter cerebral glutamatergic and cholinergic systems but modulate antioxidant status and sodium pump in diabetic rats. 1936 73

Close correlations have recently been shown among the late onset complications encountered in diabetes and aging linked to neurobiological disorders. Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's disease and Parkinson's disease, dementia, cognitive dysfunction and hypernatremia. Beside the sex hormones other hormonal changes are also known to occur during aging and many common problems encountered in the aging process can be related to neuroendocrine phenomena. Diabetes mellitus is associated with moderate cognitive deficits and neurophysiologic and structural changes in the brain, a condition that may be referred to as diabetes encephalopathy; diabetes increases the risk of dementia especially in the elderly. The current view is that the diabetic brain features many symptoms that are best described as accelerated brain aging. This review presents and compares biochemical, physiological, electrophysiological, molecular, and pathological data from neuronal tissue of aging and hormone treated control and diabetic animals to arrive at the similarities among the two naturally occuring physiological conditions. Animal models can make a substantial contribution to understanding of the pathogenesis, which share many features with mechanism underlying brain aging. By studying the pathogenesis, targets for pharmacology can be identified, finally leading to delay or prevention of these complications. Antiaging strategies using hormone therapy, chemical and herbal compounds were carried out for reversal of aging effects. Neuronal markers have been presented in this review and similarities in changes were seen among the aging, diabetes and hormone treated (estrogen, DHEA and insulin) brains from these animals. A close correlation was observed in parameters like oxidative stress, enzyme changes, and pathological changes like lipofuscin accumulation in aging and diabetic brain.
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PMID:A metabolic and functional overview of brain aging linked to neurological disorders. 1938 58

Damage to the enteric nervous system is implicated in human disease and animal models of inflammatory bowel disease, diabetes, and Parkinson's disease, but the mechanism of death and the response of surviving neurons are poorly understood. We explored this in a coculture model of myenteric neurons, glia, and smooth muscle during exposure to the established or potential neurotoxins botulinum A, hydrogen peroxide, and acrylamide. Neuronal survival, axonal degeneration and regeneration, and neurotransmitter release were assessed during acute exposure (0-24 h) to neurotoxin and subsequent recovery (96-144 h). Unique and selective responses to each neurotoxin were found with acrylamide (0.5-2.0 mM) causing a 30% decrease in axon number without neuronal loss, whereas hydrogen peroxide (1-200 microM) caused a parallel loss in both axon and neuron number. Immunoblotting identified the loss of synaptic vesicle proteins that paralleled axon damage and was associated with marked suppression of depolarization-induced release of acetylcholine (ACh). The caspase inhibitor zVAD, but not DEVD, significantly prevented neuronal death, implying a largely caspase-3/7-independent mechanism of apoptotic death that was supported by staining for annexin V and cleaved caspase-3. In contrast, botulinum A (2 microg/ml) caused a 40% decrease in ACh release without effect on neuronal survival or axon structure. By 96 h after exposure to acrylamide or hydrogen peroxide, axon number was restored to or even surpassed the level of time-matched controls, regardless of partial neuronal loss, but ACh release remained markedly suppressed. Neural responses to toxic factors are initially unique but then converge upon robust axonal regeneration, whereas neurotransmitter release is both vulnerable to damage and slow to recover.
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PMID:Discrete responses of myenteric neurons to structural and functional damage by neurotoxins in vitro. 1940 12

We investigated a long-term exercise-induced neuroplasticity and spatial memory recovery in 15 rats in a treadmill as follows: normal control rats (NC), streptozotocin (STZ)-induced diabetic control rats (DC), and STZ-induced diabetic rats exercising in a treadmill (DE). As per the DE group, the running exercise in a treadmill was administered for 30 minutes a day for 6 weeks. Neuronal immediate-early gene (IEG) expression (c-Fos) in the hippocampus and radial arm maze (RAM) tests were measured and revealed that the c-Fos levels in DE were significantly higher than those in NC and DC (p < 0.05). Behavioral data analysis indicated that spatial memory performance scores, obtained from the RAM test, were significantly different among the three groups (p < 0.05). The memory scores of NC and DE were higher than those of DC (p < 0.05). These findings suggest that exercising in the treadmill increased neuronal immediate-early gene expression associated with neuroplasticity, thereby improving spatial memory. This is the first experimental evidence in literature that supports the efficacy of exercise-induced neuroplasticity and spatial motor memory in diabetes care.
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PMID:Long-term treadmill exercise-induced neuroplasticity and associated memory recovery of streptozotocin-induced diabetic rats: an experimenter blind, randomized controlled study. 1945 38


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