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)

Hippocampal neuronal apoptosis accompanied by impairment of cognitive function occurs in primary diabetic encephalopathy. In this study, we investigated the neuroprotective mechanism of the iridoid glycoside, aucubin, using rats (n=8). Diabetes mellitus was induced in the rats by intraperitoneal (i.p.) injection of streptozotocin (60 mg/kg body weight). After 65 d, half of the DM rats were administered aucubin (5 mg/kg; i.p.) for 15 d, yielding treatment DM+A. A third group of rats received no streptozotocin or aucibin, and served as controls (CON). Encephalopathy was assessed using Y-maze behavioral testing. Rats were euthanized on Day 87, and hippocampi were excised for visual (light and transmission electron microscopic) and immunochemical (Western blot; immunohistochemical) assessments of the CA1 subfield for apoptosis and expression of regulatory proteins Bcl-2 and Bax. Treatment responses to all the parameters examined (body weight, plasma glucose, Y-maze error rates, pyramidal cell ultrastructure, proportions of apoptotic cells, levels of expression of Bcl-2 and Bax, and survivability of neuronal cells) were identical: there were highly significant differences between DM and CON groups (P<0.001), but the effects were significantly moderated (P<0.01) in DM+A compared with DM. These findings confirm the association of apoptosis with the encephalopathic effects of diabetes mellitus, and suggest a major role of the expression levels of Bcl-2 and Bax in the regulation of apoptotic cell death. All of the results suggest that aucubin could effectively inhibit apoptosis by modulating the expressions of Bcl-2 and Bax genes.
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PMID:Neuroprotection of aucubin in primary diabetic encephalopathy. 1848 69

Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here, we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed with a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral--CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high-calorie diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines.
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PMID:Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. 1865 34

Diabetes mellitus (DM) may give rise to cognitive impairment, but the pathological mechanism involved was still unknown. We investigated the thrombospondin-I (TSP-I) expression level in hippocampus of streptozotocin-induced diabetic rats, which, as a matricellular, calcium-binding protein that participates in cellular responses to growth factors, cytokines and injury, has been indicated as important synaptogenic components recently. We employed 20 streptozotocin (STZ)-induced diabetic rats. The weight, blood sugar and urine sugar were measured before and after model induction in diabetes and normal groups. We did immunohistochemical localization of TSP-I and RT-PCR was applied to determine TSP-I mRNA level in the hippocampus of both groups. Moreover, transmission electron microscope (TEM) was used to study the ultrastuctural changes of the hippocampus. All data were analyzed by the independent samples t-test. We found that the expression of TSP-I markedly decreased in the hippocampal neuronal cells. Moreover, TEM results showed the ultrastructures of diabetic hippocampus, including area CA1 and DG, neurons were characterized by mitochondria swelling, increased heterochromatin accumulation and reduced synaptic contacts. The present study provides experimental evidences that decreased TSP-I expression may help to explain the reduced synaptogenesis and altered hippocampal ultrastucture, both of which may contribute to the pathogenesis of diabetic dementia.
Exp Clin Endocrinol Diabetes 2008 Jun
PMID:Decreased thrombospondin-I (TSP-I) expression in the hippocampus of streptozotocin-induced diabetic rats. 1870 Feb 75

It is known that long-term diabetes mellitus causes hippocampal dysfunction, however, early events leading to diabetes-related impairments of hippocampal tissue remain obscure. The present study was performed to examine temporal and spatial patterns of neuronal damage and astrogliosis in hippocampal CA1-C3 areas during the early stage of streptozotocin-induced diabetes in rats. NeuN and GFAP immunohistochemistry was used to visualize neurons and glial cells. Immunopositive cells were counted in hippocampal CA1-CA3 areas at days 3, 7 and 14 of diabetes development using confocal Olympus FV1000 microscope. Significant decrease in the number of neurons in CA2 area was observed in diabetic rats at day 3. In contrast, in CA1 and CA3 areas NeuN-positive cell count started to decrease later being at day 7, correspondingly, by 7 and 9 % lower than that in the control. This trend developed further till day 14, when the number of neurons in CA1 and CA3 areas was, respectively, 20.3 and 18.1% smaller as compared with the control. These changes were accompanied by astrogliosis: the number of astrocytes in pyramidal cell layer was increased significantly in all examined time-points. Thus, our study demonstrates that streptozotocin-induced diabetes is associated with early neurodegeneration in Ammon's horn. It suggests that clinically relevant cognitive deficits development in diabetic patients starting from the early stage of the disease.
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PMID:Remodeling of ammon's horn during the first two weeks of experimental diabetes development. 1876 80

It is well known that the central nervous system (CNS) is vulnerable to hypoglycemia and hyperglycemia. Insulin is indispensable for serum glucose control and diabetes patients are on the relative or absolute deficient state of insulin. The role of insulin on the CNS, however, has not been fully elucidated, yet. To reveal the role of insulin on the neuronal survival, we have used in vitro system of an organotypic hippocampal slice culture from rat, and examine the neuronal cell death at the various glucose concentrations in the presence or absence of insulin. When glucose concentrations is varied to 0, 1, 3, 5 and 30 mM in the incubation medium, the neuronal cell death was minimum at 5mM, and no neuronal survival was observed under 1mM on the CA1. On the dentate gyrus granule cells (DG), on the other hand, the significant neuronal survival was observed even as low as 1mM. In the presence of 1 nM concentration of insulin, the neuronal cell death curve showed the U-shape, and the minimum death point was 3-5mM glucose concentrations at the CA1. At the DG, insulin did not show the protective effect up to 48 hours culture regardless of glucose concentration. In the absence of glucose, insulin accelerated the neuronal cell death both in the CA1 and DG. We concluded that insulin has a double-edged effect on the neuronal cell death dependent on glucose concentration, and that the CA1 and the DG have a different sensitivity to insulin in terms of cell survival.
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PMID:The double-edged effect of insulin on the neuronal cell death associated with hypoglycemia on the hippocampal slice culture. 1877 18

Type 2 diabetes recently has been identified as a risk factor for developing Alzheimer's disease (AD). The main reason for this appears to be insulin signaling failure in the brain. Furthermore, cholinergic neurons are particularly affected in the brains of AD patients. The aim of the present study is to investigate if insulin signaling-related proteins are co-located with cholinergic neuron in the CA1 region of hippocampus of mice, which could explain the early loss of cholinergic neurons in AD. Using immunohistochemistry, the insulin signaling-related proteins, such as insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), protein kinase B (PKB, also named Akt), glycogen synthase kinase-3beta (GSK-3beta) and insulin-degrading enzyme (IDE) were analysed. Choline acetyltransferase (ChAT) was selected as a marker of cholinergic neurons. In the CA1 region of hippocampus of mice, several of the insulin signaling-related proteins we had chosen are co-located with ChAT, and most double immunoreactive positive cells were pyramidal cells. The coexistences indicated that the insulin signaling may play an important part in the activities of cholinergic neurons, and the impairment of the pathway may be important in the mechanisms that underlie neurodegeneration in AD.
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PMID:Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons. 1901 38

In this study, the neuroprotection of aucubin and its mechanism were evaluated in the rat model of diabetic encephalopathy. Diabetes mellitus (DM) rats were stratified by cognitive capability (CC), and assigned to four treatment groups for aucubin treatment (doses of 0, 1, 5 or 10 mg/kg aucubin), with a further two groups of non-DM rats ranked by CC as controls for aucubin (doses of 0 or 5 mg/kg aucubin). Neuroprotection was estimated by the indexes of behavior and histology. Behavioral testing was performed in a Y-maze. The surviving neurons in CA1-CA4 and subiculum (SC) of the hippocampus were counted under a microscope. In addition, the apoptotic neurons in the CA1 of the hippocampus were also examined by using TUNEL staining. In order to clarify the mechanism of aucubin's neuroprotection, the activities of endogenous antioxidants and nitric oxide synthase (NOS) together with the content of lipid peroxide in the hippocampus were assayed. The results proved that aucubin significantly reduced the content of lipid peroxide, regulated the activities of antioxidant enzymatic and decreased the activity of NOS. All these effects indicated that aucubin was a potential neuroprotective agent and its neuroprotective effects were achieved, at least in part, by promoting endogenous antioxidant enzymatic activities.
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PMID:Aucubin prevents loss of hippocampal neurons and regulates antioxidative activity in diabetic encephalopathy rats. 1914 Jan 54

Previous studies in children with diabetes found that hyperglycemia induces memory dysfunction. In this study, we investigated memory and synaptic plasticity in streptozotocine (STZ)-induced diabetic rats during the juvenile period. We further investigated the effects of glucagon-like peptide-1 (GLP-1) on the diabetes-induced profiles. STZ (85 mg/kg, i.p.) was administered to 17-day-old Wistar rats to induce type-1 juvenile diabetes mellitus (JDM). In the Y-maze test, JDM rats showed significant impairment of learning and memory, which were improved by GLP-1 (7-36) amide (1 microg/5 microl/rat, i.c.v.). Extracellular recording at Schaffer collateral synapses in the CA1 region of hippocampal slices showed that long-term potentiation and paired-pulse facilitation in JDM rats were similar to age-matched control rats. However, the input-output relation was strengthened, and long-term depression (LTD) and responses of N-methyl d-aspartic acid through NR2B subunits were weakened in the JDM rats. GLP-1 (7-36) amide (100 nM) increased the magnitude of LTD and the responses through NR2B in the JDM rats. These results indicate that the lack of LTD and NR2B responses may contribute to impairment of memory associated with JDM, suggesting the potential usefulness of GLP-1 in the treatment of memory dysfunction in JDM.
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PMID:The influences of juvenile diabetes on memory and hippocampal plasticity in rats: improving effects of glucagon-like peptide-1. 1932 Nov 33

Insulin-induced severe hypoglycemia causes brain damage. The hypothesis to be tested was that diabetes portends to more extensive brain tissue damage following an episode of severe hypoglycemia. Nine-week-old male streptozotocin-diabetic (DIAB; n = 10) or vehicle-injected control (CONT; n = 7) Sprague-Dawley rats were subjected to hyperinsulinemic (0.2 U.kg(-1).min(-1)) severe hypoglycemic (10-15 mg/dl) clamps while awake and unrestrained. Groups were precisely matched for depth and duration (1 h) of severe hypoglycemia (CONT 11 +/- 0.5 and DIAB 12 +/- 0.2 mg/dl, P = not significant). During severe hypoglycemia, an equal number of episodes of seizure-like activity were noted in both groups. One week later, histological analysis demonstrated extensive neuronal damage in regions of the hippocampus, especially in the dentate gyrus and CA1 regions and less so in the CA3 region (P < 0.05), although total hippocampal damage was not different between groups. However, in the cortex, DIAB rats had significantly (2.3-fold) more dead neurons than CONT rats (P < 0.05). There was a strong correlation between neuronal damage and the occurrence of seizure-like activity (r(2) > 0.9). Separate studies conducted in groups of diabetic (n = 5) and nondiabetic (n = 5) rats not exposed to severe hypoglycemia showed no brain damage. In summary, under the conditions studied, severe hypoglycemia causes brain damage in the cortex and regions within the hippocampus, and the extent of damage is closely correlated to the presence of seizure-like activity in nonanesthetized rats. It is concluded that, in response to insulin-induced severe hypoglycemia, diabetes uniquely increases the vulnerability of specific brain areas to neuronal damage.
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PMID:Diabetes increases brain damage caused by severe hypoglycemia. 1943 50

Type 2 diabetes has been identified as a risk factor for Alzheimer disease (AD). Insulin signalling is often impaired in AD, contributing to the neurodegeneration seen in AD. Previous studies have shown that the incretin glucagon-like peptide 1 (GLP-1) helps to normalise insulin signalling in type 2 diabetes. GLP-1 also plays important roles in neuronal activity and brain functions. We tested the specific role of GLP-1 receptors in synaptic plasticity and cognitive processes in a GLP-1 receptor knockout (Glp1r(-/-)) mouse model. In an open field assessment, no general difference in exploratory and anxiety was found except for a small decrease in running speed was found (p<0.05). In an object recognition task, Glp1r(-/-) mice explored objects in a similar way to WT controls but did not learn to differentiate between novel and familiar objects (p<0.05) while in an object relocation task, no impairment was observed. In a water maze task, Glp1r(-/-) mice were impaired in the acquisition phase (p<0.001), and also in the probe recall task (p<0.05). LTP in area CA1 of the hippocampus was severely impaired in Glp1r(-/-) mice (p<0.0001). Paired-pulse facilitation was also impaired at 25ms interstimulus interval (p<0.05) but not at longer intervals. The results demonstrate that the murine GLP-1R plays an important role in the control of synaptic plasticity and in some forms of memory formation. The results shed light on the molecular processes that underlie the neuroprotective properties of GLP-1 analogues in animal models of Alzheimer's disease.
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PMID:Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease. 1957 62


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