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

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.
 ...
PMID:Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. 1536 3

The aim of this study is to explore the mechanism by which diabetes exaggerates cerebral stroke and its outcome. Since ischemia can be related to not only necrosis but apoptosis as well, we compared the development of apoptosis in STZ-diabetic rats and STZ-diabetic rats subjected to occlusion of the middle cerebral artery (MCA). 24-48 hr following MCA occlusion the animals were killed, the brain removed and prepared for evaluation by several indexes of apoptosis: nucleosomal DNA fragmentation, TUNEL staining, activation of caspase-3 and alteration in the expression of Bax and Bcl2. DNA fragmentation was not detected in the cortex of normal and diabetic animals, but was evident following MCA occlusion in diabetic rats. Bax expression was increased in the cortex of normal rats following MCA occlusion and this expression was further increased in the cortex of MCA occluded diabetic rats. Bcl2 expression was not changed in any of the groups. In the hippocampus, DNA fragmentation was not evident in control rats but was observed in diabetic rats. Ischemic injury did not enhance DNA laddering in diabetic animals. The expression of Bax was increased in diabetic rats but was not increased following MCA occlusion. Bcl2 expression was not changed by ischemia in any of the animal models. These data suggest that diabetes may enhance the development of stroke via increased cortical apoptotic activity but this was not additive in the hippocampus following ischemic injury.
 ...
PMID:Diabetes enhances apoptosis induced by cerebral ischemia. 1553 78

Functional damage to microvascular endothelial cells by hyperglycemia is thought to be one of the critical risk factors in the impaired wound healing seen with diabetes mellitus. It is also thought that free radical stress plays a significant role in this endothelial cell dysfunction. In the present study, the effect of a free radical scavenger, MCI 186, on the endothelial cell dysfunction of cultured cells induced by high-glucose conditions was studied. Human dermal microvascular endothelial cells were cultured with high-glucose medium (50 mM) with or without MCI-186 (10 microM) for 7 days. Fifty mM mannitol was used as an osmotic control in this study. After this treatment, cell proliferation, activation of mitogen-activated protein kinase (MAPK), the level of apoptosis, and caspase-3 activation induced by removal of growth factors or tumor necrosis factor-alpha treatment were studied. High-glucose conditions significantly decreased cell proliferation and increased apoptosis levels with the activation of caspase-3 induced by growth factor removal. The high-glucose condition significantly activated MAPK. MCI-186 treatment improved cellular proliferation and reduced apoptosis and caspase-3 activation induced by high-glucose conditions. MCI-186 also inhibited the activation of MAPK. On the other hand, MCI-186 did not alter the level of apoptosis and caspase-3 activation induced by TNF-alpha treatment. In conclusion, we suggest that MCI-186 may be beneficial for improving the endothelial cell dysfunction induced by hyperglycemia.
 ...
PMID:Protective effects of a free radical scavenger, MCI-186, on high-glucose-induced dysfunction of human dermal microvascular endothelial cells. 1555 51

Erythropoietin (Epo) has been reported to inhibit apoptosis of neuron and erythroid cells. In this study, we examined an effect of high glucose on apoptosis of endothelial cells and investigated an anti-apoptotic effect of Epo. Human aortic endothelial cells were incubated with normal or high glucose for 72 h, and apoptotic cells were detected by TUNEL assay. Simultaneously, Epo (100 U/ml) was added to the high glucose medium to examine an inhibitory effect on the apoptosis induced by high glucose. Activity of caspase-3 was also measured using a specific substrate. To investigate a possible mechanism of Epo's action on apoptosis, phosphorylation of Akt was examined by applying Epo. Incubation with high glucose increased apoptosis of endothelial cells, whereas this effect was prevented by co-incubation with Epo. Caspase-3 activity was also increased (1.4-fold) by incubation with high glucose, and the activation of caspase-3 was normalized to the control level by co-incubation with Epo. Furthermore, Epo-induced phosphorylation of Akt in dose-dependent manner. In conclusion, we demonstrated that incubation with high glucose activated caspase-3 and induced apoptosis of endothelial cells. Epo was shown to phosphorylate Akt, leading to the inhibition of caspase-3 activation and apoptosis induced by high glucose. These results suggest that reduced production of Epo in patients with end-stage of nephropathy may accelerate diabetic angiopathy and that replacing therapy with Epo might inhibit endothelial cell apoptosis and diabetic angiopathy.
Diabetes Res Clin Pract 2004 Dec
PMID:Effect of erythropoietin on endothelial cell apoptosis induced by high glucose. 1556 57

The transplantation of pancreatic islets for the treatment of type I diabetes is hindered by the enormous loss of cells due to early apoptotic events. Genetic engineering of islets with cytoprotective genes is an important strategy aimed to enhance the survival of these cells in the transplant setting. The present study was designed to evaluate and compare the effects of five genes on a cell line derived from insulin-producing beta-cells, NIT-1. Cells were transduced using a Maloney murine leukemia virus (MLV) vector coding for yellow fluorescent protein (YFP) and for one of the following antiapoptotic genes: cFLIP, FADD-DN, BcL-2, PI-9, and ICAM-2. These genes were able to protect NIT-1 cells from cytokine-induced apoptosis to varying degrees ranging from no protection to significant protection equivalent to an optimal dose of a chemical caspase inhibitor. The data demonstrate that cFLIP, FADD-DN, and PI-9 are significantly more effective in protecting NIT-1 cells than BcL-2 and ICAM-2. Additionally, the data show that despite its weak in vitro inhibition of caspase-3, PI-9 affords significant protection against TNF-alpha-induced apoptosis in these cells. These genes may be ideal candidates to augment islet survival following transplantation.
 ...
PMID:Retrovirally transferred genes inhibit apoptosis in an insulin-secreting cell line: implications for islet transplantation. 1556 61

In type 1 diabetes, autoimmune inflammation of pancreatic islets of Langerhans ('insulitis') results in destruction of insulin-producing beta cells. Cytokines released from islet-infiltrating mononuclear cells are known to be cytotoxic both directly and by upregulating Fas for FasL-induced apoptosis. To investigate the role of caspase-3, a major effector of apoptosis in beta-cell death, we asked whether cytokine- and/or FasL-induced apoptosis was associated with increased activity of caspase-3 in NIT-1 insulinoma cells and islets of autoimmune diabetes-prone NOD mice. Measurement of caspase-3 activity using a fluorogenic cleavage assay was validated in NOD mouse thymocytes undergoing dexamethasone (Dex)-induced apoptosis. For cytokine-induced apoptosis, NIT-1 cells or islets were exposed to IL-1 beta and IFN-gamma for 24 h. Caspase-3-like activity was increased 2.1+/-0.7 and 2.4+/-0.9-fold in lysates of cytokine-treated NIT-1 cells and NOD mouse islets, respectively. However, NIT-1 cells exhibited 2.1% (4.7 pg active caspase-3/microg protein) and islets 0.8% (1.9 pg active caspase-3/microg protein) of the active caspase-3 content observed in Dex-treated thymocytes (225.1 pg active caspase-3/microg protein). After 24 h cytokine-exposure, the percentage of Fas-positive NIT-1 cells increased from 1.4+/-1.1 to 29.7+/-11.6%. Addition of FasL for a further 3 h increased caspase-3-like activity an additional 1.8-fold in cytokine-treated NIT-1 cells. In summary, exposure of NOD mouse insulinoma cells or islets to IL-1 beta and IFN-gamma for 24 h induced caspase-3-like activity that, in the case of insulinoma cells at least, can be further enhanced by interaction of cytokine-induced Fas receptor with FasL. Compared to thymocytes, insulinoma cells and islets from NOD mice were characterised by low basal and cytokine-induced caspase-3 activity.
 ...
PMID:Cytokines activate caspase-3 in insulinoma cells of diabetes-prone NOD mice directly and via upregulation of Fas. 1557 24

In diabetes, peripheral nerves suffer deficient neurotrophic support-a situation which resembles axotomy. This raises the question: does inappropriate establishment of an axotomised neuronal phenotype contribute to diabetic neuropathy, and in extremis, does this provoke apoptosis? We hybridized reverse-transcribed RNA, from the dorsal root ganglia (DRG) of 8-week streptozotocin (STZ)-induced diabetic rats, to Affymetrix Rat Genome U34A chips and scanned the array for expression of (a) genes that are upregulated by axotomy, (b) proapoptotic and (c) anti-apoptotic genes. Expression of the axotomy-responsive genes coding for growth-associated protein 43 (GAP-43), galanin, neuropeptide Y (NPY), pre-pro-vasoactive intestinal polypeptide (pre-pro-VIP), neuronal nitric oxide synthase (nNOS), protease nexin 1, heat-shock protein 27 (HSP 27) and myosin light chain kinase II (MLCK II) was unaffected in ganglia from diabetic rats compared to controls; thus, no axotomised phenotype was established. The expression of the majority of proapoptotic genes in the DRG was also unaltered (bax, bad, bid, bok, c-Jun, p38, TNFR1, caspase 3 and NOS2). Similarly there was no change in expression of the majority of antiapoptotic genes (bcl2, bcl-xL, bcl-w, NfkappaB). These alterations in gene expression make it clear that neither axotomy nor apoptotic phenotypes are established in neurones in this model of diabetes.
 ...
PMID:Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes. 1558 61

Troglitazone, a thiazolidinedione containing compound, was widely used to treat non-insulin dependent-diabetes. Unfortunately, troglitazone was associated with a sporadic liver toxicity that led to a cessation of its use clinically. Here we show that troglitazone induces a rapid and dose-dependent drop of mitochondrial membrane potential in liver HepG2 cells. The decrease in mitochondrial membrane potential induced by 100 microM troglitazone was completed after 5 min and similar in magnitude to that caused by carbonyl cyanide m-chloro phenylhydrazone. The troglitazone-induced loss of mitochondrial membrane potential preceded changes in cell permeability and cell count. In addition, troglitazone-induced a rise of intracellular calcium, subsequent to the drop in mitochondrial membrane potential, which was blocked by EGTA and the Na+/Ca2+ exchange inhibitor bepridil. Finally, application of 100 microM troglitazone for 24h to HepG2 cells resulted in activation of caspase 3. The results of this study shed light on the molecular mechanisms by which troglitazone can cause cytotoxicity.
 ...
PMID:Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells. 1558 58

Coptidis rhizoma (CR) is a herb used in many traditional prescriptions against diabetes mellitus in Asia for centuries. Our purpose was to determine the protective effect and its action mechanism of CR on the cytotoxicity of pancreatic beta-cells. Nitric oxide (NO) is believed to play a key role in the process of pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM). Exposure of RINm5F cells to chemical NO donor such as S-nitroso-N-acetylpenicillamine (SNAP) induced apoptotic events such as the disruption of mitochondrial membrane potential (Deltapsim), cytochrome c release from mitochondria, activation of caspase-3, poly (ADP-ribose) polymerase cleavage and DNA fragmentation. Also, exposure of SNAP led to LDH release into medium, one of the necrotic events. However, pretreatment of RINm5F cells with CR extract protected both apoptosis and necrosis through the inhibition of Deltapsim disruption in SNAP-treated RINm5F cells. In addition, rat islets pretreated with CR extract retained the insulin-secretion capacity even after the treatment with IL-1beta. These results suggest that CR may be a candidate for a therapeutic or preventing agent against IDDM.
 ...
PMID:Protective effect of Coptidis Rhizoma on S-nitroso-N-acetylpenicillamine (SNAP)-induced apoptosis and necrosis in pancreatic RINm5F cells. 1558 68

Both aging and diabetes are characterized by the formation of advanced glycation end products (AGEs). Both exhibit other similarities including deficits in wound healing that are associated with higher rates of fibroblast apoptosis. In order to investigate a potential mechanism for enhanced fibroblast apoptosis in diabetes and aged individuals, experiments were carried out to determine whether the predominant advanced glycation end product in skin, N-epsilon-(carboxymethyl) lysine (CML)-collagen, could induce fibroblast apoptosis. In vivo experiments established that CML-collagen but not unmodified collagen induced fibroblast apoptosis and that apoptosis was dependent upon caspase-3, -8, and -9 activity. In vitro experiments demonstrated that CML-collagen but not control collagen induced a time- and dose-dependent increase in fibroblast apoptosis. By use of blocking antibodies, apoptosis was shown to be mediated through receptor for AGE signaling. AGE-induced apoptosis was largely dependent on the effector caspase, caspase-3, which was activated through both cytoplasmic (caspase-8-dependent) and mitochondrial (caspase-9) pathways. CML-collagen had a global effect of enhancing mRNA levels of pro-apoptotic genes that included several classes of molecules including ligands, receptors, adaptor molecules, mitochondrial proteins, and others. However, the pattern of expression was not identical to the pattern of apoptotic genes induced by tumor necrosis factor alpha.
 ...
PMID:Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. 1559 Jun 48


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>