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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High glucose-induced apoptosis in vascular endothelial cells may contribute to the acceleration of atherosclerosis associated with diabetes. Here, we show that erythropoietin attenuates high glucose-induced apoptosis in cultured human aortic endothelial cells (HAECs). Exposure of HAECs to high glucose level for 72h significantly increased the number of apoptotic cells compared with normal glucose level, as evaluated by TUNEL assay. Simultaneous addition of erythropoietin (100 U/ml) significantly attenuated high glucose-induced apoptosis. In parallel, exposure to high glucose level induced caspase-3 activation and erythropoietin also prevented it. Erythropoietin stimulated Akt phosphorylation in a dose-dependent manner (1-100 U/ml). PI3 kinase inhibitor, wortmannin or LY294002 eliminated erythropoietin's inhibitory effect on caspase-3 activity. In conclusion, erythropoietin may attenuate high glucose-induced endothelial cell apoptosis via PI-3 kinase pathway. Replacing therapy with erythropoietin is often used for correction of renal anemia, but may have potential in preventing atherosclerosis in diabetic patients with end-stage renal failure.
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PMID:Erythropoietin attenuated high glucose-induced apoptosis in cultured human aortic endothelial cells. 1599 82

Stroke is the third leading cause of death and disability, and the risk for ischemic stroke is greater in diabetics. Previous studies have demonstrated both structural and functional nervous system changes in diabetes, and these changes may be enhanced by apoptosis. In the present study, we evaluated several indexes of both necrosis and apoptosis in the CNS of normals and two different models of diabetes (insulinopenic and insulin-resistant). Studies were conducted following middle cerebral artery occlusion (MCAO) with or without reperfusion. The sensory motor cortex (layer-5 and -6) and the CA1 and CA3 sectors of the hippocampus were analyzed following MCAO. We observed that both insulinopenic and insulin-resistant diabetic rats have increased basal level of apoptosis that is uniformly and bilaterally distributed as indicated by both caspase-3 activity and TUNEL staining. Twenty-four hours after MCAO, apoptosis was further increased in both diabetic models. Reperfusion after a 2 h MCAO compared to 24 h MCAO was associated with a decrease in TUNEL staining and caspase-3 activity in the control animal but exacerbated apoptosis, especially in the hippocampus of insulin-resistant diabetic rats. MCAO-induced lesion volumes were greater in insulinopenic rats compared to insulin-resistant and control rats. We conclude that both insulinopenic and insulin-resistant diabetic animals have increased apoptosis in the CNS in response to MCAO, and restoration of blood flow especially in the insulinopenic diabetic animals paradoxically exacerbates this process. Furthermore, restoration of blood flow did not decrease lesion volume in insulinopenic diabetic animals.
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PMID:Cerebral ischemia induced apoptosis and necrosis in normal and diabetic rats. 1603 84

Apoptosis of pancreatic beta cells is implicated in the onset of type 1 and type 2 diabetes. Consequently, strategies aimed at increasing the resistance of beta cells toward apoptosis could be beneficial in the treatment of diabetes. RasGAP, a regulator of Ras and Rho GTPases, is an atypical caspase substrate, since it inhibits, rather than favors, apoptosis when it is partially cleaved by caspase-3 at position 455. The antiapoptotic signal generated by the partial processing of RasGAP is mediated by the N-terminal fragment (fragment N) in a Ras-phosphatidylinositol 3-kinase-Akt-dependent, but NF-kappaB-independent, manner. Further cleavage of fragment N at position 157 abrogates its antiapoptotic properties. Here we demonstrate that an uncleavable form of fragment N activates Akt, represses NF-kappaB activity, and protects the conditionally immortalized pancreatic insulinoma betaTC-tet cell line against various insults, including exposure to genotoxins, trophic support withdrawal, and incubation with inflammatory cytokines. Fragment N also induced Akt activity and protection against cytokine-induced apoptosis in primary pancreatic islet cells. Fragment N did not alter insulin cell content and insulin secretion in response to glucose. These data indicate that fragment N protects beta cells without affecting their function. The pathways regulated by fragment N are therefore promising targets for antidiabetogenic therapy.
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PMID:Expression of an uncleavable N-terminal RasGAP fragment in insulin-secreting cells increases their resistance toward apoptotic stimuli without affecting their glucose-induced insulin secretion. 1604 10

Chronic hyperglycemia is toxic to pancreatic beta-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying beta-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic beta-cell line, we show that chronic exposure to high glucose increases cell death mediated by Bax oligomerization, cytochrome C release, and caspase-3 activation. During apoptosis, glucokinase (GCK) expression decreases in high-glucose-treated cells, concomitant with a decrease in cellular ATP production and insulin secretion. Moreover, exposure to a chronically high dose of glucose decreases interactions between GCK and mitochondria with an increase in Bax binding to mitochondria and cytochrome C release. These events are prevented by GCK overexpression, and phosphorylation of proapoptotic Bad proteins in GCK-overexpressing cells is prolonged compared with Neo-transfected cells. Similar results are obtained using primary islet cells. Collectively, these data demonstrate that beta-cell apoptosis from exposure to chronic high glucose occurs in relation to lowered GCK expression and reduced association with mitochondria. Our results show that this may be one mechanism by which glucose is toxic to beta-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax- and GCK-controlled signaling to promote apoptosis or proliferation.
Diabetes 2005 Sep
PMID:Exposure to chronic high glucose induces beta-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic beta-cells. 1612 48

Several groups have reported apoptosis of dorsal root ganglion (DRG) cells as a prominent feature of diabetic polyneuropathy (DPN), although this has been controversial. Here, we examined subacute (4-month) type 1 diabetic BB/Wor rats with respect to sensory nerve functions, DRG and sural nerve morphometry, pro- and antiapoptotic proteins, and the expression of neurotrophic factors and their receptors. Sensory nerve conduction velocity was reduced by 13% and was accompanied by significant hyperalgesia. The numbers of DRG neurons including substance P-and calcitonin gene-related peptide-positive neurons were not altered, although they showed significant atrophy. Sural nerve morphometry showed decreased numbers of myelinated and unmyelinated fibers. Active caspase-3 and Bax expressions were increased, whereas antiapoptotic Bcl-xl and heat shock protein (HSP) 27 expressions in DRGs were increased. Nerve growth factor (NGF) contents in sciatic nerves and the expression of NGF receptor TrkA in DRGs were decreased. Immunohistochemistry showed increased numbers of active caspase-3-, HSP70-, and HSP27-positive neurons. Examinations of DRGs revealed no structural evidence of apoptosis but rather progressive hydropic degenerative changes. We conclude that apoptotic stress is induced in DRGs but is counterbalanced by survival elements in subacute type 1 diabetic BB/Wor rats and that distal nerve fiber loss reflects a dying-back phenomenon caused by impaired neurotrophic support.
Diabetes 2005 Nov
PMID:Apoptotic stress is counterbalanced by survival elements preventing programmed cell death of dorsal root ganglions in subacute type 1 diabetic BB/Wor rats. 1624 57

A high dose of tumor necrosis factor (TNF)-alpha induces endothelial dysfunction and enhances apoptosis in vitro. The present study was conducted to examine whether incubating human umbilical vein endothelial cells (HUVECs) with serum from Type 2 diabetic patients complicated with retinopathy and/or microalbuminemia demonstrate endothelial dysfunction. Serum levels of TNF-alpha and vascular endothelial growth factor (VEGF) were elevated in diabetic patients. Plasma levels of TNF-alpha, two soluble TNF-alpha receptors (sTNFR), and VEGF were assessed in diabetic patients (CD, n=21) complicated with retinopathy and/or nephropathy, uncomplicated diabetic patients (UD, n=18), and in healthy normal participants (NS, n=16). In HUVECs incubated with patient's serum, endothelial constitutive nitric oxide synthase (eNOS) protein expressions were measured by Western blot analysis. Apoptosis in HUVECs was determined by optical microscopy, DNA fragmentation, and CPP32-like protease activity. Serum TNF-alpha, sTNFR-I, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, in CD were significantly higher than in UD or NS. While, serum sTNFR-I and VEGF levels were significantly increased in the both diabetic patients, compared with those of NS, no difference was observed in the serum TNF-alpha, sTNFR-II, and ADMA levels between UD and NS. eNOS down-regulation and apoptosis were seen in HUVECs incubated with serum from CD for 24 h, but those observations were completely counteracted in the incubation by the addition of the antihuman TNF-alpha antibody. These results imply that eNOS down-regulation in CD is associated with high serum TNF-alpha levels despite of high serum of VEGF levels. Therefore, endothelial dysfunction in diabetic patients complicated with microangiopathy may, in part, be attributed to high serum TNF-alpha levels.
J Diabetes Complications
PMID:High serum TNF-alpha level in Type 2 diabetic patients with microangiopathy is associated with eNOS down-regulation and apoptosis in endothelial cells. 1626 Mar 52

Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of the pancreatic ATP-sensitive K+ channel (K(ATP) channel), which is essential for triggering insulin secretion via membrane depolarization. Sulfonylureas, such as glibenclamide and tolbutamide, act as K(ATP) channel blockers and are widely used in diabetes treatment. These antidiabetic substances are known to induce apoptosis in pancreatic beta-cells or beta-cell lines under certain conditions. However, the precise molecular mechanisms of this sulfonylurea-induced apoptosis are still unidentified. To investigate the role of SUR in apoptosis induction, we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either SUR1, the smooth muscular isoform SUR2B, or the mutant SUR1(M1289T) at which a single amino acid in transmembrane helix 17 (TM17) was exchanged by the corresponding amino acid of SUR2. By analyzing cell detachment, nuclear condensation, DNA fragmentation, and caspase-3-like activity, we observed a SUR1-specific enhancement of glibenclamide-induced apoptosis that was not seen in SUR2B, SUR1(M1289T), or control cells. Coexpression with the pore-forming Kir6.2 subunit did not significantly alter the apoptotic effect of glibenclamide on SUR1 cells. In conclusion, expression of SUR1, but not of SUR2B or SUR1(M1289T), renders cells more susceptible to glibenclamide-induced apoptosis. Therefore, SUR1 as a pancreatic protein could be involved in specific variation of beta-cell mass and might also contribute to the regulation of insulin secretion at this level. According to our results, TM17 is essentially involved in SUR1-mediated apoptosis. This effect does not require the presence of functional Kir6.2-containing K(ATP) channels, which points to additional, so far unknown functions of SUR.
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PMID:Glibenclamide-induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform SUR1 but not by expression of SUR2B or the mutant SUR1(M1289T). 1630 72

Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
Diabetes 2005 Dec
PMID:Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. 1630 47

Mild ischemia-reperfusion (IR) injury to diabetic peripheral nerve is known to cause severe ischemic fiber degeneration. Little information is available on its effects on Schwann cell (SC). In this study, we evaluated oxidative stress and apoptosis of SC following mild IR, using immunohistochemistry in streptozotocin (STZ)- induced diabetic rats. Twenty-six rats were divided into four groups according to the duration of diabetes: 1- month STZ-induced diabetic group (n=7) and age-matched control group (n=7); 4-month STZ-induced diabetic group (n=6) and age-matched control group (n=6). Using our established IR model of 3 h of ischemia followed by 7 days of reperfusion, sciatic and tibial nerves were harvested and labeled with 8-hydroxydeoxyguanosine (8-OHdG; oxidative stress marker), caspase-3 (apoptotic executor), and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) activity (apoptotic indicator). Marked positive staining with 8-OHdG, caspase-3, and TUNEL were found in diabetic ischemic nerves (right side) following IR in both 1-month and 4-month groups. Only mild positive staining or no staining was seen in the nonischemic side (left side) of diabetic and age-matched control groups. Co-labeling with S-100 confirmed that the cells labeled with 8-OHdG, caspase3, and TUNEL were SC. SC was susceptible to oxidative injury and apoptosis in experimental diabetic neuropathy when subjected to mild IR injury.
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PMID:Ischemia-reperfusion injury causes oxidative stress and apoptosis of Schwann cell in acute and chronic experimental diabetic neuropathy. 1635 15

Oxidative stress is increased in the retina in diabetes; the levels of oxidatively modified DNA and nitrosylated proteins are elevated, and antioxidant defense enzymes are impaired. The levels of superoxides are elevated in the retina, and the mitochondria become dysfunctional with proapoptotic protein, Bax, translocating from the cytosol into the mitochondria, and cytochrome c leaking out from the mitochondria. This is accompanied by increased retinal capillary cell apoptosis, and the formation of acellular capillaries and pericyte ghosts, the early signs of retinopathy in animal models of diabetic retinopathy. Inhibition of superoxides inhibits glucose -induced mitochondrial dysfunction, activation of caspase-3, and cell death in retinal capillary cells. In animal models, long-term administration of lipoic acid or other antioxidants inhibits the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine and capillary cell apoptosis in the retina. Understanding the role of mitochondria in the development of retinopathy in diabetes should help identify therapies that can neutralize superoxides and inhibit their dysfunction and, ultimately, the development of retinopathy.
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PMID:Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. 1635 21


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