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Chronic Hyperglycemia (chronic + hyperglycemia)
Selected AbstractsThioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2009Lorena Perrone Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF-A, and ICAM1. TXNIP silencing by siRNA impedes RAGE and HG effects while stable over-expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK-NF-,B signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP-induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over-expression in EC abolishes H3K9 tri-methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF-,B-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy. J. Cell. Physiol. 221: 262,272, 2009. © 2009 Wiley-Liss, Inc [source] Oxidative stress in the pathogenesis of experimental diabetic neuropathyJOURNAL OF NEUROCHEMISTRY, Issue 2003P. A. Low We evaluated the effects of chronic hyperglycemia on L5 DRG neurons. Experimental diabetic neuropathy (EDN) was induced by streptozotocin. We studied peripheral nerve after 1, 3, 12 months of diabetes. A conduction deficit was present from the first month and persisted over 12 months, affecting mainly sensory fibers. 8-Hydroxy-deoxyguanosine labeling was significantly increased at all time points in DRG neurons, indicating oxidative injury. Caspase-3 labeling was increased at all three time-points, indicating commitment to the efferent limb of the apoptotic pathway. Apoptosis was confirmed by a significant increase in the percent of neurons undergoing apoptosis (TUNEL staining) at 1 month (8%), 3 months (7%) and 12 months (11%). Morphometry of DRG showed a selective loss (42%) of the largest neurons. These findings support the concept that oxidative stress leads to oxidative injury of DRG neurons, with mitochondrium as a specific target, leading to apoptosis and a predominantly sensory neuropathy. [source] REVIEW ARTICLE: Hyperglycemia: a prothrombotic factor?JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2010B. A. LEMKES Summary., Diabetes mellitus is characterized by a high risk of atherothrombotic events. What is more, venous thrombosis has also been found to occur more frequently in this patient group. This prothrombotic condition in diabetes is underpinned by laboratory findings of elevated coagulation factors and impaired fibrinolysis. Hyperglycemia plays an important role in the development of these hemostatic abnormalities, as is illustrated by the association with glycemic control and the improvement upon treatment of hyperglycemia. Interestingly, stress induced hyperglycemia, which is often transient, has also been associated with poor outcome in thrombotic disease. Similar laboratory findings suggest a common effect of acute vs. chronic hyperglycemia on the coagulation system. Many mechanisms have been proposed to explain this prothrombotic shift in hyperglycemia, such as a direct effect on gene transcription of coagulation factors caused by hyperglycemia-induced oxidative stress, loss of the endothelial glycocalyx layer, which harbours coagulation factors, and direct glycation of coagulation factors, altering their activity. In addition, both chronic and acute hyperglycemia are often accompanied by hyperinsulinemia, which has been shown to have prothrombotic effects as well. In conclusion, the laboratory evidence of the effects of both chronic and acute hyperglycemia suggests a prothrombotic shift. Additionally, hyperglycemia is associated with poor clinical outcome of thrombotic events. Whether intensive treatment of hyperglycemia can prevent hypercoagulability and improve clinical outcome remains to be investigated. [source] Emerging Concepts in the Pathophysiology of Type 2 Diabetes MellitusMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 3 2009Prasanth N. Surampudi MD Abstract Type 2 diabetes mellitus is a multifactorial metabolic disorder. It is characterized by chronic hyperglycemia, insulin resistance, and a relative insulin secretion defect. The prevalence of type 2 diabetes mellitus has risen worldwide in large part because of an increase in obesity and sedentary lifestyles. The underlying pathophysiology and complications of type 2 diabetes mellitus are still being elucidated. Recent advances in diabetes research have helped us to gain a better understanding about insulin resistance and insulin secretion defects. The evolving understanding about the influence of the incretin effect, insulin signal transduction, adipose tissue, intra,islet cell communication, and inflammation is changing the way in which we view type 2 diabetes mellitus. This new understanding will eventually provide us with new treatment approaches to help patients who have type 2 diabetes mellitus. This article gives a review of the current and emerging concepts of the pathophysiology of type 2 diabetes mellitus. Mt Sinai J Med 76: 216,226, 2009. © 2009 Mount Sinai School of Medicine [source] Toward a cell-based cure for diabetes: advances in production and transplant of beta cellsMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 4 2008Kathryn C. Claiborn Abstract Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells of the pancreatic islets of Langerhans. Although developments in exogenous insulin therapy have greatly improved clinical outcomes in patients with diabetes, the ability of the pancreatic beta cell to exquisitely regulate the delivery of insulin and maintain normal levels of blood glucose is still far superior to what can be achieved by external delivery of insulin. As a result, the majority of patients with type 1 diabetes still experience the complications of chronic hyperglycemia or serious and potentially life-threatening hypoglycemia. The shortcomings of medical therapy have driven research toward more direct approaches of beta cell replacement. Indeed, the specificity of beta cell loss in type 1 diabetes makes this disease a particularly attractive candidate for cell-based therapies. In order for significant progress to be made, however, a thorough understanding of beta cell biology and more broadly islet biology is necessary. This review addresses recent advances in developmental biology that have expanded our understanding of islet cell differentiation, assesses the promise and limitations of islet transplantation, and discusses the future of alternative sources of beta cells, including directed differentiation of stem cells, replication of adult beta cells, and transdifferentiation of nonislet cells to a beta cell fate. Mt Sinai J Med 75:362,371, 2008. © 2008 Mount Sinai School of Medicine [source] Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memoryPEDIATRIC DIABETES, Issue 6 2008John I Malone Background/Objective:, We previously reported that chronic hyperglycemia, but not hypoglycemia, was associated with the reduction of neuronal size in the rat brain. We hypothesized that hyperglycemia-induced changes in neuronal structure would have negative consequences, such as impaired learning and memory. We therefore assessed the effects of hyperglycemia and hypoglycemia on neuronal dendritic structure and cognitive functioning in young rats. Design/Methods:, Experimental manipulations were conducted on male Wistar rats for 8 wk, beginning at 4 wk of age. At the completion of the treatments, all rats were trained in the radial-arm water maze, a spatial (hippocampus-dependent) learning and memory task. Three groups of rats were tested: an untreated control group, a streptozotocin-induced diabetic (STZ-D) group, and an intermittent hypoglycemic group. Following behavioral training, the brains of all animals were examined with histologic and biochemical measurements. Results:, Peripheral hyperglycemia was associated with significant increases in brain sorbitol (7.5 ± 1.6 vs. 5.84 ± 1.0 ,M/mg) and inositol (9.6 ± 1.4 vs. 7.1 ± 1.1 ,M/mg) and reduced taurine (0.65 ± 0.1 vs. 1.3 ± 0.1 mg/mg). Histologic evaluation revealed neurons with reduced dendritic branching and spine density in STZ-D rats but not in control or hypoglycemic animals. In addition, the STZ-D group exhibited impaired performance on the water maze memory test. Conclusions:, Hyperglycemia, but not hypoglycemia, was associated with adverse effects on the brain polyol pathway activity, neuronal structural changes, and impaired long-term spatial memory. This finding suggests that the hyperglycemic component of diabetes mellitus has a greater adverse effect on brain functioning than does intermittent hypoglycemia. [source] Acute effect of antidiabetic 1,4-dihydropyridine compound cerebrocrast on cardiac function and glucose metabolism in the isolated, perfused normal rat heartCELL BIOCHEMISTRY AND FUNCTION, Issue 2 2008Janina Briede Abstract Diabetes mellitus (DM) is an important cardiovascular risk factor and is associated with abnormalities in endothelial and vascular smooth muscle cell function, evoked by chronic hyperglycemia and hyperlipidemia. Chronic insulin deficiency or resistance is marked by decreases in the intensity of glucose transport, glucose phosphorylation, and glucose oxidation, plus decreases in ATP levels in cardiac myocytes. It is important to search for new agents that promote glucose consumption in the heart and partially inhibit extensive fatty acid beta-oxidation observed in diabetic, ischemia. When the oxygen supply for myocardium is decreased, the heart accumulates potentially toxic intermediates of fatty acid beta-oxidation, that is, long-chain acylcarnitine and long-chain acyl-CoA metabolites. Exogenous glucose and heart glycogen become an important compensatory source of energy. Therefore we studied the effect of the antidiabetic 1,4-dihydropyridine compound cerebrocrast at concentrations from 10,10,M to 10,7,M on isolated rat hearts using the method of Langendorff, on physiological parameters and energy metabolism. Cerebrocrast at concentrations from 10,10,M to 10,7,M has a negative inotropic effect on the rat heart. It inhibits L -type Ca2+channels thereby diminishing the cellular Ca2+ supply, reducing contractile activity, and oxygen consumption, that normally favors enhanced glucose uptake, metabolism, and production of high-energy phosphates (ATP content) in myocardium. Cerebrocrast decreases heart rate and left ventricular (LV) systolic pressure; at concentrations of 10,10,M and 10,9,M it evokes short-term vasodilatation of coronary arteries. Increase of ATP content in the myocytes induced by cerebrocrast has a ubiquitous role. It can preserve the integrity of the cell plasma membranes, maintain normal cellular function, and inhibit release of lactate dehydrogenase (LDH) from cells that is associated with diabetes and heart ischemia. Administration of cerebrocrast together with insulin shows that both compounds only slightly enhance glucose uptake in myocardium, but significantly normalize the rate of contraction and relaxation (,±,dp/dt). The effect of insulin on coronary flow is more pronounced by administration of insulin together with cerebrocrast at a concentration of 10,7,M. Cerebrocrast may promote a shift of glucose consumption from aerobic to anerobic conditions (through the negative inotropic properties), and may be very significant in prevention of cardiac ischemic episodes. Copyright © 2007 John Wiley & Sons, Ltd. [source] | |||||||||||||