Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the well-documented effect of irbesartan, an angiotensin AT1 receptor antagonist, on diabetic nephropathy, its effect on mortality related to multiple metabolic risk factors is unknown. To address this question, obese fa/fa Zucker rats were submitted to a 13-month treatment by irbesartan (30 mg/kg/day p.o.). Vehicle-treated obese fa/fa Zucker rats exhibited an important mortality (72%), which was markedly reduced by irbesartan (22%, P<0.05). Mortality in control lean fa/+ rats attained 12%. Irbesartan diminished the elevation in urinary protein excretion, plasma creatinine and urea nitrogen levels, and reduced the extent of glomerular and tubulo-interstitial lesions together with a reduction of urinary monocyte chemoattractant protein-1 excretion in fa/fa Zucker rats. Irbesartan treatment prevented the rise in plasma total cholesterol, triglycerides and glucose levels, and partially corrected low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio in fa/fa Zucker rats. Therefore, prolonged irbesartan treatment preserves renal function and metabolic profile, and substantially increases survival in obese fa/fa Zucker rats.
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PMID:Long-term blockade of angiotensin AT1 receptors increases survival of obese Zucker rats. 1651 82

It is recognized that brain oxygen deprivation results in increased glycolysis and lactate accumulation. Moreover, glucose metabolism is altered during starvation or diet, resulting in increased plasma ketones (acetoacetate + beta-hydroxybutyrate; BHB). We investigated glucose and lactate adaptation to hypoxia in concurrence with diet-induced ketosis. Male Wistar rats were fed standard (STD), ketogenic (high fat; KG), or carbohydrate-rich (low fat; CHO) diets for 3 wks and then exposed to hypobaric (0.5 ATM) or normobaric atmosphere for 3 wks while on their diets. Lactate, ketones, and glucose concentrations were measured in plasma (mM) and brain tissue (mmol/g). Plasma and tissue ketone levels were elevated up to 12-fold in the KG fed groups compared with other groups (STD and CHO), with the hypoxic KG group reaching the highest levels (2.6 +/- 1.3 mM and 0.3 +/- 0.1 mmol/g; mean +/- SD). Tissue lactate levels in the hypoxic ketotic rats (4.7 +/- 1.3 mM) were comparable with normoxic STD (5.0 +/- 0.7 mM) and significantly lower (ANOVA P < .05) than the hypoxic STD rats (6.1 +/- 1.0 mM). These data indicate that adaptation to hypoxia did not interfere with ketosis, and that ketosis during hypoxia may lower lactate levels in brain, suggesting decreased glycolysis or increased glucose disposal.
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PMID:Adaptation to chronic hypoxia during diet-induced ketosis. 1659 34

Histone H2AX phosphorylated on Ser-139, defined as gammaH2AX, is a reporter of DNA double-strand breaks (DSBs). While H2AX undergoes phosphorylation after induction of DNA damage by genotoxic agents or during physiological events that involve DNA recombination, it also is phosphorylated in untreated normal and tumor cells. We recently reported that this constitutive H2AX phosphorylation (CHP) is markedly reduced by the antioxidant N-acetyl-L-cysteine (NAC), and postulated that it reflects the oxidative DNA damage ("endogenous DSBs") induced by reactive oxygen species (ROS) generated by metabolic activity during progression through the cell cycle. In the present study, we provide evidence that growth of cells from three human lymphoblastoid cell lines TK6, NH32 and WTK1 in the presence of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) led to a distinct reduction in the level of CHP. The reduction of CHP was more pronounced in S and G(2)M than in G(1) phase cells. Constitutive activation of ATM was also reduced. The data suggest that a decrease in a cell's metabolic activity as a result of inhibition of glycolysis by 2-DG reduces generation of ROS which leads to the reduction of oxidative DNA damage. The data also point out that ATM may play a role in CHP induced by oxidative DNA damage. Therefore, the assay of CHP by multiparameter cytometry provides the means to measure effects of antioxidants and metabolic inhibitors on endogenous oxidative DNA damage in relation to cell cycle phase.
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PMID:2-deoxy-D-glucose reduces the level of constitutive activation of ATM and phosphorylation of histone H2AX. 1662 6

AT1 receptor blockers and ACE inhibitors decrease the risk for new onset diabetes mellitus. The phenomenon could be related to a direct angiotensin II effect on tissue metabolism. To address the issue, we recruited eighteen obese hypertensive patients. Patients were randomized to double-blind treatment with either valsartan (n = 8) or atenolol (n = 10) for thirteen weeks. They underwent an oral glucose tolerance test before and during active treatment, while metabolism was monitored through subcutaneous and intramuscular microdialysis and indirect calorimetry. After glucose ingestion, venous glucose and insulin concentrations increased rapidly while systemic free fatty acid concentrations were suppressed. Dialysate glucose and lactate concentrations increased briskly in adipose tissue and in skeletal muscle. Dialysate glycerol decreased profoundly in both tissues. Respiratory quotient increased markedly after glucose ingestion. These responses were identical at baseline and during active treatment either drug. We conclude that AT1 receptor blockade in obese hypertensive patients has no effect on interstitial glucose supply, lipolysis, and substrate oxidation. One possible explanation is that angiotensin II levels in obese hypertensives are not sufficient to elicit the metabolic changes that have been observed after direct angiotensin II application. The exact mechanism by which inhibition of the renin-angiotensin-aldosterone system decreases the diabetes risk remains unresolved and requires further study.
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PMID:The effect of oral glucose loads on tissue metabolism during angiotensin II receptor and beta-receptor blockade in obese hypertensive subjects. 1671 29

The pathophysiology of the diabetic kidney (e.g., hypertrophy, increase urinary albumin excretion (UAE) is still ill-defined. Parathyroid hormone-related protein (PTHrP) is overexpressed in several nephropathies, but its role remains unclear. We evaluated the effect of high glucose on PTHrP and the PTH1 receptor (PTH1R) protein (by Western blot and immunohistochemistry) in the kidney of mice ith streptozotocin-induced diabetes, and in several mouse renal cells in vitro. Diabetic mice showed a significantly increased renal expression of PTHrP and PTH1R proteins with 2-8 weeks from the onset of diabetes. These animals exhibited an intense immunostaining for both proteins in the renal tubules and glomeruli. Using transgenic mice overexpressing PTHrP targeted to the renal proximal tubule, we found a significant increase in the renal hypertrophy index and in UAE in these diabetic mice relative to their control littermates. Moreover, logistic regression analysis showed a significant association between both PTHrP and PTH1R protein levels and UAE in all diabetic mice throughout the study. High-glucose (25 mm) medium was found to increase PTHrP and PTH1R in tubuloepithelial cells, mesangial cells and podocytes in vitro. Moreover, this increase in PTHrP (but not that of PTH1R) was inhibited by the AT1 receptor antagonist losartan. Collectively, these results indicate that the renal PTHrP/PTH1R system is upregulated in streptozotozin-induced diabetes in mice, and appears to adversely affect the outcome of diabetic renal disease. Our findings also suggest that angiotensin II might have a role in the PTHrP upregulation in this condition.
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PMID:The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes. 1678 82

This study investigates the mechanisms whereby angiotensin II (Ang II) signaling contributes to cell growth and glucose metabolism in cultured vascular smooth muscle cells (VSMCs) from male Wistar fatty rats (WF) and their littermates (Wistar lean rats, WL). The levels of the medial outgrowth rate of VSMCs and Ang II type-1 receptors (AT1R) in aortae from WF were more enhanced than those in aortae from WL, but the level of Ang II type-2 receptors (AT2R) was not different. A mixture of insulin and Ang II additively increased the values of [(3)H]-thymidine incorporation in WF and WL, which was inhibited by olmesartan, an AT1 receptor blockade (ARB), but not by PD123,319, an AT2 receptor blockade. Similarly, insulin and Ang II phosphorylated extracellular-regulated protein kinase 1/2, retinoblastoma tumor suppressor protein, and cyclic AMP response element binding protein, and these levels were higher in WF than in WL. In contrast, the phosphorylation was suppressed by olmesartan but not PD123,319. Insulin-stimulated Akt phosphorylation and 2-deoxy-d-glucose uptake in WF were significantly reduced by Ang II, and the reduction was ameliorated by olmesartan but not PD123,319. Differently from the result of Akt, the phosphorylation of the insulin-stimulated insulin receptor beta-subunit was not affected by Ang II, olmesartan, or PD123,319. However, the phosphorylation of insulin-stimulated insulin-related substrate (IRS)-1 was suppressed by Ang II, and the suppression was ameliorated by olmesartan, but not PD123,319, in both WF and WL. In contrast, the phosphorylation of IRS-1 on Ser(307) was elevated by the Ang II, and the elevation was suppressed by olmesartan, but not by PD123,319, in both WF and WL. These findings demonstrated that Ang II signaling contributes to cell proliferation and inhibition of the insulin signaling pathways through AT1R, but not trough AT2R, in both non-diabetic and diabetic VSMCs.
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PMID:Role of angiotensin II type-1 and type-2 receptors on vascular smooth muscle cell growth and glucose metabolism in diabetic rats. 1693 5

DNA in live cells undergoes continuous oxidative damage caused by metabolically generated endogenous as well as external oxidants and oxidant-inducers. The cumulative oxidative DNA damage is considered the key factor in aging and senescence while the effectiveness of anti-aging agents is often assessed by their ability to reduce such damage. Oxidative DNA damage also preconditions cells to neoplastic transformation. Sensitive reporters of DNA damage, particularly the induction of DNA double-strand breaks (DSBs), are activation of ATM, through its phosphorylation on Ser 1981, and phosphorylation of histone H2AX on Ser 139; the phosphorylated form of H2AX has been named gammaH2AX. We review the observations that constitutive ATM activation (CAA) and H2AX phosphorylation (CHP) take place in normal cells as well in the cells of tumor lines untreated by exogenous genotoxic agents. We postulate that CAA and CHP, which have been measured by multiparameter cytometry in relation to the cell cycle phase, are triggered by oxidative DNA damage. This review also presents the findings on differences in CAA and CHP in various cell lines as well as on the effects of several agents and growth conditions that modulate the extent of these histone and ATM modifications. Specifically, described are effects of the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), and the glutathione synthetase inhibitor buthionine sulfoximine (BSO) as well as suppression of cell metabolism by growth at higher cell density or in the presence of the glucose antimetabolite 2-deoxy-D-glucose. Collectively, the reviewed data indicate that multiparameter cytometric measurement of the level of CHP and/or CAA allows one to estimate the extent of ongoing oxidative DNA damage and to measure the DNA protective-effects of antioxidants or agents that reduce or amplify generation of endogenous ROS.
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PMID:Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants. 1694 Jul 54

Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.
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PMID:ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. 1708 7

Hypertension is often associated with an impairment of glucose tolerance and is a risk factor for the development of type 2 diabetes mellitus. The occurrence of diabetes may be also influenced by the selection of the type of antihypertensive treatment. While it has been shown that the use of older type antihypertensives - diuretics and beta-blockers - may precipitate diabetes, newer drugs which inhibit the renin-angiotensin system have a positive effect on glucose tolerance. Several recent clinical trials of ACE-inhibitors and AT1-blockers have demonstrated a decreased risk of the occurrence of diabetes in comparison with placebo or conventional antihypertensive drugs. The mechanisms responsible for the antidiabetic effect of these newer antihypertensive agents remain largely speculative. Insulin resistance may be improved in several ways, e.g. by changes in microcirculation or direct effects on insulin response and glucose transport in target organ cells. However, as shown in experimental studies, improved islet function and insulin secretion may also have role due to an inhibitory effect on the local renin-angiotensin system in the pancreas. Ongoing prospective clinical trials having the occurrence of diabetes as a primary specified endpoint should confirm the preventive potential of the inhibitors of the renin-angiotensin system. Since direct comparisons are lacking, current data are inconclusive as to the superiority of one of the two classes of these inhibitors or of any single drug. Nevertheless, inhibitors of the renin-angiotensin system should definitely represent first choice antihypertensive agents for persons with additional risk factors such as family history of diabetes, obesity or impaired glucose tolerance.
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PMID:[Prevention of type 2 diabetes mellitus due to antihypertensive treatment affecting renin-angiotensin system]. 1709 2

During aging increases in body weight, insulin resistance, and elevated systolic pressure contribute to the development of metabolic syndrome. Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 (AT1) receptor antagonist or angiotensin converting enzyme inhibitor improves insulin sensitivity and decreases risk of new onset (type II) diabetes. However, the role of the brain RAS in mediating development of insulin insensitivity during aging is not known. Therefore, we compared responses to an oral glucose load in transgenic rats with selective antisense suppression of brain angiotensinogen (ASrAogen); (mRen2)27 rats with high brain angiotensin II; and control Hannover Sprague-Dawley (SD) rats, at wk 16 and 68 of age. ASrAogen animals had lower body weight than either SD or (mRen2)27 rats at both ages (p < 0.001). The oral glucose tolerance test at 16 wk in (mRen2)27 animals revealed a higher glucose-insulin index (154,421 +/- 11,231 units; p < 0.05) and a lower glucose-insulin index in ASrAogen rats (41,580 +/- 10,923 units, p < 0.05) compared to SD rats (97,134 +/- 19,822 units), suggesting insulin resistance in the (mRen2)27 and enhanced insulin sensitivity in the ASrAogen relative to SD rats. At 68 wk, the glucose-insulin index remained low in the ASrAogen rats as evidence of maintained insulin sensitivity during aging compared with either SD or (mRen2)27 (p < 0.05). SD animals do not differ from (mRen2)27 rats at 68 wk indicating the development of a state of relative insulin resistance with increased age in the SD rats. Moreover, there was a positive correlation (r = 0.44; p < 0.05) between body weight and the glucose-insulin index in SD, but not ASrAogen or (mRen2)27 rats. The relationships between insulin and leptin, insulin and glucose, and leptin and body weight observed in SD rats were absent in ASrAogen and (mRen2)27 rats. We conclude that the glial RAS plays a role in development of insulin resistance as well as influencing weight gain associated with early aging.
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PMID:Rats with low brain angiotensinogen do not exhibit insulin resistance during early aging. 1732 75


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