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)

Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the A-T mutated (ATM) gene. The gene encodes a serine/threonine kinase with important roles in the cellular response to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although these functions might explain the cancer predisposition of A-T patients, the molecular mechanisms leading to glucose intolerance and diabetes mellitus (DM) are unknown. We have investigated the pathogenesis of DM in a mouse model of A-T. Here we show that young Atm-deficient mice show normal fasting glucose levels and normal insulin sensitivity. However, oral glucose tolerance testing revealed delayed insulin secretion and resulting transient hyperglycemia. Aged Atm-/- mice show a pronounced increase in blood glucose levels and a decrease in insulin and C-peptide levels. Our findings support a role for ATM in metabolic function and point toward impaired insulin secretion as the primary cause of DM in A-T.
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PMID:Impaired insulin secretion in a mouse model of ataxia telangiectasia. 1735 10

Two mercury-resistant strains of heterotrophic, aerobic, marine bacteria, designated AT1(T) and AS1(T), were isolated from water samples collected from the Er-Jen River estuary, Tainan, Taiwan. Cells were Gram-negative rods that were motile by means of a single polar flagellum. Buds and prosthecae were produced. The two isolates required NaCl for growth and grew optimally at about 30 degrees C, 2-4 % NaCl and pH 7-8. They grew aerobically and were incapable of anaerobic growth by fermenting glucose or other carbohydrates. They grew and expressed Hg(2+)-reducing activity in liquid media containing HgCl(2). Strain AS1(T) reduced nitrate to nitrite. The predominant isoprenoid quinone was Q(8) (91.3-99.9 %). The polar lipids of strain AT1(T) consisted of phosphatidylethanolamine (46.6 %), phosphatidylglycerol (28.9 %) and sulfolipid (24.5 %), whereas those of AS1(T) comprised phosphatidylethanolamine (48.2 %) and phosphatidylglycerol (51.8 %). The two isolates contained C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH (22.4-33.7 %), C(16 : 0) (19.0-22.7 %) and C(18 : 1)omega7c (11.3-11.7 %) as the major fatty acids. Strains AT1(T) and AS1(T) had DNA G+C contents of 43.1 and 45.3 mol%, respectively. Phylogeny based on 16S rRNA gene sequences, together with data from morphological, physiological and chemotaxonomic characterization, indicated that the two isolates could be classified as representatives of two novel species in the genus Alteromonas, for which the names Alteromonas tagae sp. nov. (type strain AT1(T)=BCRC 17571(T)=JCM 13895(T)) and Alteromonas simiduii sp. nov. (type strain AS1(T)=BCRC 17572(T)=JCM 13896(T)) are proposed.
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PMID:Alteromonas tagae sp. nov. and Alteromonas simiduii sp. nov., mercury-resistant bacteria isolated from a Taiwanese estuary. 1755 Oct 31

AMPK is an AMP-activated protein kinase that plays an important role in regulating cellular energy homeostasis. Metabolic stress, such as heat shock and glucose starvation, causes an energy deficiency in the cell and leads to elevated levels of intracellular AMP. This results in the phosphorylation and activation of AMPK. LKB1, a tumor suppressor, has been identified as an upstream kinase of AMPK. We found that in response to treatment with 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), the LKB1 deficient cancer cell line, HeLa, exhibited AMPK-alpha phosphorylation. This indicates the existence of an LKB1-independent AMPK-alpha phosphorylation pathway. ATM is a protein that is deficient in the disease ataxia telangiectasia (A-T). We measured the activation of AMPK by AICAR in the normal mouse embryo fibroblast cell line, A29, and the mouse cell line lacking the ATM protein, A38. In A38 cells, the level of AICAR-induced AMPK-alpha phosphorylation was significantly lower than that found in A29 cells. Furthermore, phosphorylation of AMPK in HeLa and A29 cells was inhibited by an ATM specific inhibitor, KU-55933. Our results demonstrate that AICAR treatment could lead to phosphorylation of AMPK in an ATM-dependent and LKB1-independent manner. Thus, ATM may function as a potential AMPK kinase in response to AICAR treatment.
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PMID:AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner. 1778 44

In patients with acute myocardial infarction (AMI), the mechanisms behind the increased mortality related to glucose levels (GL) are poorly understood. The main purpose of this study is to analyze the relationship between baseline glucose and left ventricular enlargement (LVE). We analyzed 52 patients with a first ST-elevation AMI <24 h of evolution. Glucose levels were obtained upon admission (median time, 3 h after the beginning of chest pain). The median GL was 123.5 mg/dl, and patients above this limit were considered hyperglycemic (n=26). Left ventricular enlargement was analyzed comparing two radionuclide ventriculographies, the first obtained within 4 days post-AMI (median, 55 h) and the second 6 months later (median, 188.5 days), taking into account the difference in the obtained end-systolic volumes. Myocardial reperfusion was evaluated comparing ST resolution between a first ECG done immediately upon hospital arrival with a second ECG performed 2 h after treatment. By univariate analysis, LVE correlated significantly with baseline hyperglycemia (P<.001), failed reperfusion by ECG criteria (P<.001), and no use of ACE inhibitors or AT1 blockers (P=.046) and aspirin (P=.046). A history of previous diabetes did not correlate significantly with LVE at 6 months. In the adjusted model, basal hyperglycemia (P<.001) and failed reperfusion (P=.001) were the only variables independently correlated with LVE. In conclusion, baseline glucose is a powerful and independent predictor of LVE after AMI, which reinforces the importance of a tight glucose control during the initial phase of the disease.
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PMID:Baseline glucose and left ventricular remodeling after acute myocardial infarction. 1782 53

Recent evidence suggests a crosstalk between angiotensin II (Ang II) and insulin. However, whether this crosstalk affects glucose uptake, particularly in terms of actin filament involvement, has not yet been studied in vascular smooth muscle cells. Pretreatment of cells with either Ang II or cytochalasin D disarranged actin filaments in a time-dependent manner and inhibited glucose uptake. However, insulin increased actin reorganization and glucose uptake. Membrane fractionation studies showed that Ang II decreased GLUT-1 at the cell membrane, whereas it increased GLUT-1 in the cytoplasm, indicating that Ang II may cause internalization of GLUT-1 via actin disorganization, consequently decreasing glucose uptake. The effects of Ang II on glucose uptake and actin reorganization were blocked by AT1 receptor antagonist, but not by AT2 antagonist. Either P38 or ERK1/2 inhibitors partially reversed the Ang II-inhibited actin reorganization and glucose uptake, suggesting that MAPK signaling pathways could be involved as downstream events in Ang II signaling, and this signaling may interfere with insulin-induced actin reorganization and glucose uptake. These data imply that Ang II induces insulin resistance by decreasing glucose uptake via disarrangement of actin filaments, which provides a novel insight into understanding of insulin resistance by Ang II at the molecular level.
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PMID:Angiotensin II decreases glucose uptake by downregulation of GLUT1 in the cell membrane of the vascular smooth muscle cell line A10. 1787 54

To define some of the specific cellular effects of chronic hypoxia on the small intestine, we measured the concentration of glucose transporter 2 (GLUT2) at two sites, the jejunum and ileum. Wister rats were subjected to 21-day normoxia (n = 6) or to continuous 21-day hypobaric hypoxia approximately 0.5 ATM (n = 5). Western blot analysis was performed and the abundance of GLUT2 protein was quantified as relative densitometric units and normalized to actin. GLUT2 content was similar in the jejunum and ileum under normoxic (jejunum = 0.65 +/- 0.13 mean +/- SD; ileum = 0.56 +/- 0.22 OD; mean difference 0.09, p = 0.09) and hypoxic conditions (jejunum = 0.56 +/- 0.14 OD mean +/- SD; ileum = 0.58 +/- 0.16; mean difference -0.01, p = 0.42). GLUT2 decreased by 14% of the mean normoxic jejunal levels whereas ileal GLUT2 was slightly increased. A maximum decline in weight of 15% occurred at day 4 followed by a blunted rate of weight gain for rats in the hypoxic group. Thus, sustained exposure to hypobaric hypoxia reduced the availability of GLUT2 for glucose transport in the jejunum. Regulating small intestinal content of glucose transporters may be an important mechanism for tissue adaptation to chronic hypoxia. This finding provides initial insight into hypoxic tolerance of the gut to chronic hypobaric hypoxic exposure.
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PMID:Hypobaric hypoxia reduces GLUT2 transporter content in rat jejunum more than in ileum. 1829 Mar 45

The angiogenic, neovascular proliferative retinopathies, proliferative diabetic retinopathy (PDR), and age-dependent macular degeneration (AMD) complicated by choroidal neovascularization (CNV), also termed exudative or "wet" AMD, are common causes of blindness. The antidiabetic thiazolidinediones (TZDs), rosiglitazone, and troglitazone are PPARgamma agonists with demonstrable antiproliferative, and anti-inflammatory effects, in vivo, were shown to ameliorate PDR and CNV in rodent models, implying the potential efficacy of TZDs for treating proliferative retinopathies in humans. Activation of the angiotensin II type 1 receptor (AT1-R) propagates proinflammatory and proliferative pathogenic determinants underlying PDR and CNV. The antihypertensive dual AT1-R blocker (ARB), telmisartan, recently was shown to activate PPARgamma and improve glucose and lipid metabolism and to clinically improve PDR and CNV in rodent models. Therefore, the TZDs and telmisartan, clinically approved antidiabetic and antihypertensive drugs, respectively, may be efficacious for treating and attenuating PDR and CNV humans. Clinical trials are needed to test these possibilities.
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PMID:PPARgamma Agonists: Potential as Therapeutics for Neovascular Retinopathies. 1850 99

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia and oculocutaneous telangiectasias. Patients with A-T also have high incidences of type 2 diabetes mellitus. The gene mutated in this disease, ATM (A-T, mutated), encodes a protein kinase. Previous studies have demonstrated that cytoplasmic ATM is an insulin-responsive protein and a major upstream activator of Akt following insulin treatment. To further investigate the function of ATM in insulin signal transduction, insulin resistance was induced in rats by feeding them a high-fat diet. Muscle tissue of rats with insulin resistance had both dramatically reduced ATM levels and substantially decreased Akt phosphorylation at Ser473 in comparison to that of regular chow-fed controls. The decreased ATM expression suggests that ATM is involved in the development of insulin resistance through down-regulation of Akt activity. The role of ATM in activation of Akt was further confirmed in mouse embryonic fibroblast (MEF) A29 (ATM+/+) and A38 (ATM-/-) cells. In addition, insulin-mediated Akt phosphorylation in mouse L6 muscle cells was greatly reduced by KU-55933, a specific inhibitor of ATM. A 2-deoxyglucose incorporation assay showed that this inhibitor also caused a significant reduction in insulin-mediated glucose uptake in L6 cells. An immunofluorescence experiment demonstrated that in L6 cells transfected with wild-type (WT) ATM, insulin caused a dramatic increase of the cell surface glucose transporter 4 (GLUT4), while in cells transfected with kinase-dead (KD) ATM, translocation of GLUT4 to the cell surface in response to insulin was markedly inhibited.
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PMID:ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells. 1853 19

Several enzymatic sources of reactive oxygen species (ROS) were described as potential reasons of eNOS uncoupling in diabetes mellitus. In the present study, we investigated the effects of AT1-receptor blockade with chronic telmisartan (25 mg/kg/day, 6.5 weeks) therapy on expression of the BH4-synthesizing enzyme GTP-cyclohydrolase I (GCH-I), eNOS uncoupling, and endothelial dysfunction in streptozotocin (STZ, 60 mg/kg iv, 7 weeks)-induced diabetes mellitus (type I). Telmisartan therapy did not modify blood glucose and body weight. Aortas from diabetic animals had vascular dysfunction as revealed by isometric tension studies (acetylcholine and nitroglycerin potency). Vascular and cardiac ROS produced by NADPH oxidase, mitochondria, eNOS, and xanthine oxidase were increased in the diabetic group as was the expression of NADPH oxidase subunits at the protein level. The expression of GCH-I and the phosphorylation of eNOS at Ser1177 was decreased by STZ treatment. Therapy with telmisartan normalized these parameters. The present study demonstrates for the first time that AT1-receptor blockade by telmisartan prevents downregulation of the BH4 synthase GCH-I and thereby eNOS uncoupling in experimental diabetes. In addition, telmisartan inhibits activation of superoxide sources like NADPH oxidase, mitochondria, and xanthine oxidase. These effects may explain the beneficial effects of telmisartan on endothelial dysfunction in diabetes.
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PMID:AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. 1853 57

Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulin-induced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin II-aldosterone systems and their role in glucose metabolism and diabetes prevention.
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PMID:The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. 1885 18


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