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

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.
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PMID:Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. 1101 58

Hyperinsulinemia in diabetes mellitus is a significant risk factor in the development of atherosclerosis and early restenosis after balloon angioplasty. These manifestations could be mediated by the ability of insulin to potentiate the cellular proliferative and reparative response of vascular cell types to local stimuli. Here we demonstrate that insulin stimulates DNA synthesis in aortic endothelial cells. Reverse transcription-polymerase chain reaction and Northern blotting revealed that insulin induces the expression and transcriptional activity of the immediate early gene and zinc finger transcription protein, early growth response factor-1 (Egr-1). Western immunoblot analysis revealed that insulin-inducible Egr-1 expression was inhibited using phosphorothioate-specific antisense oligonucleotides targeting Egr-1 mRNA. These agents blocked endothelial cell DNA synthesis stimulated by insulin in a dose-dependent manner and inhibited the capacity of insulin to potentiate the reparative response of endothelial cells to mechanical injury in vitro. These oligonucleotides also attenuated wound repair in smooth muscle cells. DNA synthesis induced by insulin was suppressed by inhibitors of two upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-phosphate (PI 3-K), whereas p38 kinase inhibitors had no effect. These present findings demonstrate that insulin-inducible DNA synthesis and repair after injury are processes critically dependent upon the activation of Egr-1. Additionally, they implicate this transcription factor as a potential target for the inhibition of restenosis in diabetics.
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PMID:Early growth response factor-1 mediates insulin-inducible vascular endothelial cell proliferation and regrowth after injury. 1125 35

Insulin controls glucose uptake by translocating GLUT4 and other glucose transporters to the plasma membrane in muscle and adipose tissues by a mechanism that appears to require protein kinase C (PKC)-zeta/lambda operating downstream of phosphatidylinositol 3-kinase. In diabetes mellitus, insulin-stimulated glucose uptake is diminished, but with hyperglycemia, uptake is maintained but by uncertain mechanisms. Presently, we found that glucose acutely activated PKC-zeta/lambda in rat adipocytes and rat skeletal muscle preparations by a mechanism that was independent of phosphatidylinositol 3-kinase but, interestingly, dependent on the apparently sequential activation of the dantrolene-sensitive, nonreceptor proline-rich tyrosine kinase-2; components of the extracellular signal-regulated kinase (ERK) pathway, including, GRB2, SOS, RAS, RAF, MEK1 and ERK1/2; and, most interestingly, phospholipase D, thus yielding increases in phosphatidic acid, a known activator of PKC-zeta/lambda. This activation of PKC-zeta/lambda, moreover, appeared to be required for glucose-induced increases in GLUT4 translocation and glucose transport in adipocytes and muscle cells. Our findings suggest the operation of a novel pathway for activating PKC-zeta/lambda and glucose transport.
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PMID:Glucose activates protein kinase C-zeta /lambda through proline-rich tyrosine kinase-2, extracellular signal-regulated kinase, and phospholipase D: a novel mechanism for activating glucose transporter translocation. 1146 95

A high concentration of circulating low-density lipoproteins (LDL) is a major risk factor for atherosclerosis. Native LDL and LDL modified by glycation and/or oxidation are increased in diabetic individuals. LDL directly stimulate vascular smooth muscle cell (VSMC) proliferation; however, the mechanisms remain undefined. The extracellular signal-regulated kinase (ERK) pathway mediates changes in cell function and growth. Therefore, we examined the cellular effects of native and modified LDL on ERK phosphorylation in VSMC. Addition of native, mildly modified (oxidized, glycated, glycoxidized) and highly modified (highly oxidized, highly glycoxidized) LDL at 25 microg/ml to rat VSMC for 5 min induced a fivefold increase in ERK phosphorylation. To elucidate the signal transduction pathway by which LDL phosphorylate ERK, we examined the roles of the Ca(2+)/calmodulin pathway, protein kinase C (PKC), src kinase, and mitogen-activated protein kinase kinase (MEK). Treatment of VSMC with the intracellular Ca(2+) chelator EGTA-AM (50 micromol/l) significantly increased ERK phosphorylation induced by native and mildly modified LDL, whereas chelation of extracellular Ca(2+) by EGTA (3 mmol/l) significantly reduced LDL-induced ERK phosphorylation. The calmodulin inhibitor N-(6-aminohexyl)-1-naphthalenesulfonamide (40 micromol/l) significantly decreased ERK phosphorylation induced by all types of LDL. Downregulation of PKC with phorbol myristate acetate (5 micromol/l) markedly reduced LDL-induced ERK phosphorylation. Pretreatment of VSMC with a cell-permeable MEK inhibitor (PD-98059, 40 micromol/l) significantly decreased ERK phosphorylation in response to native and modified LDL. These findings indicate that native and mildly and highly modified LDL utilize similar signaling pathways to phosphorylate ERK and implicate a role for Ca(2+)/calmodulin, PKC, and MEK. These results suggest a potential link between modified LDL, vascular function, and the development of atherosclerosis in diabetes.
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PMID:Activation of MAPK by modified low-density lipoproteins in vascular smooth muscle cells. 1150 43

To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia. At a high glucose concentration, O-glycosylation of p53 occurred between 10 and 20 min, reached its peak at 1 h, and then decreased with time. Angiotensin II synthesis increased at 45 min and 1 h, resulting in p38 mitogen-activated protein (MAP) kinase-driven p53 phosphorylation at Ser 390. p53 phosphorylation was absent at the early time points, becoming evident at 1 h, and increasing progressively from 3 h to 4 days. Phosphorylated p53 at Ser 18 and activated c-Jun NH(2)-terminal kinases were identified with hyperglycemia, whereas extracellular signal-regulated kinase was not phosphorylated. Upregulation of p53 was associated with an accumulation of angiotensinogen and AT(1) and enhanced production of angiotensin II. Bax quantity also increased. These multiple adaptations paralleled the concentrations of glucose in the medium and the duration of the culture. Myocyte death by apoptosis directly correlated with glucose and angiotensin II levels. Inhibition of O-glycosylation prevented the initial synthesis of angiotensin II, p53, and p38-MAP kinase (MAPK) phosphorylation and apoptosis. AT(1) blockade had no influence on O-glycosylation of p53, but it interfered with p53 phosphorylation; losartan also prevented phosphorylation of p38-MAPK by angiotensin II. Inhibition of p38-MAPK mimicked at a more distal level the consequences of losartan. In conclusion, these in vitro results support the notion that hyperglycemia with diabetes promotes myocyte apoptosis mediated by activation of p53 and effector responses involving the local renin-angiotensin system.
Diabetes 2001 Oct
PMID:Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. 1157 21

Nonenzymatic glycation is increased in diabetes. The role of advanced glycation end products has been implicated in many of the complications of diabetes, whereas the effects of early-glycation Amadori-modified proteins on vascular cells alone are poorly defined. In the present study, we show that glycated serum albumin (GSA) induces a parallel activation of the redox-responsive transcription factors (nuclear factor kappaB) and AP-1 and increases activity of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK in vascular smooth muscle cells (VSMCs). GSA increased expression of early response genes, c-fos and c-jun, and inflammatory genes, monocyte chemoattractant peptide (MCP-1), and interleukin (IL)-6. These effects were comparable to bacterial lipopolysaccharide, tumor necrosis factor-alphaa, (TNF-alphaa), IL-1alphab, angiotensin II, epidermal growth factor, and the phorbol ester PMA. One of signaling pathways by which GSA activates VSMCs appears to be via nuclear factor kappaB activation, leading to induction of MCP-1 and IL-6 gene expression, comparable to the effects of lipopolysaccharide, TNF-alphaa, and IL-1alphab. Another signaling cascade by which GSA activates VSMCs is the ERK-->c-Fos-->AP-1 pathway, which may lead to stimulation of cell proliferation and migration. These effects are comparable to the effects of angiotensin II, epidermal growth factor, and PMA. Incubation of VSMCs with the antioxidant N-acetylcysteine suppressed GSA-elicited mRNA induction of MCP-1 and IL-6. Inhibition of p38 MAPK but not ERK caused attenuation of MCP-1 and IL-6 mRNA induction. Finally, GSA caused a significant stimulation of VSMC growth and migration. These findings suggest that GSA may play a role in diabetic atherogenesis by activating VSMCs, leading to induction of inflammatory mediators in the vessel wall, as well as proliferation and migration of VSMCs.
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PMID:Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). 1179 73

We have previously reported that high glucose stimulates osteopontin (OPN) expression through protein kinase C-dependent pathway, as well as the hexosamine pathway, in cultured rat aortic smooth muscle cells (SMC). The finding prompted us to study in vivo expression of OPN in diabetes mellitus. In the present study, we found by immunohistochemistry that medial layers of the carotid arteries of streptozotocin (STZ)-induced diabetic rats, as well as the forearm arteries of diabetic patients, stained positive with OPN antibodies, whereas the staining of control rats, as well as nondiabetic patients, was negative. We also found that OPN stimulated migration and enhanced platelet-derived growth factor (PDGF)-mediated DNA synthesis of cultured rat aortic SMC. OPN and PDGF synergistically activated focal adhesion kinase (FAK), as well as extracellular signal-regulated kinase (ERK), which seems to be a reason for OPN-induced enhancement of PDGF-mediated DNA synthesis. Taken together, our present results raise a possibility that OPN plays a role in the development of diabetic vascular complications.
J Diabetes Complications
PMID:Hyperglycemia-induced alteration of vascular smooth muscle phenotype. 1187 70

Recent studies have demonstrated that p44/42(MAPK) extracellular signal-regulated kinase (ERK)1 and -2-dependent Na(+)-K(+)-2Cl(-) co-transporter (NKCC) activity may contribute to total potassium uptake by skeletal muscle. To study the precise mechanisms regulating NKCC activity, rat soleus and plantaris muscles were stimulated ex vivo by insulin or isoproterenol (ISO). Both hormones stimulated total uptake of the potassium congener (86)Rb by 25--70%. However, only ISO stimulated the NKCC-mediated (86)Rb uptake. Insulin inhibited the ISO-stimulated NKCC activity, and this counteraction was sensitive to the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 in the predominantly slow-twitch soleus muscle. Pretreatment of the soleus muscle with the phosphatidylinositol (PI) 3-kinase inhibitors wortmannin and LY294002 or with SB203580 uncovered an insulin-stimulated NKCC activity and also increased the insulin-stimulated phosphorylation of ERK. In the predominantly fast-twitch plantaris muscle, insulin-stimulated NKCC activity became apparent only after inhibition of PI 3-kinase activity, accompanied by an increase in ERK phosphorylation. PI 3-kinase inhibitors also abolished insulin-stimulated p38 MAPK phosphorylation in the plantaris muscle and Akt phosphorylation in both muscles. These data demonstrated that insulin inhibits NKCC-mediated transport in skeletal muscle through PI 3-kinase-sensitive and SB203580-sensitive mechanisms. Furthermore, differential activation of signaling cascade elements after hormonal stimulation may contribute to fiber-type specificity in the control of potassium transport by skeletal muscle.
Diabetes 2002 Mar
PMID:Insulin and isoproterenol differentially regulate mitogen-activated protein kinase-dependent Na(+)-K(+)-2Cl(-) cotransporter activity in skeletal muscle. 1187 58

Methylglyoxal (MG), a reactive dicarbonyl produced during glucose metabolism, induced a dose- and time-dependent increase in aldose reductase (AR) mRNA level in rat aortic smooth muscle cells (SMCs). AR has been implicated in the pathogenesis of diabetic complications, whereas the clinical efficacy of AR inhibitors has not been unequivocally proven. The enzyme catalyzes the reduction of glucose in the polyol pathway, as well as that of MG, which is known to be a preferred substrate of AR. A maximum of 4.5-fold induction of AR mRNA by MG was accompanied by elevated enzyme activity and protein levels and was completely abolished in the presence of cycloheximide or actinomycin D. Pretreatment of SMCs with N-acetyl-L-cysteine significantly suppressed the MG-induced AR expression, whereas DL-buthionine-(S,R)-sulfoximine further augmented the MG-induced increase in AR mRNA level. Intracellular levels of reactive oxygen species determined using 2',7'-dichlorofluorescein diacetate were significantly elevated in SMCs treated with MG, suggesting the involvement of oxidative stress in this process. However, inconsistent with our previous findings on oxidative stress-induced up-regulation of AR, the inhibition of extracellular signal-regulated kinase by 2'-amino-3'-methoxyflavone (PD98059) did not affect MG-induced AR expression, whereas blockade of the p38 mitogen-activated protein kinase pathway by 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl) imidazol (SB203580) significantly suppressed the induction. The cytotoxic effect of MG on SMCs was significantly enhanced in the presence of the AR inhibitor ponalrestat, indicating a protective role of AR against MG-induced cell damage. Taken together, these observations indicated that substrate-induced induction of AR by MG during hyperglycemic conditions may hinder vascular remodeling and accelerate the development of vascular lesions in diabetes.
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PMID:Substrate-induced up-regulation of aldose reductase by methylglyoxal, a reactive oxoaldehyde elevated in diabetes. 1196 Nov 37

Changes in glucose metabolism during diabetes are linked to an increased risk for the development of cancer. Increased activity of aldose reductase, the rate-limiting polyol pathway enzyme that converts glucose into sorbitol, mediates pathologies associated with diabetes and is thought to be involved in increased resistance to chemotherapeutic drugs. Thus, increased intracellular sorbitol levels may serve a protective function in cancer cells. In these studies we determined whether an inhibitor of aldose reductase could enhance the effectiveness of anticancer agents. Our findings indicate that treatment with the aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (EBPC), enhances the cytotoxic effects of the anticancer agents doxorubicin and cisplatin in HeLa cervical carcinoma cells. To establish a mechanistic basis for the increased cytotoxicity by EBPC, we examined the activity of the extracellular signal-regulated kinase (ERK) pathway, which is an important regulator of cell growth. Interestingly, treatment with EBPC in combination with the chemotherapeutic drugs increased ERK activity as compared to treatment with the chemotherapeutic drugs, suggesting a possible role for the ERK pathway in mediating doxorubicin- or cisplatin-induced cell death. Consistent with this possibility, inhibition of ERK activation by the MEK inhibitor, U0126, reversed the EBPC-mediated enhancement of cell death. In summary, these data provide evidence that adjuvant therapy with aldose reductase inhibitors improves the effectiveness of chemotherapeutic drugs, possibly through an ERK pathway-mediated mechanism.
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PMID:Inhibition of aldose reductase enhances HeLa cell sensitivity to chemotherapeutic drugs and involves activation of extracellular signal-regulated kinases. 1239 72


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