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

The mitogen-activated protein (MAP) kinases and ribosomal S6 protein kinases in the skeletal muscle of insulin-resistant long-term (2 and 6 months' duration) diabetic rats were investigated to understand further the changes in insulin intracellular signaling pathways that accompany diabetes. The effects of insulin-mimetic vanadium compounds on the activity of these kinases were also examined. In the insulin-resistant 2-month diabetic rats, the basal activities of MAP kinases were relatively unchanged, while the basal activities of S6 kinases were significantly increased. Intravenous injection of insulin moderately activated both the 42-kDa MAP kinase (p42mapk) and a 44-kDa MAP kinase (p44erk1) in the 2-month control rats but not in the 2-month diabetic rats. Insulin treatment markedly stimulated the activity of a novel 31-kDa S6 kinase and the previously described 90-kDa ribosomal S6 kinase encoded by one of the rsk genes (p90rsk) in the 2-month control rats, while the effect was substantially reduced in the diabetic rats. In the 6-month diabetic rats, the basal phosphotransferase activities of both MAP kinases were depressed threefold or greater. This correlated with reductions in the amount of immunoreactive p42mapk and p44erk1 proteins in extracts from the diabetic rats. The basal activity of the 31-kDa S6 kinase activity was also reduced fourfold in the 6-month diabetic rats. Treatment of the 2-month diabetic rats with vanadyl sulfate resulted in euglycemia, prevented the increase in the basal activity of S6 kinase, and improved the activation of S6 kinase by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Oct
PMID:Skeletal muscle mitogen-activated protein kinases and ribosomal S6 kinases. Suppression in chronic diabetic rats and reversal by vanadium. 755 49

Mechanical forces are important modulators of cellular function in many tissues and are particularly important in the cardiovascular system. The endothelium, by virtue of its unique location in the vessel wall, responds rapidly and sensitively to the mechanical conditions created by blood flow and the cardiac cycle. In this study, we examine data which suggest that steady laminar shear stress stimulates cellular responses that are essential for endothelial cell function and are atheroprotective. We explore the ability of shear stress to modulate atherogenesis via its effects on endothelial-mediated alterations in coagulation, leukocyte and monocyte migration, smooth muscle growth, lipoprotein uptake and metabolism, and endothelial cell survival. We also propose a model of signal transduction for the endothelial cell response to shear stress including possible mechanotransducers (integrins, caveolae, ion channels, and G proteins), intermediate signaling molecules (c-Src, ras, Raf, protein kinase C) and the mitogen activated protein kinases (ERK1/2, JNK, p38, BMK-1), and effector molecules (nitric oxide). The endothelial cell response to shear stress may also provide a mechanism by which risk factors such as hypertension, diabetes, hypercholesterolemia, and sedentary lifestyle act to promote atherosclerosis.
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PMID:Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. 959 24

The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.
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PMID:Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. 993 Nov 33

Various growth factors and vasoactive substances are implicated in the pathogenesis of renal growth seen in early diabetes mellitus (DM). Mitogen-activated protein kinase (MAPK) is an important mediator of these extracellular stimuli. Protein kinase C (PKC), an enzyme known to be stimulated in DM, also activates MAPK. Thus, MAPK activity was examined in glomeruli from streptozotocin-induced DM rats. MAPK activity, measured as myelin basic protein kinase, was elevated by approximately 50% in DM versus controls (CON). Increased protein contents of p42mapk and p44mapk, as well as increased tyrosine phosphorylation and mobility shift of p42mapk, were also observed in DM. Tyrosine dephosphorylation of pp42mapk, on the other hand, assessed by incubating glomerular membrane with or without sodium orthovanadate (vanadate), was significantly diminished in DM. Protein expression of MAPK phosphatase-1 (MKP-1), a dual specificity phosphatase that inactivates MAPK, was approximately 60% of CON. Reduction in MKP-1 was reproduced in cultured mesangial cells grown under high glucose (30 mM; HG). The suppression of MKP-1 was PKC-dependent since incubation of HG cells with phorbol 12-myristate 13-acetate for 24 h abolished it. Furthermore, calcium ionophore A23187 reversed the suppression, suggesting that blunted Ca2+ signalling, characteristic of HG cells secondary to PKC stimulation, may be the cause. These results demonstrate that glomerular MAPK is activated in DM by multiple mechanisms i.e., increases in protein contents, increased phosphorylation, and decreased dephosphorylation of the enzyme due to suppression of MKP-1. These alterations may have an implication in the pathogenesis of diabetic nephropathy.
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PMID:Mechanisms of mitogen-activated protein kinase activation in experimental diabetes. 1020 57

Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta-cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation.
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PMID:Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppression of nitric oxide production in macrophages. 1048 7

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is a 28-kDa plasma protein that binds to IGF-I and IGF-II with high affinity. IGFBP-1 is elevated in the blood as a result of sepsis, AIDS, excessive alcohol consumption, and diabetes and may, in part, be responsible for the wasting observed during these pathophysiological conditions. The liver is the principal site of IGFBP-1 synthesis, and we have previously shown that proinflammatory cytokines can directly stimulate IGFBP-1 secretion in a human hepatoma cell line (HepG2). The purpose of the present study was to investigate the role of the MAP kinase pathway in regulating IGFBP-1 synthesis by IL-1beta. We show that IL-1beta stimulates the phosphorylation of ERK-1 and -2 in a time- and dose-dependent manner. In addition, the MAP kinase-kinase MEK-1 and the ribosomal S6-kinase RSK-1 are also phosphorylated in response to IL-1beta. The transcription factor CREB, a potential substrate of both protein kinase A (PKA) and RSK-1, is phosphorylated in response to IL-1beta and cAMP in HepG2 cells. The ability of IL-1beta to stimulate the expression of IGFBP-1 and the phosphorylation of the above kinases was specifically inhibited by PD98059, a MEK-1 inhibitor. cAMP also stimulated IGFBP-1 synthesis, but PD98059 failed to block the cAMP effect. Conversely, a PKA inhibitor (H-89) inhibited the ability of cAMP, but not IL-1beta to stimulate IGFBP-1 synthesis. The effect of IL-1beta and cAMP on IGFBP-1 messenger RNA (mRNA) accumulation was additive. IL-1beta, cAMP, PD98059, and H-89 had similar effects on the accumulation of IGFBP-1 protein and mRNA. IL-1beta and cAMP did not change the half-life of IGFBP-1 mRNA, but PD98059 and SB202190, a p38 MAP kinase inhibitor, destabilized IGFBP-1 mRNA and blocked the phosphorylation of RSK-1 in response to IL-1beta. Our data demonstrate that the MAP kinase signal transduction pathway plays an important role in the regulation of IGFBP-1 synthesis by IL-1beta.
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PMID:Stimulation of insulin-like growth factor binding protein-1 synthesis by interleukin-1beta: requirement of the mitogen-activated protein kinase pathway. 1096 86

To characterize the differentiation events that selectively target insulin-producing cells to interleukin (IL)-1beta-induced apoptosis, we studied IL-1beta signaling via mitogen-activated protein kinase (MAPK) and stress-activated protein kinase in 2 pancreatic endocrine cell lines. We studied the glucagon-secreting AN-glu cell line and the insulin and the islet amyloid polypeptide-producing beta-cell line (AN-ins cells), which is derived by stable transfection of AN-glu cells with the transcription factor pancreatic duodenal homeobox factor-1. AN-ins cells were more sensitive to the cytotoxic action of IL-1beta. This increased sensitivity was not associated with a more pronounced IL-l-induced nitric oxide production in AN-ins cells, but it correlated with a more marked activation of the 3 MAPKs extracellular signal-regulated kinases (ERKs)-1/2, c-Jun NH2-terminal kinase (JNK), and p38 MAPK (p38). This led to increased phosphorylation of the transcription factors c-Jun, Elk-1, and ATF2 and of heat shock protein 25. Inhibition of ERK-1/2 and p38 did not prevent but aggravated IL-1beta-induced cell death. In contrast, inhibition of JNK by transfection with the dominant negative inhibitor of the JNK-binding domain prevented apoptosis in both cell types. Cell death could be elicited by overexpressing the catalytic domain of MAPK kinase kinase 1, a specific activator of JNK and nuclear factor-kappaB, which does not recruit ERK-1/2 or p38. Coactivation of ERK-1/2 with JNK did not prevent apoptosis. In conclusion, increased MAPK signaling in response to IL-1beta may represent a novel molecular marker of beta-cell differentiation. JNK inhibition represents an effective means of preventing IL-1beta-activated beta-cell destruction.
Diabetes 2000 Sep
PMID:The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. 1096 30

Insulin resistance contributes to a number of metabolic disorders, including type II diabetes, hypertension, and atherosclerosis. Cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6, and hormones, such as growth hormone, are known to cause insulin resistance, but the mechanisms by which they inhibit the cellular response to insulin have not been elucidated. One mechanism by which these agents could cause insulin resistance is by inducing the expression of cellular proteins that inhibit insulin receptor (IR) signaling. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling pathways, the expression of which is regulated by certain cytokines. SOCS proteins are therefore attractive candidates as mediators of cytokine-induced insulin resistance. We have found that SOCS-1 and SOCS-6 interact with the IR when expressed in human hepatoma cells (HepG2) or in rat hepatoma cells overexpressing the human IR. In SOCS-1-expressing cells, insulin treatment increases the extent of interaction with the IR, whereas in SOCS-6-expressing cells the association with the IR appears to require insulin treatment. SOCS-1 and SOCS-6 do not inhibit insulin-dependent IR autophosphorylation, but both proteins inhibit insulin-dependent activation of ERK1/2 and protein kinase B in vivo and IR-directed phosphorylation of IRS-1 in vitro. These results suggest that SOCS proteins may be inhibitors of IR signaling and could mediate cytokine-induced insulin resistance and contribute to the pathogenesis of type II diabetes.
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PMID:Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. 1134 31

The cytokine interleukin-1 beta (IL-1 beta) is cytotoxic to rat pancreatic beta-cells and has been implicated in the pathogenesis of insulin-dependent diabetes mellitus. IL-1 beta causes expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). NO may be the mediator of the cytotoxic effect of IL-1 beta in rat islets and beta-cell lines. Glucose has been shown to modulate the effects of IL-1 beta on accumulated insulin release and potentiate NO production in rat islets, but the biochemical mechanism is unknown. IL-1 beta activates the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and c-jun NH2-terminal kinase (JNK) in rat islets and beta-cells. Glucose may modulate MAPK activity although contrasting data have been published. The aim of this study was to investigate whether glucose potentiated IL-1 beta-induced p38 and ERK1/2 activity in rat islets. It was shown that glucose alone increased the phosphorylation of the MAPK substrates Elk-1 and activating transcription factor 2 (ATF2). D-glucose potentiated the p38 activity induced by a low concentration of IL-1 beta, whereas no effect was seen at high concentrations of IL-1 beta. Inhibition of p38 activity prevented IL-1 beta-induced nitrite production in the presence of D-glucose. We conclude that IL-1 beta-induced NO production in the presence of glucose is signalled by the p38 pathway.
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PMID:Glucose potentiates interleukin-1 beta (IL-1 beta)-induced p38 mitogen-activated protein kinase activity in rat pancreatic islets of Langerhans. 1139 23

Troglitazone (TRO) and rosiglitazone (RSG) belong to the thiazolidinedione class (insulin-sensitizing agents) and exert many of their metabolic effects as peroxisome proliferator-activated receptor gamma (PPARgamma) ligands. In the present study we examined the effects of TRO and RSG on LDL-induced VSMC growth. Pretreatment of VSMC with 1 microM TRO or 0.1 microM RSG completely blocked the LDL-induced cell proliferation as measured by [3H]thymidine incorporation into DNA and by determination of the cell number. We then examined with Western blotting whether these growth suppressing effects are mediated through the mitogen-activated protein kinase (MAPK) pathway, a common signaling pathway activated by growth factors. TRO and RSG had no effect on the LDL-induced stimulation of the MAP kinases ERK1/2, p38 and SAP/JNK. We conclude that thiazolidinediones are potent inhibitors of LDL-induced VSMC growth acting downstream of the cytoplasmic activation of MAPK.
Exp Clin Endocrinol Diabetes 2001
PMID:Troglitazone and rosiglitazone inhibit the low density lipoprotein-induced vascular smooth muscle cell growth. 1145 32


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