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

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

Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo.
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PMID:The lipid phosphatase SHIP2 controls insulin sensitivity. 1134 20

Protease inhibitors used in the treatment of HIV infection have been causally associated with lipodystrophy and insulin resistance and were shown to alter adipocyte differentiation in cultured cells. We aimed to delineate the mechanism by which indinavir impaired adipocyte function. We report that indinavir altered neither the growth nor insulin sensitivity of 3T3-F442A preadipocytes, nor did it alter the initial step of their differentiation, i.e., clonal proliferation. However, adipose conversion was inhibited by indinavir (by 50-60%), as shown by 1) the decrease in the number of newly formed adipocytes; 2) the lower level of the adipogenic protein markers, sterol regulatory element-binding protein-1 (SREBP-1), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and the insulin receptor (IR); and 3) the lack of SREBP-1 and PPAR-gamma immunoreactivity in the nucleus of most indinavir-treated cells. Partial adipose conversion also correlated with an accumulation of SREBP-1 at the nuclear periphery and an alteration in its electrophoretic mobility. Defective expression and nuclear localization of PPAR-gamma probably resulted from the decreased level of nuclear SREBP-1. Indinavir also rendered 3T3-F442A adipocytes resistant to insulin for mitogen-activated protein kinase activation at a step distal to IR substrate-1 tyrosine phosphorylation. Hence, indinavir impairs differentiation at an early step of adipose conversion probably involving the process controlling SREBP-1 intranuclear localization.
Diabetes 2001 Jun
PMID:The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. 1137 39

The cofactor of mitochondrial dehydrogenase complexes and potent antioxidant alpha-lipoic acid has been shown to lower blood glucose in diabetic animals. alpha-Lipoic acid enhances glucose uptake and GLUT1 and GLUT4 translocation in 3T3-L1 adipocytes and L6 myotubes, mimicking insulin action. In both cell types, insulin-stimulated glucose uptake is reduced by inhibitors of p38 mitogen-activated protein kinase (MAPK). Here we explore the effect of alpha-lipoic acid on p38 MAPK, phosphatidylinositol (PI) 3-kinase, and Akt1 in L6 myotubes. alpha-Lipoic acid (2.5 mmol/l) increased PI 3-kinase activity (31-fold) and Akt1 (4.9-fold). Both activities were inhibited by 100 nmol/l wortmannin. alpha-Lipoic acid also stimulated p38 MAPK phosphorylation by twofold within 10 min. The phosphorylation persisted for at least 30 min. Like insulin, alpha-lipoic acid increased the kinase activity of the alpha (2.8-fold) and beta (2.1-fold) isoforms of p38 MAPK, measured by an in vitro kinase assay. Treating cells with 10 micromol/l of the p38 MAPK inhibitors SB202190 or SB203580 reduced the alpha-lipoic acid-induced stimulation of glucose uptake by 66 and 55%, respectively. In contrast, SB202474, a structural analog that does not inhibit p38 MAPK, was without effect on glucose uptake. In contrast to 2-deoxyglucose uptake, translocation of GLUT4myc to the cell surface by either alpha-lipoic acid or insulin was unaffected by 20 micromol/l of SB202190 or SB203580. The results suggest that inhibition of 2-deoxyglucose uptake in response to alpha-lipoic acid by inhibitors of p38 MAPK is independent of an effect on GLUT4 translocation. Instead, it is likely that regulation of transporter activity is sensitive to these inhibitors.
Diabetes 2001 Jun
PMID:The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. 1137 49

Because high D-glucose significantly stimulates endothelial cell death, we examined the molecular mechanisms of high D-glucose-induced endothelial apoptosis. Treatment of human aortic endothelial cells with high D-glucose (25 mmol/l), but not mannitol and L-glucose, resulted in a significant decrease in cell number and a significant increase in apoptotic cells as compared with a physiological concentration (5 mmol/l). Interestingly, high D-glucose treatment significantly increased bax protein, accompanied by translocation of bax protein from cytosol to mitochondria-enriched heavy membrane fraction. In contrast, the expression and distribution of bcl-2 protein were not altered by high D-glucose. In addition, the activity of caspase-3 proteases was increased after exposure to high glucose, whereas caspase inhibitors prevented endothelial cell death induced by high D-glucose. On the other hand, p38 mitogen-activated protein kinase (MAPK) was markedly phosphorylated and showed sustained phosphorylation after stimulation. A specific inhibitor of p38 MAPK, SB 203580, and the overexpression of kinase-inactive p38 MAPK significantly attenuated cell death induced by high D-glucose in human aortic endothelial cells, whereas at 6 h after high D-glucose treatment, SB 203580 and overexpression of kinase-inactive p38 MAPK did not attenuate caspase-3 activation induced by high D-glucose. Importantly, caspase inhibitors significantly attenuated the sustained phosphorylation of p38 MAPK induced by high D-glucose. Thus, we finally focused the MAPK kinase (MEK) kinase 1 (MEKK1) to further examine the cross-talk between p38 MAPK and the bax-caspase proteases pathway. High D-glucose treatment induced MEKK1 cleavage, whereas caspase inhibitors significantly attenuated the cleavage. Importantly, kinase-inactive MEKK1 also blocked the phosphorylation of p38 MAPK induced by high D-glucose. Here, we demonstrated that high D-glucose induced apoptosis in human endothelial cells through activation of the bax-caspase proteases pathway and through phosphorylation of p38 MAPK mediated by MEKK1. Phosphorylation of p38 MAPK downstream of the bax-caspase pathway may play a pivotal role in endothelial apoptosis mediated by high D-glucose.
Diabetes 2001 Jun
PMID:Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells. 1137 50

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.
Diabetes 2001 Jun
PMID:Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. 1137 53

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

This review will provide insight on potential intracellular signalling mechanisms by which insulin and exercise/contraction increases glucose metabolism and gene expression. Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) and can be activated in skeletal muscle by two separate and distinct signalling pathways; one stimulated by insulin and the second by muscle contractions. Impaired insulin action on whole body glucose uptake is a hallmark feature of type II (non-insulin-dependent) diabetes mellitus. Defects in insulin signal transduction through the insulin-receptor substrate-1/phosphatidylinositol 3-kinase pathway are associated with reduced insulin-stimulated glucose transporter 4 translocation and glucose transport activity in skeletal muscle from type II diabetic patients. Studies performed using glucose transporter 4-null mice show that this glucose transporter isoform plays a major role in mediating exercise-stimulated glucose uptake in skeletal muscle. Level of physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity. Exercise training leads to alterations in expression and activity of key proteins involved in insulin signal transduction. These changes may be related to increased signal transduction through the mitogen-activated protein kinase (MAPK) signalling cascades. Because MAPK is associated with increased transcriptional activity, these signalling cascades are candidates for these exercise-induced changes in protein expression. Understanding the molecular mechanism for the activation of signal transduction pathways will provide a link for defining new strategies to enhance glucose metabolism and improve health in the general population.
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PMID:Intracellular mechanisms underlying increases in glucose uptake in response to insulin or exercise in skeletal muscle. 1141 37

Impairment of the fibrinolytic system, caused primarily by increases in the plasma levels of plasminogen activator inhibitor (PAI) type 1, are frequently found in diabetes and the insulin-resistance syndrome. Among the factors responsible for the increases of PAI-1, insulin has recently attracted attention. In this study, we analyzed the effects of insulin on PAI-1 biosynthesis in HepG2 cells, paying particular attention to the signaling network evoked by this hormone. Experiments performed in CHO cells overexpressing the insulin receptor indicate that insulin increases PAI-1 gene transcription through interaction with its receptor. By using inhibitors of the different signaling pathways evoked by insulin-receptor binding, it has been shown that the biosynthesis of PAI-1 is due to phosphatidylinositol (PI) 3-kinase activation, followed by protein kinase C and ultimately by mitogen-activated protein (MAP) kinase activation and extracellular signal-regulated kinase 2 phosphorylation. We also showed that this pathway is Ras-independent. Transfection of HepG2 cells with several truncations of the PAI-1 promoter coupled to a CAT gene allowed us to recognize two major response elements located in the regions between -804 and -708 and between -211 and -54. Electrophoretic mobility shift assay identified three binding sites for insulin-induced factors, all colocalized with putative Sp1 binding sites. Using supershifting antibodies, the binding of Sp1 could only be confirmed at the binding site located just upstream from the transcription start site of the PAI-1 promoter. A construct comprising four tandem repeat copies of the -93/-62 region of the PAI-1 promoter linked to CAT was transcriptionally activated in HepG2 cells by insulin. These results outline the central role of MAP kinase activation in the regulation of PAI-1 induced by insulin.
Diabetes 2001 Jul
PMID:Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: insights into the signaling pathway. 1142 72

During embryonic life, the development of a proper mass of mature pancreatic tissue is thought to require the proliferation of precursor cells, followed by their differentiation into endocrine or acinar cells. We investigated whether perturbing the proliferation of precursor cells in vitro could modify the final mass of endocrine tissue that develops. For that purpose, we used activators or inhibitors of signals mediated by receptor tyrosine kinases. We demonstrated that when embryonic day 13.5 rat pancreatic epithelium is cultured in the presence of PD98059, an inhibitor of the mitogen-activated protein (MAP) kinase, epithelial cell proliferation is decreased, whereas endocrine cell differentiation is activated. On the other hand, in the presence of epidermal growth factor (EGF), an activator of the MAP kinase pathway, the mass of tissue that develops is increased, whereas the absolute number of endocrine cells that develops is decreased. Under this last condition, a large number of epithelial cells proliferate but remain undifferentiated. In a second step, when EGF is removed from the pool of immature pancreatic epithelial cells, the cells differentiate en masse into insulin-expressing cells. The total number of insulin-expressing cells that develop can thus be increased by first activating the proliferation of immature epithelial cells with growth factors, thus allowing an increase in the pool of precursor cells, and next allowing their differentiation into endocrine cells by removing the growth factor. This strategy suggests a possible tissue engineering approach to expanding beta-cells.
Diabetes 2001 Jul
PMID:Epidermal growth factor increases undifferentiated pancreatic embryonic cells in vitro: a balance between proliferation and differentiation. 1142 78


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