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)

Many cytokines increase their receptor affinity for Janus kinases (JAKs). Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. Intriguingly, insulin acting through its own receptor kinase also activates JAK2. However, the impact of such activation on insulin action remains unknown. To determine the contribution of JAK2 to insulin signaling, we transfected L6 myotubes with siRNA against JAK2 (siJAK2), reducing JAK2 protein expression by 75%. Insulin-dependent phosphorylation of IRS1/2 and Shc was not affected by siJAK2, but insulin-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-related kinase, p38, and Jun NH2-terminal kinase and their respective upstream kinases MKK1/2, MKK3/6, and MKK4/7 was significantly lowered when JAK2 was depleted, correlating with a significant drop in insulin-mediated cell proliferation. These effects were reproduced by the JAK2 inhibitor AG490. Conversely, insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation were not affected by siJAK2. Interestingly, in two insulin-resistant states, siJAK2 led to partial restoration of Akt phosphorylation and glucose uptake stimulation but not of the MAPK pathway. These results suggest that JAK2 may depress the Akt to glucose uptake signaling axis selectively in insulin-resistant states. Inhibition of JAK2 may be a useful strategy to relieve insulin resistance of metabolic outcomes.
Diabetes 2006 Apr
PMID:Opposite effect of JAK2 on insulin-dependent activation of mitogen-activated protein kinases and Akt in muscle cells: possible target to ameliorate insulin resistance. 1656 15

Protein tyrosine phosphatases regulate important processes in eukaryotic cells and have critical functions in many human diseases including diabetes to cancer. Here, we report that the human Vaccinia H1-related (VHR) dual-specific protein tyrosine phosphatase regulates cell-cycle progression and is itself modulated during the cell cycle. Using RNA interference (RNAi), we demonstrate that cells lacking VHR arrest at the G1-S and G2-M transitions of the cell cycle and show the initial signs of senescence, such as flattening, spreading, appearance of autophagosomes, beta-galactosidase staining and decreased telomerase activity. In agreement with this notion, cells lacking VHR were found to upregulate p21(Cip-Waf1), whereas they downregulated the expression of genes for cell-cycle regulators, DNA replication, transcription and mRNA processing. Loss of VHR also caused a several-fold increase in serum-induced activation of its substrates, the mitogen-activated protein (MAP) kinases Jnk and Erk. VHR-induced cell-cycle arrest was dependent on this hyperactivation of Jnk and Erk, and was reversed by Jnk and Erk inhibition or knock-down. We conclude that VHR is required for cell-cycle progression as it modulates MAP kinase activation in a cell-cycle phase-dependent manner.
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PMID:Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. 1660 64

Diabetic nephropathy is associated with increased accumulation of the extracellular matrix (ECM) in the kidney, which ultimately leads to kidney failure. This may occur due to excessive synthesis of ECM components or reduced degradation, a process primarily mediated by matrix metalloproteinases (MMPs). The direct effect of insulin on ECM synthesis and degradation in glomerular mesangial cells (GMCs) is unclear. Here, we show an increased gelatinase activity in conditioned media from insulin-treated rat GMCs, determined by gelatin zymography. Furthermore, we show using the specific inhibitors LY294002 and PD98059 that insulin induced increased gelatinase activity via an intracellular signalling mechanism involving phosphatidylinositol-3 kinase (PI-3K) and the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs) respectively. In addition, we demonstrate that PI-3 kinase and ERK1/2 MAPK are activated by insulin in GMCs. The appearance of protease activity at approximately 72 kDa suggested that MMP-2 activity may be induced by insulin, however, we did not detect an increase in MMP-2 expression by Western blotting. In summary, our results suggest that insulin can induce gelatinase activity in GMCs, and it is possible that loss of this input in insulin-resistant type 2 diabetic individuals may contribute to ECM accumulation and the development of nephropathy.
Diabetes Obes Metab 2006 May
PMID:Insulin increases gelatinase activity in rat glomerular mesangial cells via ERK- and PI-3 kinase-dependent signalling. 1663 87

Postprandial dyslipidemia is recognized as an important complication of insulin-resistant states, and recent evidence implicates intestinal lipoprotein overproduction as a causative factor. The mechanisms linking intestinal lipoprotein overproduction and aberrant insulin signaling in intestinal enterocytes are currently unknown. Intestinal insulin sensitivity and lipid metabolism were studied in a fructose-fed hamster model of insulin resistance and metabolic dyslipidemia. Intestinal lipoprotein production in chow-fed hamsters was responsive to the inhibitory effects of insulin, and a decrease in circulating levels of triglyceride-rich apolipoprotein (apo)B48-containing lipoproteins occurred 60 min after insulin administration. However, fructose-fed hamster intestine was not responsive to the insulin-induced downregulation of apoB48-lipoprotein production, suggesting insulin insensitivity at the level of the intestine. Enterocytes from the fructose-fed hamster exhibited normal activity of the insulin receptor but reduced levels of insulin receptor substrate-1 phosphorylation and mass and Akt protein mass. Conversely, the protein mass of the p110 subunit of phosphatidylinositol 3-kinase, protein tyrosine phosphatase-1B, and basal levels of phosphorylated extracellular signal-related kinase (ERK) were significantly increased in the fructose-fed hamster intestine. Modulating the ERK pathway through in vivo inhibition of mitogen-activated protein/ERK kinase 1/2, the upstream activator of ERK1/2, we observed a significant decrease in intestinal apoB48 synthesis and secretion. Interestingly, enhanced basal ERK activity in the fructose-fed hamster intestine was accompanied by an increased activation of sterol regulatory element-binding protein. In summary, these data suggest that insulin insensitivity at the level of the intestine and aberrant insulin signaling are important underlying factors in intestinal overproduction of highly atherogenic apoB48-containing lipoproteins in the insulin-resistant state. Basal activation of the ERK pathway may be an important contributor to the aberrant insulin signaling and lipoprotein overproduction in this model.
Diabetes 2006 May
PMID:Intestinal insulin resistance and aberrant production of apolipoprotein B48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine. 1664 88

The existence of a tissue renin-angiotensin (RAS) system independent of the circulating RAS has prompted the search for cellular binding sites for angiotensinogen and for renin in order to explain their tissue uptake. Two receptors that bind with similar affinity mature renin and prorenin were identified, the mannose-6-phosphate receptor (M6P-R) and a specific receptor. The M6P-R is a clearance receptor that binds exclusively the glycosylated forms of renin and prorenin. Binding of renin and prorenin to the M6P-R is followed by internalization and degradation, and the intracellular proteolysis of prorenin in mature renin did not provoke any generation of intracellular angiotensins. In contrast to the M6P-R, (pro)renin bound to the specific receptor was not degraded. Instead, receptor-bound renin showed increased catalytic activity, and receptor-bound prorenin exhibited full catalytic activity. This 'gain of activity' was explained by a conformational change of the (pro)renin molecule upon binding. Furthermore, (pro)renin binding provoked a rapid activation of the mitogen-activated protein kinases p44/p42, indicating that the receptor has mediated specific, angiotensin II-independent effects of (pro)renin. This receptor represents an elegant concept to explain the existence of active prorenin in vivo, and it provides a pathological role for prorenin in situations with paradoxical low renin and high prorenin concentrations such as in diabetes. Experimental models of rats overexpressing the receptor either in vascular smooth muscle cells and developing high blood pressure or with ubiquitous expression associated with glomerulosclerosis and proteinuria confirm a role for the receptor in cardiovascular and renal diseases.
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PMID:Renin/prorenin receptors. 1667 20

Diseases such as hypertension, atherosclerosis and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many stimuli influence cellular changes, including mechanical forces, such as shear stress, and vasoactive agents, of which angiotensin II (Ang II) appears to be amongst the most important. Ang II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive oxygen species (ROS). Mechanical forces, comprising both unidirectional laminar and oscillatory shear, are increasingly being recognized as important inducers of vascular NO and ROS generation. In general, laminar flow is associated with upregulation of eNOS and NO production and increased expression of antioxidants glutathione peroxidase and superoxide dismutase, thereby promoting a healthy vascular wall and protecting against oxidative vascular injury. On the other hand, oscillatory shear is linked to increased ROS production with consequent oxidative damage, as occurs in hypertension. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca(2+) concentration, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, low concentrations of intracellular ROS play an important role in normal redox signaling involved in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review describes some of the redox-sensitive signaling pathways that are involved in the functional and structural vascular changes associated with hypertension.
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PMID:Redox signaling in hypertension. 1676 37

The mitogen-activated protein kinases (MAPK) play critical roles in the pathogenesis of diabetes and obesity. The MAPKs are inactivated by MAPK phosphatases (MKPs) either in the cytosol or nucleus. Here we show that mice lacking the nuclear-localized MKP, MKP-1 (mkp-1(-/-)), have enhanced Erk, p38 MAPK and c-Jun NH(2)-terminal kinase (JNK) activities in insulin-responsive tissues as compared with wild-type mice. Although JNK promotes insulin resistance, mkp-1(-/-) mice exhibited unimpaired insulin-mediated signaling and glucose homeostasis. We reconciled these results by demonstrating that in mkp-1(-/-) mice, JNK activity was increased in the nucleus, but not the cytosol. Significantly, mkp-1(-/-) mice are resistant to diet-induced obesity due to enhanced energy expenditure, but succumb to glucose intolerance on a high fat diet. These results suggest that nuclear regulation of the MAPKs by MKP-1 is essential for the management of metabolic homeostasis in a manner that is spatially uncoupled from the cytosolic actions of the MAPKs.
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PMID:Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. 1681 33

Molecular mechanisms underlying diabetes-induced painful neuropathy are poorly understood. We have demonstrated, in rats with streptozotocin-induced diabetes, that mechanical hyperalgesia, a common symptom of diabetic neuropathy, was correlated with an early increase in extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) phosphorylation in the spinal cord and dorsal root ganglion at 3 weeks after induction of diabetes. This change was specific to hyperalgesia because nonhyperalgesic rats failed to have such an increase. Immunoblot analysis showed no variation of protein levels, suggesting a post-translational regulation of the corresponding kinases. In diabetic hyperalgesic rats, immunocytochemistry revealed that all phosphorylated mitogen-activated protein kinases (MAPKs) colocalized with both the neuronal (NeuN) and microglial (OX42) cell-specific markers but not with the astrocyte marker [glial fibrillary acidic protein (GFAP)] in the superficial dorsal horn-laminae of the spinal cord. In these same rats, a 7-day administration [5 microg/rat/day, intrathecal (i.t.)] of 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), and anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), which inhibited MAPK kinase, p38, and JNK, respectively, suppressed mechanical hyperalgesia, and decreased phosphorylation of the kinases. To characterize the cellular events upstream of MAPKs, we have examined the role of the NMDA receptor known to be implicated in pain hypersensitivity. The prolonged blockade of this receptor during 7 days by (5R, 10S)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine hydrogen maleate (MK801; 5 microg/rat/day, i.t.), a noncompetitive NMDA receptor antagonist, reversed hyperalgesia developed by diabetic rats and blocked phosphorylation of all MAPKs. These results demonstrate for the first time that NMDA receptor-dependent phosphorylation of MAPKs in spinal cord neurons and microglia contribute to the establishment and longterm maintenance of painful diabetic hyperalgesia and that these kinases represent potential targets for pain therapy.
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PMID:Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. 1686 81

Amylin-mediated islet beta-cell death is implicated in diabetogenesis. We previously reported that fibrillogenic human amylin (hA) evokes beta-cell apoptosis through linked activation of Jun N-terminal kinase 1 (JNK 1) and a caspase cascade. Here we show that p38 kinase [p38 mitogen-activated protein (MAP) kinase] became activated by hA treatment of cultured beta-cells whereas extracellular signal-regulated kinase (ERK) did not; by contrast, nonfibrillogenic rat amylin (rA) altered neither. Pretreatment with the p38 kinase-inhibitor SB203580 decreased hA-induced apoptosis and caspase-3 activation by approximately 30%; as did combined SB203580 and JNK inhibitor I, by about 70%; and the combination of SB203580, the JNK inhibitor I and a caspase-8 inhibitor, by 100%. These findings demonstrate the requirement for concurrent activation of the p38 kinase, JNK and caspase-8 pathways. We further showed that hA elicits time-dependent activation of activating transcription factor 2 (ATF-2), which was largely suppressed by SB203580, indicating that this activation is catalyzed mainly by p38 kinase. Furthermore, hA-induced apoptosis was suppressed by specific antisense ATF-2, and increased phospho-ATF-2 (p-ATF-2) was associated with increased CRE (cAMP-response element) DNA binding and CRE-mediated transcriptional activity, as well as enhancement of c-jun promoter activation. We also detected changes in the phosphorylation status and composition of the CRE complex that may play important roles in regulation of distinct downstream target genes. These studies establish p38 MAP kinase-mediated activation of ATF-2 as a significant mechanism in hA-evoked beta-cell death, which may serve as a target for pharmaceutical intervention and effective suppression of beta-cell failure in type-2 diabetes.
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PMID:Activation of activating transcription factor 2 by p38 MAP kinase during apoptosis induced by human amylin in cultured pancreatic beta-cells. 1686 89

The c-Jun N-terminal kinases (JNKs) form a subfamily of the mitogen-activated protein kinases (MAPK). These signalling pathways regulate various processes such as mitosis, cellular differentiation, stress response or apoptosis in multicellular organisms. There is rising evidence about the role of JNKs activities in neurodegenerative and metabolic diseases as well as in immunological disorders. The physiological functions of JNKs, however, remain to be elucidated. Recent data have demonstrated an essential role of JNKs in the cardiovascular system and the regulation of carbon hydrate and glucose metabolism. Therefore, we have investigated the contractility of blood vessels in mice with genetically deleted JNK1, JNK2, JNK3 and JNK2+3 isoforms and their respective wildtypes. The contractility of the isolated segments from A. carotis communis was measured by small blood vessel wire myograph. Contraction induced by 80 mM KCl was significantly increased in arteries from JNK2+3 double knockout compared to controls and single knockouts. The maximal contraction generated by the alpha-agonists phenylephrine or noradrenaline (10 microM) was significantly enhanced in JNK2+3 knockout arteries compared with arteries from the remaining strains. Inhibition of NOS by Nw-nitro-l-arginine did not change the pattern of vasoconstriction, but vasoconstriction by noradrenaline following NOS inhibition was significantly enhanced in the arteries from JNK2+3 double knockout mice. In conclusion, genetic deletion of JNK2+3 in mice results in altered contractility of carotid arteries and this might depend on the function of the smooth muscles rather than on the endothelium. These findings have implications for the long-term treatment with pharmacological JNK inhibitors for neurodegenerative or metabolic diseases such as stroke or diabetes.
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PMID:Enhanced contractility of small blood vessels in JNK knockout mice. 1694 3


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