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

Aberrant neurofilament phosphorylation occurs in many neurodegenerative diseases, and in this study, two animal models of type 1 diabetes--the spontaneously diabetic BB rat and the streptozocin-induced diabetic rat--have been used to determine whether such a phenomenon is involved in the etiology of the symmetrical sensory polyneuropathy commonly associated with diabetes. There was a two- to threefold (P < 0.05) elevation of neurofilament phosphorylation in lumbar dorsal root ganglia (DRG) of diabetic rats that was localized to perikarya of medium to large neurons using immunocytochemistry. Additionally, diabetes enhanced neurofilament M phosphorylation by 2.5-fold (P < 0.001) in sural nerve of BB rats. Neurofilaments are substrates of the mitogen-activated protein kinase (MAPK) family, which includes c-jun NH2-terminal kinase (JNK) or stress-activated protein kinase (SAPK1) and extracellular signal-regulated kinases (ERKs) 1 and 2. Diabetes induced a significant three- to fourfold (P < 0.05) increase in phosphorylation of a 54-kDa isoform of JNK in DRG and sural nerve, and this correlated with elevated c-Jun and neurofilament phosphorylation. In diabetes, ERK phosphorylation was also increased in the DRG, but not in sural nerve. Immunocytochemistry showed that JNK was present in sensory neuron perikarya and axons. Motoneuron perikarya and peroneal nerve of diabetic rats showed no evidence of increased neurofilament phosphorylation and failed to exhibit phosphorylation of JNK. It is hypothesized that in sensory neurons of diabetic rats, aberrant phosphorylation of neurofilament may contribute to the distal sensory axonopathy observed in diabetes.
Diabetes 1999 Apr
PMID:Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. 1010 7

Advanced glycation end products (AGEs) are generated during long term diabetes and are correlated with the development of diabetic complications, such as retinopathy. Diabetic retinopathy is characterized by an increased retinal neovascularization due to the action of the angiogenic factor, vascular endothelial growth factor (VEGF). In this report, we show that injection of insulin and glycated albumin (Alb-AGE) to mice increases VEGF mRNA expression in eyes. Insulin and Alb-AGE stimulate VEGF mRNA and protein expression in retinal epithelial cells (ARPE-19). Alb-AGE-induced VEGF expression is not modulated by the use of antioxidants, N-acetyl-l-cysteine or pyrrolidinedithiocarbamate, or by an inhibitor of phosphatidylinositol 3-kinase (PI3K), wortmannin. However, using an inhibitor of ERK activation, U0126, we show that Alb-AGE stimulates VEGF expression through an ERK-dependent pathway. Accordingly, we found that Alb-AGE activated mitogen-activate protein kinase, ERK1/2, JNK1/2, but not p38, and that Alb-AGE did not activate PI3K and PKB. Moreover, Alb-AGE activated the transcription factor, hypoxia inducible factor-1 (HIF-1) DNA binding activity. This activation is mediated by an increase in accumulation of the HIF-1alpha protein through an ERK-dependent pathway. Thus, stimulation of VEGF expression by Alb-AGE, through the activation of HIF-1, could play an important role in the development of diabetic retinopathy.
 ...
PMID:Regulation of vascular endothelial growth factor expression by advanced glycation end products. 1157 Dec 95

Cytokines have been shown to have dramatic effects on pancreatic islets and insulin-secreting beta-cell lines. It is well established that cytokines such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and gamma-interferon (IFN-gamma) inhibit beta-cell function and are cytotoxic to human and rodent pancreatic islets in vitro. Despite the pleiotropic effects of cytokines on beta-cells, the specific signal transduction pathways and molecular events involved in beta-cell dysfunction remain largely unresolved. In this report, we have examined IL-1beta stimulation of c-Jun NH(2)-terminal kinase (JNK) activity in insulin-secreting clonal cell lines. We demonstrate that IL-1beta transiently activates 46- and 54-kDa isoforms of JNK in cultured RINm5F beta-cells. Furthermore, IL-1beta stimulation of JNK activity is specific, because TNF-alpha and IFN-gamma were without effect. Stable overexpression of JNK1 in RINm5F cells increased levels of activated JNK without affecting kinase activity. JNK-interacting protein (JIP) associates with endogenous as well as overexpressed JNK, suggesting that JIP may serve to regulate JNK activity. Finally, we demonstrate that activated JNK is fully retained in cytoplasmic and membrane compartments without any nuclear translocation. Together, these data indicate that IL-1beta-stimulated JNK activity may be distinctly targeted to cytoplasmic and/or membrane compartments in clonal insulin-producing cells, and that JIP may serve to localize JNK activity to specific substrates.
Diabetes 2001 Dec
PMID:Interleukin-1beta stimulation of c-Jun NH(2)-terminal kinase activity in insulin-secreting cells: evidence for cytoplasmic restriction. 1172 54

Fibrillogenic human amylin elicits pancreatic beta-cell apoptosis that may contribute to development of type-2 diabetes. Here, we demonstrated that activation of a caspase cascade is necessary for induction of apoptosis by fibrillogenic amylin variants in two pancreatic beta-cell lines. Human amylin, as well as truncated 8-37human amylin, evoked sequential activation of caspases-8 and -3, and apoptosis, whereas non-beta-sheet forming and non-fibrillogenic homologs, such as [25,28,29triprolyl]human amylin, did not, implying that the beta-sheet conformer is required for human amylin-induced caspase activation. Significant inhibition of apoptosis was evoked by a selective caspase-1 inhibitor, indicating that caspase-1 is also essential for activation of the caspase cascade. Furthermore, we showed that specific jnk1 antisense oligonucleotides, which suppress phospho-JNK1 expression, effectively decreased human amylin-induced activation of c-Jun. Studies of the interplay between the caspase cascade and the JNK pathway showed that both apoptosis and caspase-3 activation were suppressed by treatment with a JNK inhibitor and by transfection of antisense jnk1 oligonucleotides or antisense-c-jun, whereas a selective inhibitor of caspases-1 and -3 prevented apoptosis but not c-Jun activation. Thus, the JNK1 activation preceded activation of caspases-1 and -3. However, selective JNK inhibition had no effect on caspase-8 activation, and selective caspase-8 inhibition only partially suppressed apoptosis and c-Jun activation, indicating that caspase-8 may partially act upstream of the JNK pathway. Our studies demonstrate a functional interaction of a caspase cascade and JNK1. Fibrillogenic amylin can evoke a JNK1-mediated apoptotic pathway, which is partially dependent and partially independent of caspase-8, and in which caspase-3 acts as a common downstream effector.
 ...
PMID:Fibrillogenic amylin evokes islet beta-cell apoptosis through linked activation of a caspase cascade and JNK1. 1453 96

Parathyroid hormone-related protein (PTHrP) increases the content and mRNA level of insulin in a mouse beta-cell line, MIN6, and primary-cultured mouse islets. We examined the mechanism of PTHrP-induced insulin expression. The PTHrP effect was markedly augmented by SB203580, a mitogen-activated protein (MAP) kinase inhibitor, and SB203580 itself increased insulin expression extensively, even without PTHrP. Because SB203580 inhibits both p38 and c-jun NH(2)-terminal kinases (JNKs), we investigated the JNK-specific inhibitor SP600125. SP600125 also increased insulin content and its mRNA level. PTHrP induced dephosphorylation of JNK1/2, and PTHrP-induced insulin expression was blocked by a dominant-negative type JNK-APF. We suspected that dual specificity MAP kinase phosphatases (MKPs) may be involved in the PTHrP-induced insulin expression by inactivating JNK1/2. MIN6 cells contained at least five MKPs, among which only MKP-1 was inducible by PTHrP. PTHrP-induced insulin expression was blocked by the MKP-1 expression inhibitor Ro-31-8220, indicating that the PTHrP effect is mediated by MKP-1. Indeed, adenoviral MKP-1 expression increased insulin expression by decreasing a phosphorylation form of JNKs and a resulting phosphorylated form of c-jun in MIN6 cells. The phosphorylated form of c-jun is known to repress cAMP-dependent insulin gene promoter activity. Thus, MKP-1 controls the insulin expression by downregulating a JNK/c-jun pathway.
Diabetes 2003 Nov
PMID:Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells. 1457 90

The c-Jun N-terminal protein kinases (JNKs) form one subfamily of the mitogen-activated protein kinase (MAPK) group of serine/threonine protein kinases. The JNKs were first identified by their activation in response to a variety of extracellular stresses and their ability to phosphorylate the N-terminal transactivation domain of the transcription factor c-Jun. One approach to study the function of the JNKs has included in vivo gene knockouts of each of the three JNK genes. Whilst loss of either JNK1 or JNK2 alone appears to have no serious consequences, their combined knockout is embryonic lethal. In contrast, the loss of JNK3 is not embryonic lethal, but rather protects the adult brain from glutamate-induced excitotoxicity. This latter example has generated considerable enthusiasm with JNK3, considered an appropriate target for the treatment of diseases in which neuronal death should be prevented (e.g. stroke, Alzheimer's and Parkinson's diseases). More recently, these gene knockout animals have been used to demonstrate that JNK could provide a suitable target for the protection against obesity and diabetes and that JNKs may act as tumour suppressors. Considerable effort is being directed to the development of chemical inhibitors of the activators of JNKs (e.g. CEP-1347, an inhibitor of the MLK family of JNK pathway activators) or of the JNKs themselves (e.g. SP600125, a direct inhibitor of JNK activity). These most commonly used inhibitors have demonstrated efficacy for use in vivo, with the successful intervention to decrease brain damage in animal models (CEP-1347) or to ameliorate some of the symptoms of arthritis in other animal models (SP600125). Alternative peptide-based inhibitors of JNKs are now also in development. The possible identification of allosteric modifiers rather than direct ATP competitors could lead to inhibitors of unprecedented specificity and efficacy.
 ...
PMID:Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. 1502 53

The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1beta-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic beta-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1beta activation of JNK in beta-cells are largely unknown. In this study, we investigated whether Ca(2+) plays a role for IL-1beta-induced JNK activation. In insulin-secreting rat INS-1 cells cultured in the presence of 11 mm glucose, combined pharmacological blockade of L- and T-type Ca(2+) channels suppressed IL-1beta-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1beta-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1beta-induced in vitro kinase activity toward c-jun after collective L- and T-type Ca(2+) channel blockade was confirmed in primary rat and ob/ob mouse islets and in mouse betaTC3 cells. Ca(2+) influx, specifically via L-type but not T-type channels, contributed to IL-1beta activation of JNK. Activation of p38 and ERK in response to IL-1beta was also dependent on L-type Ca(2+) influx. Membrane depolarization by KCl, exposure to high glucose, treatment with Ca(2+) ionophore A23187, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca(2+) ATPase, all caused an amplification of IL-1beta-induced JNK activation in INS-1 cells. Finally, a chelator of intracellular free Ca(2+) [bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid-acetoxymethyl], an inhibitor of calmodulin (W7), and inhibitors of Ca(2+)/calmodulin-dependent kinase (KN62 and KN93) partially reduced IL-1beta-stimulated c-jun phosphorylation in INS-1 or betaTC3 cells. Our data suggest that Ca(2+) plays a permissive role in IL-1beta activation of the JNK signaling pathway in insulin-secreting cells.
 ...
PMID:Calcium has a permissive role in interleukin-1beta-induced c-jun N-terminal kinase activation in insulin-secreting cells. 1583 71

The c-Jun NH(2)-terminal kinase isoform (JNK) 1 is implicated in type 2 diabetes. However, a potential role for the JNK2 protein kinase in diabetes has not been established. Here, we demonstrate that JNK2 may play an important role in type 1 (insulin-dependent) diabetes that is caused by autoimmune destruction of beta cells. Studies of nonobese diabetic mice demonstrated that disruption of the Mapk9 gene (which encodes the JNK2 protein kinase) decreased destructive insulitis and reduced disease progression to diabetes. CD4(+) T cells from JNK2-deficient nonobese diabetic mice produced less IFN-gamma but significantly increased amounts of IL-4 and IL-5, indicating polarization toward the Th2 phenotype. This role of JNK2 to control the Th1/Th2 balance of the immune response represents a mechanism of protection against autoimmune diabetes. We conclude that JNK protein kinases may have important roles in diabetes, including functions of JNK1 in type 2 diabetes and JNK2 in type 1 diabetes.
 ...
PMID:Disruption of the Jnk2 (Mapk9) gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes. 1586 47

IFN-gamma and TNF-alpha are major proinflammatory cytokines implicated in islet beta-cell destruction, which results in type-1 diabetes; however, the underlying mechanism is not clear. Using pancreatic beta-cell line MIN6N8 cells, co-treatment with TNF-alpha and IFN-gamma, but neither cytokine alone, synergistically induced apoptosis, correlated with the activation of the JNK/SAPK, which resulted in the production of reactive oxidative species (ROS) and loss of mitochondrial transmembrane potential (delta psi m). Additionally, cells transfected with wild-type JNK1 became more susceptible to apoptosis induced by TNF-alpha/IFN-gamma through ROS production and loss of delta psi m, while cascading apoptotic events were prevented in dominant-negative JNK1-transfected or JNK inhibitor SP600125-treated cells. As the antioxidant, N-acetyl-cysteine, failed to completely suppress apoptosis induced by TNF-alpha/IFN-gamma, an additional pathway was considered to be involved. The level of p53 was significantly increased through synergistic activation of JNK by TNF-alpha/IFN-gamma. Furthermore, the synergistic effect of TNF-alpha/IFN-gamma on apoptosis and ROS production was further potentiated by the overexpression of wild-type p53, but not with mutant p53. This synergistic activation of JNK/SAPK by TNF-alpha/IFN-gamma was also induced in insulin-expressing pancreatic islet cells, and increased ROS production and p53 level, which was significantly inhibited by SP600125. Collectively, these data demonstrate that TNF-alpha/IFN-gamma synergistically activates JNK/SAPK, playing an important role in promoting apoptosis of pancreatic beta-cell via activation of p53 pathway together with ROS.
 ...
PMID:Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway. 1590 80

The c-Jun N-terminal kinases (JNKs), which are essential regulators of physiological and pathological processes, are involved in several diseases including diabetes, atherosclerosis, stroke, and Parkinson's and Alzheimer's diseases. Inhibition of JNKs suppresses pathological features of these diseases but the many physiological functions of these enzymes argue against the use of sustained, systemic, nonspecific inhibition in the treatment of these diseases. For example, deletion of the gene that encodes JNK1 prevents insulin resistance but disrupts neuronal cytoarchitecture and initiates the pathology of Alzheimer's disease. Thus, it is not sufficient to inhibit selectively either JNKs or individual isoforms of JNK. Instead, the aim is to inhibit the damaging actions of JNK. This can be achieved using peptides that selectively block molecular domains of individual JNK signaling complexes (exclusively) that form under pathological conditions. To date, peptide inhibitors of JNK have been successful in protecting against ischemia-induced brain damage and insulin resistance following obesity. In this review, we discuss novel pharmacological strategies to inhibit JNK and the limitations of these strategies.
 ...
PMID:Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage. 1605 42


1 2 3 4 5 6 7 Next >>