Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF-alpha) inhibits insulin action, in part, by activating c-jun NH(2)-terminal kinases (JNK). However, the precise mechanisms by which TNF-alpha activates JNK are unknown. Recently, we confirmed that hyperglycemia increased mitochondrial reactive oxygen species (ROS) production, and which can associate with the pathogenesis of diabetic vascular complications. In addition, apoptosis signal-regulating kinase 1 (ASK1) was reported to activate the JNK and p38 signaling pathways and is required for TNF-alpha-induced apoptosis. Here we demonstrate that TNF-alpha increases mitochondrial ROS production and ASK1 activity, and that these TNF-alpha-induced phenomena associate with JNK activation, increase in Ser(307) phosphorylation of IRS-1 and decrease in insulin-stimulated tyrosine phosphorylation of IRS-1, all of which are believed to be the molecular basis of TNF-alpha-induced insulin resistance. We claim that mitochondrial ROS production may be a key factor not only in diabetic vascular complications, but also in the development of type 2 diabetes. This integrating paradigm could provide a new conceptual framework for further research and therapies for the treatment of type 2 diabetes.
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PMID:Impact of mitochondrial ROS production in the pathogenesis of insulin resistance. 1748 67

The hallmark of type 2 diabetes is pancreatic beta-cell dysfunction and insulin resistance. Normal beta-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, beta-cell function gradually deteriorates and insulin resistance becomes aggravated. Such phenomena are collectively called "glucose toxicity". Under diabetic conditions, oxidative stress is induced and the JNK pathway is activated, which is involved in "glucose toxicity". Activation of the JNK pathway suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Consequently, the JNK pathway plays a crucial role in the progression of pancreatic beta-cell dysfunction and insulin resistance and thus could be a potential therapeutic target for the "glucose toxicity" found in diabetes.
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PMID:Involvement of oxidative stress and the JNK pathway in glucose toxicity. 1749 1

Diabetic nephropathy (DN) remains a major complication in both type 1 and type 2 diabetes. Systemic administration of antitransforming growth factor-beta (TGF-beta) antibody has shown some promise in mouse models of DN. However, chronic blockade of the multifunctional TGB-beta could be problematic. Several downstream effects of TGF-beta are mediated by connective tissue growth factor (CTGF), which is up-regulated in several renal cells and secreted in the urine in the diabetic state. Using murine models of DN (type 1 and type 2) and a CTGF antisense oligonucleotide (ASO) of novel chimeric chemistry, we evaluated the specific role of this target in DN. In the type 1 model of DN, C57BL6 mice were made diabetic using streptozotocin injections and hyperglycemic animals were treated with CTGF ASOs (20 mg/kg/2 qw) for 4 months. ASO, but not mismatch control oligonucleotide, -treated animals showed significant reduction in target CTGF expression in the kidney with a concomitant decrease in proteinuria and albuminuria. Treatment with the CTGF ASO for 8 wk reduced serum creatinine and attenuated urinary albuminuria and proteinuria in diabetic db/db mice, a model of type 2 DN. The ASO also reduced expression of genes involved in matrix expansion such as fibronectin and collagen (I and IV) and an inhibitor of matrix degradation, PAI-1, in the renal cortex, contributing to significant reversal of mesangial expansion in both models of DN. Pathway analyses demonstrated that diabetes-induced phosphorylation of p38 MAPK and its downstream target CREB was also inhibited by the ASO. Our results strongly suggest that blocking CTGF using a chimeric ASO holds substantial promise for the treatment of DN.
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PMID:Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. 1755 73

Free fatty acids (FFAs) exert divergent effects on beta-cells. Acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs beta-cell function and induces apoptosis. The G protein-coupled receptor 40 (GPR40) is preferentially expressed in beta-cells and is activated by a wide range of FFAs. In this study, we used small interfering RNA technology and apoptosis assay in mouse beta-cell NIT-1 to address the role of GPR40 in beta-cell lipoapoptosis and function. Results showed that palmitate induced beta-cell apoptosis, which was not mediated through GPR40, whereas oleate protected NIT-1 cells from palmitate-induced lipoapoptosis, which was mediated at least in part through GPR40. Moreover, by detecting the activation of the phosphatidylinositol 3-kinase and MAP kinase (MAPK) pathways, we found that oleate promoted the activation of extracellular signal-regulated protein kinase-MAPK pathway mainly via GPR40, increased the expression of early growth response gene-1, leading to the anti-lipoapoptotic effect on NIT-1 cells. It was suggested that GPR40 might be implicated in the control of beta-cell mass plasticity and GPR40 probably provide a link between obesity and type 2 diabetes.
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PMID:The role of G protein-coupled receptor 40 in lipoapoptosis in mouse beta-cell line NIT-1. 1755 34

Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas, and by resistance to insulin's effects. Such a deficiency results in increased concentrations of glucose and other metabolites in the blood, which in turn damages many of the body's systems, in particular the eyes, kidneys, nerves, heart and blood vessels. There are two major types of diabetes mellitus: Type 1 diabetes (insulin-dependent diabetes, IDDM or juvenile onset diabetes) and Type 2 diabetes (non-insulin-dependent diabetes, NIDDM or adult-onset). Chronic hyperglycemia is a major initiator of diabetic micro- and cardiovascular complications, such as retinopathy, neuropathy and nephropathy. Several hyperglycemia-induced mechanisms may induce vascular dysfunctions, which include increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol (DAG) and the subsequent activation of protein kinase C (PKC) isoforms and accelerated non-enzymatic formation of advanced glycated end products. It is likely that each of these mechanisms may contribute to the known pathophysiologic features of diabetic complications. Others and we have shown that activation of the DAG-PKC pathway is associated with many vascular abnormalities in the retinal, renal, neural and cardiovascular tissues in diabetes mellitus. DAG-PKC pathway affects cardiovascular function in many ways, such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix (ECM) synthesis/turnover, cell growth, angiogenesis, cytokine activation and leucocyte adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha, beta1/2 and delta isoforms in retina, aorta, heart, renal glomeruli and circulating macrophages have been reported in diabetes. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis, excessive apoptosis and changes in enzymatic activity alterations such as Na(+)-K(+)-ATPase, cPLA(2), PI3Kinase and MAP kinase. Inhibition of PKC, especially the beta1/2 isoform has been reported to prevent or normalize many vascular abnormalities in the tissues described above. Clinical studies have shown that ruboxistaurin, a PKCbeta isoform selective inhibitor, normalize endothelial dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in diabetic patients. Thus, PKC activation involving several isoforms is likely to be responsible for some of the pathologies in diabetic retinopathy, nephropathy and cardiovascular disease. PKC isoform selective inhibitors are likely new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease with very little side effects.
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PMID:The role of protein kinase C activation and the vascular complications of diabetes. 1757 31

Reduced sensitivity to insulin in adipose, muscle, and liver tissues is a hallmark of type 2 diabetes. Animal models and patients with type 2 diabetes exhibit elevated levels of circulating retinol-binding protein (RBP4), and RBP4 can induce insulin resistance in mice. However, little is known about how RBP4 affects insulin signaling. We examined the mechanisms of action of RBP4 in primary human adipocytes. RBP4-treated adipocytes exhibited the same molecular defects in insulin signaling, via IRS1 to MAP kinase, as in adipocytes from patients with type 2 diabetes. Without affecting autophosphorylation of the insulin receptor, RBP4 blocked the insulin-stimulated phosphorylation of IRS1 at serine (307) [corresponding to serine (302) in the murine sequence] and concomitantly increased the EC50 (from 0.5 to 2 nM) for insulin stimulation of IRS1 phosphorylation at tyrosine. The phosphorylation of IRS1 at serine (312) [corresponding to serine (307) in the murine sequence] was not affected in cells from diabetic patients and was also not affected by RBP4. The EC50 for insulin stimulation of downstream phosphorylation of MAP kinase ERK1/2 was increased (from 0.2 to 0.8 nM) by RBP4. We show that ERK1/2 phosphorylation is similarly impaired in adipocytes from patients with type 2 diabetes. However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. When insulin-resistant adipocytes from patients with type 2 diabetes were incubated with antibodies against RBP4, insulin-induced phosphorylation of IRS1 at serine (307) was normalized and the EC50 for insulin stimulation of ERK1/2 phosphorylation was reduced. Endogenous levels of RBP4 were markedly reduced in adipocytes from obese or type 2 diabetic subjects, whereas expression levels of RBP4 mRNA were unaffected. These findings indicate that RBP4 may be released from diabetic adipocytes and act locally to inhibit phosphorylation of IRS1 at serine (307), a phosphorylation site that may integrate nutrient sensing with insulin signaling.
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PMID:Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. 1757 62

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated transcription factor of the nuclear receptor superfamily that regulates genes involved in differentiation, metabolism and immunity. PPARgamma-ligands are used for therapy of type 2 diabetes and hold the promise for treatment of inflammation and cancer. As a central regulatory component, PPARgamma activity is well regulated during various cellular processes, and indeed mitogenic stimulation often suppresses PPARgamma's genomic activity. This downregulation is mediated largely by the extracellular signal-regulated kinase 1/2 (ERKs)/mitogen-activated protein kinases (MAPKs) signaling cascade, which attenuates PPARgamma's transactivation function either by an inhibitory phosphorylation or by modulating PPARgamma's nucleo-cytoplasmic compartmentalization. The latter is achieved by the mitogen-induced nuclear export of PPARgamma through its direct interaction with the ERK cascade component MAPK/ERK-kinases 1/2 (MEKs). Upon mitogenic stimulation, MEKs translocate into the nucleus, but are rapidly exported from this location by their N-terminal nuclear export signal (NES), in a process that is accompanied by the export of their interacting nuclear PPARgamma molecules. Interestingly, it was recently demonstrated that PPARgamma has cytoplasmatic activities, and therefore, the MEK-dependent shuttle may also represent a mechanism for control of the extra-nuclear/nongenomic actions of PPARgamma. Because of the similarity within nuclear receptor docking motifs, it is possible that the same mechanism may control the nuclear and cytoplasmatic activity of other receptors. The changes in the subcellular localization of PPARgamma may also represent novel targets for selective interference in patients with chronic inflammatory or proliferation-related diseases.
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PMID:MAPK kinases as nucleo-cytoplasmic shuttles for PPARgamma. 1761 13

Diabetic retinopathy (DR) develops in patients with both type 1 and type 2 diabetes and is the major cause of vision loss and blindness in the working population. The main risk factor of DR is hyperglycemia accompanied by enhanced mitochondrial production of reactive oxygen species and oxidative stress, formation of advanced glycation end products (AGE) and hexosamines, increased polyol metabolism of glucose. The severity of vascular injury depends on the individual genetic background and is modified by other metabolic and haemodynamic factors influencing numbers of intracellular signalling molecules such as PKC, MAPK or NF-kappaB. In diabetes, damage to the retina occurs in the vasculature (endothelial cells and pericytes), neurons and glia, pigment epithelial cells and infiltrating immunocompetent cells: monocytes, granulocytes, lymfocytes. These activated cells change the production pattern of a number of mediators such as growth factors, vasoactive agents, coagulation factors and adhesion molecules resulting in increased blood flow, increased capillary permeability, proliferation of extracellular matrix and thickening of basal membranes, altered cell turnover (apoptosis, proliferation, hypertrophy), procoagulant and proaggregant patterns, and finally in angiogenesis and tissue remodelling. The insights into pathophysiological mechanisms responsible for DR that are presented here could help in the development of a more targeted approach to its prevention and treatment.
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PMID:[Pathogenesis of diabetic retinopathy]. 1764 32

We hypothesized that systemically circulating peripheral blood mononuclear cells (PBMCs) reflect the pathophysiology of type 2 diabetes. PBMCs were obtained from 18 patients with type 2 diabetes and 16 non-diabetic subjects. The expression of genes in the PBMCs was analyzed by using a DNA chip followed by statistical analysis for specific gene sets for biological categories. The only gene set coordinately up-regulated by the existence of diabetes and down-regulated by glycemic control consisted of 48 genes involved in the c-Jun N-terminal kinase (JNK) pathway. In contrast, the only gene set coordinately down-regulated by the existence of diabetes, but not altered by glycemic control consisted of 92 genes involved in the mitochondrial oxidative phosphorylation (OXPHOS) pathway. Our findings suggest that genes involved in the JNK and OXPHOS pathways of PBMCs may be surrogate transcriptional markers for hyperglycemia-induced oxidative stress and morbidity of type 2 diabetes, respectively.
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PMID:Gene expression profiles in peripheral blood mononuclear cells reflect the pathophysiology of type 2 diabetes. 1765 98

Oral hypoglycemic agents have great potential for the treatment of both type 1 and type 2 diabetes. Here we report the identification of novel, small-molecule, insulin mimetics that activate the insulin receptor (IR) in vivo and in vitro, stimulate the Akt and extracellular signal-regulated kinase pathways downstream of the IR, and mimic the ability of insulin to stimulate glucose uptake, glycogen synthesis, and lipid synthesis in 3T3-L1 adipocytes. However, the compounds do not mimic the mitogenic effect of insulin. In animals, these compounds have oral hypoglycemic effects in both normal C57BL6 mice and diabetic db/db mice. Quantitative structure activity relationship modeling on data from a library of 60 compounds has highlighted structural features that are important for IR agonist activity that can be used to guide design of second and third generation compounds with greater potency and specificity.
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PMID:Identification of novel orally available small molecule insulin mimetics. 1768 71


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