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)

The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients.
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PMID:mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb). 1957 3

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We have recently shown that epidermal growth factor receptor (EGFR) transactivation mediates high glucose (HG)-induced collagen I upregulation through PI3K-PKCbeta1-Akt signaling in mesangial cells (MC). Phospholipase Cgamma1 (PLCgamma1) interacts with activated growth factor receptors and activates classic PKC isoforms. We thus studied its role in HG-induced collagen I upregulation in MC. Primary rat MC were treated with HG (30 mM) or mannitol as osmotic control. Protein kinase activation was assessed by Western blotting and collagen I upregulation by Northern blotting. Diabetes was induced in rats by streptozotocin. HG treatment for 1 h led to PLCgamma1 membrane translocation and Y783 phosphorylation, both indicative of its activation. Mannitol was without effect. PLCgamma1 Y783 phosphorylation was also seen in cortex and glomeruli of diabetic rats. HG induced a physical association between EGFR and PLCgamma1 as identified by coimmunoprecipitation. PLCgamma1 activation required EGFR kinase activity since it was prevented by the EGFR inhibitor AG1478 or overexpression of kinase-inactive EGFR (K721A). Phosphoinositide-3-OH kinase inhibition also prevented PLCgamma1 activation. HG-induced Akt S473 phosphorylation, effected by PKCbeta1, was inhibited by the PLCgamma inhibitor U73122. PLCgamma1 inhibition or downregulation by small interference RNA also prevented HG-induced collagen I upregulation. Our results indicate that EGFR-PLCgamma1 signaling mediates HG-induced PKCbeta1-Akt activation and subsequent collagen I upregulation in MC. Inhibition of EGFR or PLCgamma1 may provide attractive therapeutic targets for the treatment of diabetic nephropathy.
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PMID:EGFR-PLCgamma1 signaling mediates high glucose-induced PKCbeta1-Akt activation and collagen I upregulation in mesangial cells. 1960 47

Salicornia herbacea has been used as a folk medicine for disorders such as constipation, obesity, diabetes, and cancer. Recent studies have shown that S. herbacea has antioxidative, anti-inflammatory, immunomodulatory, antihyperglycemic, and antihyperlipidemic activities. In the present work, we investigated the protective effects of the chlorogenic acid derivative, 3-caffeoyl, 4-dihydrocaffeoyl quinic acid (CDCQ), which was isolated from S. herbacea, against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in Hepa1c1c7 cells. Pretreatment of Hepa1c1c7 cells with CDCQ significantly reduced t-BHP-induced generation of ROS, caspase-3 activation, and subsequent cell death. Also, CDCQ up-regulated heme oxygenase-1 (HO-1) expression, which conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, CDCQ-induced nuclear translocation of the transcription factor NF-E2-related factor 2 (Nrf2), which is upstream of CDCQ-induced HO-1 expression, and PI3K/Akt activation, a pathway that is involved in induced Nrf2 nuclear translocation. Taken together, these results suggest that the protective effects of CDCQ against t-BHP-induced hepatotoxicity may be due, at least in part, to its ability to scavenge ROS and to regulate the antioxidant enzyme HO-1 via the PI3K/Akt-Nrf2 signaling pathways.
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PMID:Protective mechanisms of 3-caffeoyl, 4-dihydrocaffeoyl quinic acid from Salicornia herbacea against tert-butyl hydroperoxide-induced oxidative damage. 1964 27

Retinal angiogenesis in diabetes may lead to visual impairment and even irreversible blindness in people of working age group worldwide. The main pathological feature of proliferative diabetic retinopathy (PDR) is hypoxia, and overproduction of growth factors like vascular endothelial growth factor (VEGF) and erythropoietin (Epo). This results in pathological proliferation of retinal endothelial cells (RECs), leading to new vessel formation (angiogenesis). Inhibition of angiogenesis is a promising strategy for treatment of PDR and other retinal neovascular disorders. Pigment epithelium-derived factor (PEDF), a 50-kDa protein secreted by retinal pigment epithelium, inhibits the growth of new blood vessel induced in the eye in a variety of ways with a yet elusive mechanism. Here, we investigated the possible mechanism by which PEDF inhibits VEGF- and Epo-induced angiogenic effects in RECs is mediated through PI3K/Akt pathway. PEDF treatment induced the apoptosis in RECs by activating caspase-3 and DNA fragmentation. We found a dose-dependent increase in cell survival with VEGF or Epo, which was attenuated in the presence of PEDF. In addition, PEDF significantly (P < 0.05) inhibited migration and in vitro tube formation in RECs in the presence of VEGF as like PI3K/Akt inhibitor. Of interest, PEDF effectively abrogated VEGF-mediated phosphorylation of PI3K/Akt. Further studies using RECs transfected with constitutively active and dominant-negative forms of Akt suggest that PEDF could inhibit VEGF- and also Epo-induced angiogenesis by disruption of PI3K/Akt signaling.
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PMID:PEDF inhibits VEGF- and EPO- induced angiogenesis in retinal endothelial cells through interruption of PI3K/Akt phosphorylation. 2176 85

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110alpha) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110alpha) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult ( approximately 4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice ( approximately 15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF, suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110alpha) and AF.
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PMID:Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. 1967 77

PANDER is a cytokine co-secreted with insulin from islet beta-cells. To date, the physiological function of PANDER remains largely unknown. Here we show that PANDER binds to the liver membrane by (125)I-PANDER saturation and competitive binding assays. In HepG2 cells, pre-treatment with PANDER ranging from 4 pM to 4 nM for 8h resulted in a maximal inhibition of insulin-stimulated activation of insulin receptor and insulin receptor substrate 1 by 52% and 63%, respectively. Moreover, PANDER treatment also reduced insulin-stimulated PI3K and pAkt levels by 55% and 48%, respectively. In summary, we have identified the liver as a novel target for PANDER, and PANDER may be involved in the progression of diabetes by regulating hepatic insulin signaling pathways.
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PMID:PANDER binds to the liver cell membrane and inhibits insulin signaling in HepG2 cells. 1968 28

To investigate the enteric neuropathy in diabetic rats and the role of glia cell line-derived neurotrophic factor (GDNF) and its signalling pathway PI3K/Akt in regulating enteric neurons survival. Male Sprague-Dawley (SD) rats were randomly divided into normal control group, diabetic groups (rats with diabetes for 4, 8 and 12 weeks respectively). Proximal and distal colon specimens were obtained from each rat. Phosphoinositol-3-kinase signalling pathway was analysed by Akt phosphorylation. Protein gene product 9.5 (PGP9.5) used as a pan-neuronal marker. The expressions of GDNF, phospho-Akt (p-Akt), neuronal nitric oxide synthase (nNOS) neurons, cholinergic [choline acetyltransferase (CHAT) stained] neurons and total neurons were measured by immunohistochemical streptavidin-biotin complex (SABC) methods, Western blot and real-time polymerase chain reaction methods for each specimen. (i) Expression of GDNF was significantly decreased in diabetes 8 and 12 weeks group compared with the control group in both proximal (P < 0.01) and distal (P < 0.01) colon. The change of GDNF expression was greater in the 12 weeks group than that in the 8 weeks group (P < 0.05). There were no significant differences between the 4 weeks group and the control group in expression of GDNF (P > 0.05). (ii) The change trend of Akt phosphorylation was the same with GDNF. (iii) The numbers of nNOS, CHAT neurons and total neurons in proximal and distal colon were decreased significantly during the course of diabetes (P < 0.05). Diabetes can significantly induce enteric neuropathy. This change may be mediated, in partly, via a reduction of GDNF and its main downstream signalling pathway PI3K/Akt, which is a survival signal for enteric neurons.
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PMID:Loss of enteric neurons accompanied by decreased expression of GDNF and PI3K/Akt pathway in diabetic rats. 1970 71

Muscle wasting is associated with a number of pathophysiologic conditions, including metabolic acidosis, diabetes, sepsis, and high angiotensin II levels. Under these conditions, activation of muscle protein degradation requires endogenous glucocorticoids. As the mechanism(s) underlying this dependence on glucocorticoids have not been identified, we analyzed the effects of glucocorticoids on muscle wasting in a mouse model of acute diabetes. Adrenalectomized, acutely diabetic mice given a physiologic dose of glucocorticoids exhibited decreased IRS-1-associated PI3K activity in muscle and progressive muscle atrophy. These responses were related to increased association of PI3K with the glucocorticoid receptor (GR). In mice with muscle-specific GR deletion (referred to as MGRKO mice), acute diabetes minimally suppressed IRS-1-associated PI3K activity in muscle and did not cause muscle atrophy. However, when a physiologic dose of glucocorticoids was given to mice with muscle-specific IR deletion, muscle protein degradation was accelerated. Fluorescence resonance energy transfer and an in vitro competition assay revealed that activated GRs competed for PI3K, reducing its association with IRS-1. Reexpression of WT GRs or those with a mutation in the nuclear localization signal in the muscle of MGRKO mice indicated that competition for PI3K was a prominent mechanism underlying reduced IRS-1-associated PI3K activity. This nongenomic influence of the GR contributes to activation of muscle protein degradation. We therefore conclude that stimulation of muscle proteolysis requires 2 events, increased glucocorticoid levels and impaired insulin signaling.
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PMID:Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice. 1975 15

Compelling evidence is accumulating indicating a pathophysiological role of the serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in the development and complications of diabetes. SGK1 is ubiquitously expressed with exquisitely high transcriptional volatility. Stimulators of SGK1 expression include hyperglycemia, cell shrinkage, ischemia, glucocorticoids and mineralocorticoids. SGK1 is activated by insulin and growth factors via PI3K, 3-phosphoinositide dependent kinase PDK1 and mTOR. SGK1 activates ion channels (including ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and CLCKa/Barttin), carriers (including NCC, NKCC, NHE3, SGLT1 and EAAT3), and the Na(+)/K(+)-ATPase. It regulates the activity of several enzymes (e.g., glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g., forkhead-transcription-factor FOXO3a, beta-catenin and NF-kappaB). A common SGK1 gene variant ( approximately 3 - 5% prevalence in Caucasians, approximately 10% in Africans) is associated with increased blood pressure, obesity and type 2 diabetes. In patients suffering from type 2 diabetes, SGK1 presumably contributes to fluid retention and hypertension, enhanced coagulation and increased deposition of matrix proteins leading to tissue fibrosis such as diabetic nephropathy. Accordingly, targeting SGK1 may favourably influence occurrence and course of type 2 diabetes.
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PMID:Targeting SGK1 in diabetes. 1976 91

Curcumin, an active principle contained in rhizome of Curcuma longa, has been mentioned to show merit for diabetes through its anti-oxidative and anti-inflammatory properties. In the present study, we found that curcumin caused a concentration-dependent increase of glucose uptake into skeletal muscle isolated from Wistar rats. This action was inhibited by pirenzepine at concentration enough to block muscarinic M-1 cholinoceptor (M(1)-mAChR). In radioligand binding assay, the binding of [(3)H]-pirenzepine was also displaced by curcumin in a concentration-dependent manner. In the presence of inhibitors for PLC-PI3K pathway, either U73122 (phospholipase C inhibitor) or LY294002 (phosphoinositide 3-kinase inhibitor), curcumin-stimulated glucose uptake into skeletal muscle was markedly reduced. In Western blotting analysis, the membrane protein level of glucose transporter 4 (GLUT4) increased by curcumin was also reversed by blockade of M(1)-mAChR or PLC-PI3K pathway in a same manner. In conclusion, the obtained results suggest that curcumin can activate M(1)-mAChR at concentrations lower than to scavenge free radicals for increase of glucose uptake into skeletal muscle through PLC-PI3-kinase pathway.
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PMID:Activation of muscarinic M-1 cholinoceptors by curcumin to increase glucose uptake into skeletal muscle isolated from Wistar rats. 1976 5


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