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 ubiquitous isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (uPFK-2), a product of the Pfkfb3 gene, plays a crucial role in the control of glycolytic flux. In this study, we demonstrate that Pfkfb3 gene expression is increased in streptozotocin-induced diabetic mouse liver. The Pfkfb3/-3566 promoter construct linked to the luciferase reporter gene was delivered to the liver via hydrodynamic gene transfer. This promoter was upregulated in streptozotocin-induced diabetic mouse liver compared with transfected healthy cohorts. In addition, increases were observed in Pfkfb3 mRNA and uPFK-2 protein levels, and intrahepatic fructose-2,6-bisphosphate concentration. During streptozotocin-induced diabetes, phosphorylation of both p38 mitogen-activated protein kinase and Akt was detected, together with the overexpression of the proliferative markers cyclin D and E2F. These findings indicate that uPFK-2 induction is coupled to enhanced hepatocyte proliferation in streptozotocin-induced diabetic mouse liver. Expression decreased when hepatocytes were treated with either rapamycin or LY 294002. This shows that uPFK-2 regulation is phosphoinositide 3-kinase-Akt-mammalian target of rapamycin dependent. These results indicate that fructose-2,6-bisphosphate is essential to the maintenance of the glycolytic flux necessary for providing energy and biosynthetic precursors to dividing cells.
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PMID:Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals. 1964 23

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

Hyperinsulinemia and metabolic diseases are known to be associated with a reduction in life span. In the presence of insulin resistance, insulin signaling is selectively impaired, contributing to longevity shortening. Insulin indeed activates a complex web of intracellular downstream pathways, which are involved in mechanisms regulating longevity, primarily affecting cellular proliferation and apoptosis. Insulin resistance promotes reactive oxygen species (ROS) formation and favors a pro-inflammatory milieu, both these conditions playing a critical role in the reduction of life span. Insulin resistance/hyperinsulinemia also influences longevity regulating other intracellular signaling downstream in a direct or indirect manner, such as the phosphoinositide 3-kinase pathway that appears selectively impaired by insulin resistance. Decreased NAD-dependent deacetylase sirtuin (Sirt) 1 activity may mediate the shortened life span in conditions of insulin resistance. Furthermore, insulin resistance and diabetes may also associate with the telomere shortening, another important regulator of life span. This review will focus on the main intracellular pathways and mediators regulated by insulin and altered by hyperinsulinemia/insulin resistance; it summarizes the underlying mechanisms and provides evidence of these observations in experimental animal models and in human, giving further insight on the hypothesis that insulin signaling may play an important role in life span.
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PMID:Insulin signaling and life span. 1975 20

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

Purpose. Patients with diabetes are at higher risk for delayed corneal reepithelialization and infection. Previous studies indicated that high glucose (HG) impairs epidermal growth factor receptor (EGFR) signaling and attenuates ex vivo corneal epithelial wound healing. The authors investigated the effects of antimicrobial peptide LL-37 on HG-attenuated corneal epithelial EGFR signaling and wound closure. Methods. Human corneal epithelial cells (HCECs) were stimulated with LL-37. Heparin-binding EGF-like growth factor (HB-EGF) shedding was assessed by measuring the release of alkaline phosphatase (AP) in a stable HCEC line expressing HB-EGF-AP. Activation of EGFR, phosphoinositide 3-kinase (PI3K), and extracellular signal-regulated kinases 1/2 (ERK1/2) was determined by Western blot analysis. Corneal epithelial wound closure was assessed in cultured HCECs and porcine corneas. LL-37 expression was determined by immune dot blot. Results. LL-37 induced HB-EGF-AP release and EGFR activation in a dose-dependent manner. LL-37 prolonged EGFR signaling in response to wounding. LL-37 enhanced the closure of a scratch wound in cultured HCECs and partially rescued HG-attenuated wound healing in an EGFR- and a PI3K-dependent manner and restored HG-impaired EGFR signaling in cultured porcine corneas. HG attenuated wounding-induced LL-37 expression in cultured HCECs. Conclusions. LL-37 is a tonic factor promoting EGFR signaling and enhancing epithelial wound healing in normal and high glucose conditions. With both antimicrobial and regenerative capabilities, LL-37 may be a potential therapeutic for diabetic keratopathy.
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PMID:LL-37 via EGFR transactivation to promote high glucose-attenuated epithelial wound healing in organ-cultured corneas. 1979 3

The fission yeast Schizosaccharomyces pombe is an excellent model for cellular quiescence that can be achieved experimentally with nutritional limitations. The target of rapamycin complex (TORC) is known to be important for the transition between proliferation and quiescence from yeast to humans, and the recently identified TORC components, Tti1 and Tel2, might control all of the cellular phosphoinositide 3-kinase-related kinases. New pilot studies using deletion mutants and temperature-sensitive mutants suggest that up to approximately 1000 genes are required for quiescence, and approximately 300 of these, called superhousekeeping genes, also participate in proliferation. These latest findings suggest that genes controlling quiescence are conserved from yeast to humans, and support the use of S. pombe as a model to enhance our understanding of the causes of aging, diabetes, obesity and neurodegeneration.
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PMID:Cellular quiescence: are controlling genes conserved? 1983 16

TF (tissue factor) is the main trigger of the coagulation cascade; by binding Factor VIIa it activates Factor IX and Factor X, thereby resulting in fibrin formation. Various stimuli, such as cytokines, growth factors and biogenic amines, induce TF expression and activity in vascular cells. Downstream targets of these mediators include diverse signalling molecules such as MAPKs (mitogen-activated protein kinases), PI3K (phosphoinositide 3-kinase) and PKC (protein kinase C). In addition, TF can be detected in the bloodstream, known as circulating or blood-borne TF. Many cardiovascular risk factors, such as hypertension, diabetes, dyslipidaemia and smoking, are associated with increased expression of TF. Furthermore, in patients presenting with acute coronary syndromes, elevated levels of circulating TF are found. Apart from its role in thrombosis, TF has pro-atherogenic properties, as it is involved in neointima formation by inducing vascular smooth muscle cell migration. As inhibition of TF action appears to be an attractive target for the treatment of cardiovascular disease, therapeutic strategies are under investigation to specifically interfere with the action of TF or, alternatively, promote the effects of TFPI (TF pathway inhibitor).
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PMID:Tissue factor: beyond coagulation in the cardiovascular system. 1984 9

Diabetes mellitus is an important risk factor for cardiovascular diseases. Clinical evidence supports a link between hyperglycemia, endothelial dysfunction, and vascular disorders. However, the precise molecular mechanisms causing endothelial dysfunction in diabetic patients remain unclear. An interesting novel mediator could be chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), which plays an essential role in glucose metabolism. COUP-TFII is known to be expressed in venous endothelial cells. In this study, we show COUP-TFII expression in human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells. HUVECs express glucose transporters 1, 3, 6, and 10, and the insulin receptor. Insulin in combination with glucose activates protein kinase B (PKB or Akt) phosphorylation via phosphoinositide 3-kinase (PI3-kinase). Short-term (60-240 min) stimulation of HUVECs with high glucose increased COUP-TFII expression independent of insulin. Long-term (48 h) stimulation of HUVECs with high glucose augmented expression of the insulin receptor and E-selectin, but downregulated COUP-TFII protein expression. Downregulation of COUP-TFII by shRNA leads to downregulation of E-selectin and upregulation of eNOS and glucose transporters. Our data suggest that COUP-TFII is regulated by glucose in a time- and dose-dependent manner in endothelial cells. COUP-TFII might affect endothelial function in a diabetic background.
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PMID:COUP-TFII is regulated by high glucose in endothelial cells. 1986 65

Glucose uptake activity of 11 plant foods was assessed in L6 myotubes. Among them onion and ginger showed potent enhancement of glucose transport. This effect required new protein synthesis of glucose transporters. In addition, onion-induced glucose uptake in L6 myotubes was mediated through activation of phosphoinositide 3-kinase.
Diabetes Res Clin Pract 2010 Aug
PMID:Enhancement of glucose transport by selected plant foods in muscle cell line L6. 2051 Apr 75

Adult pancreatic nonendocrine cells represent a potential alternative source of insulin-producing tissue for the treatment of diabetes. Differentiation of these cells is regulated by various signaling pathways including the phosphoinositide 3-kinase (PI3K) pathway. Therefore, we evaluated the effect of PI3K on this process. Compared with untreated cells the differentiation of human nonendocrine pancreatic cells into insulin-producing elements was increased after treatment with IGF-1, EGF, and Exendin-4, growth factors known to be activators of the PI3K pathway (12.2 +/- 3.2% vs 9.1 +/- 3.2%). Treatment with PI3K pathway inhibitor wortmannin reduced the number of differentiated beta cells from 9.1 +/- 3.2 to 0.7 +/- 0.4%. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and Exendin-4 significantly increased the expression of the transcription factor neurogenin-3, whereas the expressions of pancreatic and duodenal homeobox 1 (PDX-1), neurogenic differentiation 1 (NeuroD) were increased only among samples treated with ZnCl2 and not significantly affected by treatment with the tested growth factors. Successful differentiation of IGF-1, EGF-, and Exendin-4-treated cells into functional beta cells was confirmed by C-peptide secretion in response to 5 versus 20 mmol glucose stimulation (0.24 vs 0.91 pmol C-peptide/microg DNA). These results showed that activation of the PI3K signaling pathway might be used to stimulate the differentiation of nonendocrine pancreatic cells into insulin-producing elements.
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PMID:An acidic pH and activation of phosphoinositide 3-kinase stimulate differentiation of pancreatic progenitors into insulin-producing cells. 2069 12


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