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)

Diastolic dysfunction is an increasingly recognized complication of diabetes that develops in relatively young patients as a result of diabetic cardiomyopathy (DCM). With recent advances in echocardiographic technology now permitting the reliable assessment of diastolic function in the rat, we examined cardiac function and structure in diabetic rodents and assessed the effects of intervening with tranilast, an antifibrotic compound that has been shown to attenuate the actions of transforming growth factor-beta (TGF-beta) in cardiac fibroblasts. We also sought to examine the mechanism whereby tranilast inhibits the actions of TGF-beta. Six-week-old heterozygous (mRen-2)27 rats were randomized to receive either streptozotocin or citrate buffer and then further randomized to receive either tranilast (400 mg x kg(-1) x day(-1) by twice daily gavage) or vehicle for another 8 wk. Cell signaling was examined in neonatal cardiac fibroblasts. After 8 wk, diabetic rats showed evidence of impaired diastolic function with reduced early-to-late atrial wave ratio and prolonged deceleration time in association with fibrosis, apoptosis, and hypertrophy (all P < 0.05). Treatment with tranilast prevented the development of diastolic dysfunction and the histopathological features of DCM. While tranilast did not affect Smad phosphorylation, it significantly attenuated TGF-beta-induced p44/42 mitogen-activated protein kinase phosphorylation.
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PMID:Tranilast attenuates diastolic dysfunction and structural injury in experimental diabetic cardiomyopathy. 1772 Jul 66

Vascular changes in diabetes are characterized by reduced vasoconstriction and vascular remodeling. Previously, we demonstrated that TGF-beta1 impairs Ang II-induced contraction through reduced calcium mobilization. However, the effect of TGF-beta1 on Ang II-induced vascular remodeling is unknown. Therefore, we investigated the effect of TGF-beta1 on Ang II-induced activation of the MAPK p44/42 pathway in cultured rat aortic smooth muscle cells (RASMC). Activation of MAPK p44/42 was determined with a phospho-specific antibody. Angiotensin type 1 receptor (AT(1)) and AT(1) mRNA levels were measured by [(3)H]candesartan-binding and real-time PCR, respectively. AT(1) gene transcription activity was assessed using AT(1) promoter-reporter constructs and by a nuclear runoff assay. In TGF-beta1-pretreated cells, Ang II-induced phosphorylation of MAPK p44/42 was inhibited by 29 and 46% for p42 and p44, respectively, and AT(1) density was reduced by 31%. Furthermore, pretreatment with TGF-beta1 resulted in a 64% reduction in AT(1) mRNA levels and decreased AT(1) mRNA transcription rate by 42%. Pretreatment with TGF-beta1 blocked Ang II-induced proliferation of RASMC, while stimulating Ang II-induced upregulation of plasminogen activator inhibitor-1. In conclusion, TGF-beta1 attenuates Ang II-mediated MAPK p44/42 kinase signaling in RASMC through downregulation of AT(1) levels, which is mainly caused by the inhibition of transcription of the AT(1) gene.
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PMID:TGF-beta inhibits Ang II-induced MAPK p44/42 signaling in vascular smooth muscle cells by Ang II type 1 receptor downregulation. 1920 3

Diabetes mellitus types 1 and 2, and gestational diabetes are characterized by abnormal D-glucose metabolism and hyperglycaemia, and induce foetal endothelial dysfunction with implications in adult life increasing the risk of vascular diseases. Synthesis of nitric oxide (NO) and uptake of L-arginine (i.e. the L-arginine/NO signalling pathway) and adenosine (a vasoactive endogenous nucleoside) by the umbilical vein endothelium is altered in pathological pregnancies, including pregnancies with pre-established diabetes mellitus or in gestational diabetes. The mechanisms underlying these alterations include differential expression of equilibrative nucleoside transporters (ENTs), amino acid transporters and NO synthases (NOS). Modulation of ENTs and NOS expression and activity in endothelium involves several signalling molecules, including protein kinase C, mitogen-activated protein kinases p42 and p44, calcium and phosphatidyl inositol 3 kinase. Elevated extracellular D-glucose and diabetes alters human endothelial function. However, information regarding modulation the transport capacity as well as expression of ENTs is limited. This review focuses on the effect of diabetes mellitus and gestational diabetes, and hyperglycaemia on the reported mechanisms described for transcriptional and post-transcriptional regulation of ENTs, and the potential consequences for foetal endothelial function in these pathologies. Recent available information regarding functional consequences of an abnormal environment on the functionality of the endothelium from microvasculature of the human placenta is mentioned. The available information is scarce, but it could contribute to a better understanding of the cell and molecular basis of the altered vascular endothelial function in this pathological conditions, emphasizing the key role of this type of epithelium in fetal-placental function and the normal foetal development and growth.
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PMID:Equilibrative nucleoside transporters in fetal endothelial dysfunction in diabetes mellitus and hyperglycaemia. 1948 84

The renin-angiotensin system (RAS) is one of the most important systems in physiology and in pathology. The (pro)renin receptor ((P)RR) is a new component of the system that has attracted much attention being potentially a new therapeutic target. The receptor binds renin and the inactive proenzyme form of renin, prorenin, and the binding triggers the activation of the mitogen-activated protein kinase p42/p44 followed by up-regulation of the expression of profibrotic genes. In addition, prorenin bound to (P)RR undergoes a conformational change and becomes catalytically active. Many animal studies have tried to demonstrate a role for (P)RR in hypertension and in tissue damage associated with diabetes, but if they showed that increased (P)RR was found in kidney of diabetic mice associated with glomerulosclerosis and in heart of hypertensive rats associated with cardiac fibrosis, no definite link could be established between elevated (P)RR and cardiovascular and renal pathologies because of the absence of animal models with a tissue-specific (P)RR knock-out and a lack of a (P)RR antagonist. On the contrary, the human and the animal mutations are calling our attention to an essential role of (P)RR during early development, in particular in neuronal development.
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PMID:The (pro)renin receptor in health and disease. 2010 54

A lot of anti-diabetic agents using natural plants have been extensively studied. Ginsenosides are known to be used as a remedy for diabetes in Asian countries and American Societies. Diabetic nephropathy is a major complication of diabetes mellitus. Extracellular matrix in mesangial cells is mainly composed of fibronectin and the increase of fibronectin is a hallmark of diabetic nephropathy. Protopenaxadiol (PPD) is a major component of total ginseng. Thus, we examined the regulatory mechanism of PPD derivatives-induced preventive effect of fibronectin expression in mesangial cells cultivated under diabetic condition. In present study, ginsenoside Rb1 prevented the high glucose-induced increase of fibronectin expression in mesangial cells. Ginsenoside Rb2 and Rg3 also mildly inhibited it. However, ginsenoside Rc and Rd did not prevent the high glucose-induced increase of fibronectin expression in mesangial cells. In addition, ginsenoside Rb1 prevented high glucose-induced phosphorylation of p44/42 mitogen activated protein kinase (MAPK), p38 MAPK, JNK/SAPK, and Akt. These results suggest that ginsenoside Rb1 is the most powerful component of PPD derivatives. In conclusion, ginsenoside Rb1 prevented high glucose-induced increase of fibronectin expression via the inhibition of MAPK-Akt signaling cascade.
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PMID:Effect of protopanaxadiol derivatives in high glucose-induced fibronectin expression in primary cultured rat mesangial cells: role of mitogen-activated protein kinases and Akt. 2019 56

Cardiovascular disease involves changes in inflammatory markers. Since insulin/insulin-like growth factor 1 receptor (IGF-1R) can activate vascular endothelial growth factor to promote vascular growth, reduced IGF-1R signaling in the type I diabetic heart could be detrimental, leading to reduced, collateral blood vessel growth. This study assessed whether diabetes can induce an inflammatory phenotype to regulate molecules in the IGF-1 signaling cascade, thus mediating apoptosis. Rats were made diabetic using streptozotocin (to render them type I diabetic) for 2 months with no insulin treatment. At 2 months, rats were sacrificed under anesthesia, and the left ventricle was immediately removed and placed into cold lysis buffer for protein analyses. Western blotting, immunoprecipitation, and enzyme-linked immunosorbent assay analyses were completed to evaluate protein levels. Diabetes increased TNF-alpha, interleukin-6 (IL-6), and IL-1alpha levels in the heart. JNK and p42/p44 activity was significantly increased in the diabetic heart, while IGF-1R phosphorylation, IRS-2 tyrosine phosphorylation, and Akt activities were reduced. A significant increase in Bad protein levels and the cleavage of caspase 3 was observed in the diabetic heart. These results suggest that diabetes activates multiple inflammatory markers in the heart, which then signal a decrease in the activities of key players in the insulin-signaling cascade, namely IGF-1R, IRS-2, and Akt, to regulate apoptosis.
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PMID:Regulation of IRS-2 signaling by IGF-1 receptor in the diabetic rat heart. 2055 24

Proinflammatory cytokines and essential fatty acids (EFAs) and their metabolites are altered in coronary heart disease, stroke, diabetes mellitus, hypertension, cancer, depression, schizophrenia, Alzheimer's disease, and collagen vascular diseases, indicating that these diseases not only are low-grade systemic inflammatory conditions but also have defects in the metabolism of EFAs. EFAs and their metabolites such as eicosanoids, lipoxins, resolvins, protectins, maresins, and nitrolipids are biologically active molecules that regulate gene expression and enzyme activity, modulate inflammation, the immune response, and gluconeogenesis by direct and indirect pathways, function directly as agonists of a number of G-protein-coupled receptors, and thus regulate several cellular processes. EFAs and their metabolites activate phosphatidylinositol 3-kinase/murine thymoma viral oncogene homolog 1 (Akt) and p44/42 mitogen-activated protein kinases and stimulate gluconeogenesis and cell proliferation by Ca(2+), phospholipase C/protein kinase, events that are also necessary for stem cell proliferation. Stem cells are pluripotent and expected to be of benefit in the management of many clinical conditions. Therefore, I propose that the beneficial actions of EFAs and their metabolites seen in coronary heart disease, stroke, diabetes mellitus, hypertension, atherosclerosis, cancer, depression, schizophrenia, Alzheimer's disease, and collagen vascular diseases could be ascribed to their ability to enhance the proliferation and differentiation of embryonic stem cells in addition to their capacity to suppress inflammation.
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PMID:Influence of polyunsaturated fatty acids and their metabolites on stem cell biology. 2057 Apr 89

Stem cells are pluripotent and expected to be of benefit in the management of coronary heart disease, stroke, diabetes mellitus, cancer, and Alzheimer's disease in which pro-inflammatory cytokines are increased. Identifying endogenous bioactive molecules that have a regulatory role in stem cell survival, proliferation, and differentiation may aid in the use of stem cells in various diseases including cancer. Essential fatty acids form precursors to both pro- and anti-inflammatory molecules have been shown to regulate gene expression, enzyme activity, modulate inflammation and immune response, gluconeogenesis via direct and indirect pathways, function directly as agonists of a number of G protein-coupled receptors, activate phosphatidylinositol 3-kinase/Akt and p44/42 mitogen-activated protein kinases, and stimulate cell proliferation via Ca(2+), phospholipase C/protein kinase, events that are also necessary for stem cell survival, proliferation, and differentiation. Hence, it is likely that bioactive lipids play a significant role in various diseases by modulating the proliferation and differentiation of embryonic stem cells in addition to their capacity to suppress inflammation. Ephrin Bs and reelin, adhesion molecules, and microRNAs regulate neuronal migration and cancer cell metastasis. Polyunsaturated fatty acids and their products seem to modulate the expression of ephrin Bs and reelin and several adhesion molecules and microRNAs suggesting that bioactive lipids participate in neuronal regeneration and stem cell proliferation, migration, and cancer cell metastasis. Thus, there appears to be a close interaction among essential fatty acids, their bioactive products, and inflammation and cancer growth and its metastasis.
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PMID:Essential fatty acids and their metabolites as modulators of stem cell biology with reference to inflammation, cancer, and metastasis. 2200 53

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus. One contributing factor to DPN is altered neurotrophism due to changes in the synthesis and expression of neurotrophins. Schwann cells (SCs) are the myelin-forming cells of the peripheral nervous system that promote nerve regeneration through the expression and secretion of neurotrophic factors (NTFs). Therefore, in this study, using SCs cultured in the presence of high levels of glucose for 24 h, with and without the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor, PD98059, we investigated the effect of high glucose levels on SCs over a short period of time. The cultured cells were evaluated using 3(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst staining, immunocytochemistry, reverse transcriptase-polymerase chain reaction and western blot analysis. High glucose levels did not promote morphological abnormalities or decrease the viability of SCs. However, high glucose levels enhanced the expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and induced the activation of p42/p44 MAPK in cultured SCs in a dose-dependent manner. Additionally, the phosphorylation of p42/p44 MAPK may be associated with the expression of NTFs by SCs exposed to high glucose conditions; the excessive activation of p42/p44 MAPK inhibited the expression of NTFs. These observations demonstrate that exposure to high glucose levels lead to acutely elevated levels of NGF and BDNF in SCs over a short period of time, which may be involved in the p42/p44 MAPK pathway.
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PMID:High glucose levels increase the expression of neurotrophic factors associated with p-p42/p44 MAPK in Schwann cells in vitro. 2255 24

Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. These data indicate nicotine induces insulin resistance in skeletal muscle by activating mTOR. Therapeutic agents designed to oppose skeletal muscle mTOR activation may prevent insulin resistance in humans who are unable to stop smoking or are chronically exposed to secondhand smoke.
Diabetes 2012 Dec
PMID:Novel and reversible mechanisms of smoking-induced insulin resistance in humans. 2317 60


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