Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The detection of preclinical heart disease is a new direction in diabetes care. This comment describes the study by Vinereanu and co-workers in this issue of Clinical Science in which tissue Doppler echocardiography has been employed to demonstrate subtle systolic and diastolic dysfunction in Type II diabetic patients who had normal global systolic function and were free of coronary artery disease. The aetiology of early ventricular dysfunction in diabetes relates to complex intramyocardial and extramyocardial mechanisms. The initiating event may be due to insulin resistance, and involves abnormal myocardial substrate utilization and uncoupling of mitochondrial oxidative phosphorylation. Dysglycaemia plays an important role via the effects of oxidative stress, protein kinase C activation and advanced glycosylation end-products on inflammatory signalling, collagen metabolism and fibrosis. Extramyocardial mechanisms involve peripheral endothelial dysfunction, arterial stiffening and autonomic neuropathy. The clinical significance of the ventricular abnormalities described is unknown. Confirmation of their prognostic importance for cardiac disease in diabetes would justify routine screening for presymptomatic ventricular dysfunction, as well as clinical trials of novel agents for correcting causal mechanisms. These considerations could also have implications for patients with obesity and the metabolic syndrome.
 ...
PMID:Ventricular dysfunction in early diabetic heart disease: detection, mechanisms and significance. 1283 96

Twenty-four percent of the adult American population have the metabolic syndrome. Although somewhat counterintuitive, carefully regulated treatment with insulin has been shown to reduce insulin resistance and may also retard the development of cardiovascular disease by preventing chronic hyperglycemia, a condition that synergistically contributes to many proatherogenic pathways, including glycoxidation, the polyol pathway, advanced glycation end products, interference with normal metabolic pathways, and stimulation of protein kinase C-beta and proinflammatory pathways. This article describes some of the physiologic changes that occur when hyperglycemia and insulin resistance develop in patients with type 2 diabetes and discusses therapies, including insulin, that normalize glucose and reduce insulin resistance, thereby potentially reducing cardiovascular risk.
 ...
PMID:Insulin therapy for reducing cardiovascular risk in patients with type 2 diabetes. 1498 5

Both protein kinase C (PKC) activation and increased oxidative stress have been paid attention to as important causative factors for diabetic vascular complications. In this article, we show a PKC-dependent increase in oxidative stress in vascular tissues of diabetes and insulin resistant state. High glucose level and free fatty acids stimulate de novo diacylglycerol (DAG)-PKC pathway and subsequently stimulate reactive oxygen species (ROS) production through a PKC-dependent activation of NAD(P)H oxidase. Increasing evidence has also shown that NAD(P)H oxidase components are upregulated in micro- and macro- vascular tissues of animal models and patients of diabetes and obesity. It is also noted that increased intrinsic angiotensin II production may amplify such a PKC-dependent activation of NAD(P)H oxidase in diabetic vascular tissues. These mechanisms may play an important role in the diabetic vascular complications and the accelerated atherosclerosis associated with diabetes and obesity. In addition, recent reports have shown that NAD(P)H oxidases exist in pancreatic beta-cells and adipocytes, and this oxidase-generated ROS production may play an important role in both the progressive beta-cell dysfunction and the dysregulated adipocytokine production and subsequent obesity-induced metabolic syndrome. These results suggest that an NAD(P)H oxidase activation may be a useful therapeutic target for preventing diabetic vascular complications, progressive beta-cell dysfunction and metabolic syndrome.
 ...
PMID:NAD(P)H oxidase activation: a potential target mechanism for diabetic vascular complications, progressive beta-cell dysfunction and metabolic syndrome. 1602 68

Insulin resistance, the impaired action of insulin, has been linked to many important consequences, including Type 2 diabetes, hypertension, dyslipidemia, acanthosis nigricans and polycystic ovarian syndrome. Although there are some genetic causes for insulin resistance, the most common cause is an excess of nutrition a condition called "Nutrient Toxicity". Both excess glucose and excess fat can cause insulin resistance in muscle and fat tissues and excess fat can cause insulin resistance in the liver. High fat feeding and fat infusion rapidly lead to the development of insulin resistance caused by impairment in glucose transport. Other studies have shown defects in insulin signaling possibly secondary to activation of Protein Kinase C resulting from the accumulation of active fatty acyl CoA's. Glucose toxicity has been studied both in vivo and in vitro. In vivo it has been shown that rats over-expressing the gluconeogenic enzyme Phosphoenol Pyruvate Carboxykinase (PEPCK) develop insulin resistance in fat and muscle tissues and some features of the metabolic syndrome including mild obesity and dyslipidemia. Excess glucose entry in fat cells results in increased flux through the hexosamine biosynthesis pathway leading to activation of protein kinase C and impairment of glucose transport. Obesity resulting from excess nutrient intake can also cause insulin resistance by an increase in the production of agents that impair insulin action such as TNFalpha and resistin and a decrease in the production of an insulin sensitizing compound adiponectin. Both glucose and free fatty acids acutely stimulate insulin secretion but chronic exposure to high levels of either nutrient leads to impairment of beta cell function. The combination of insulin resistance and beta cell failure leads to diabetes. Nutrient toxicity is thus the driving cause of the diabetes epidemic that is being recorded around the world.
 ...
PMID:Mechanisms of insulin resistance caused by nutrient toxicity. 1620 73

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.
 ...
PMID:Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. 1664 97

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
 ...
PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

Obesity, the metabolic syndrome, and type 2 diabetes mellitus (T2DM) are major global health problems. Insulin resistance is frequently present in these disorders, but the causes and effects of such resistance are unknown. Here, we generated mice with muscle-specific knockout of the major murine atypical PKC (aPKC), PKC-lambda, a postulated mediator for insulin-stimulated glucose transport. Glucose transport and translocation of glucose transporter 4 (GLUT4) to the plasma membrane were diminished in muscles of both homozygous and heterozygous PKC-lambda knockout mice and were accompanied by systemic insulin resistance; impaired glucose tolerance or diabetes; islet beta cell hyperplasia; abdominal adiposity; hepatosteatosis; elevated serum triglycerides, FFAs, and LDL-cholesterol; and diminished HDL-cholesterol. In contrast to the defective activation of muscle aPKC, insulin signaling and actions were intact in muscle, liver, and adipocytes. These findings demonstrate the importance of aPKC in insulin-stimulated glucose transport in muscles of intact mice and show that insulin resistance and resultant hyperinsulinemia owing to a specific defect in muscle aPKC is sufficient to induce abdominal obesity and other lipid abnormalities of the metabolic syndrome and T2DM. These findings are particularly relevant because humans who have obesity, impaired glucose tolerance, and T2DM reportedly have defective activation and/or diminished levels of muscle aPKC.
 ...
PMID:Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. 1764 77

Saturated free fatty acid (FFA) is a major source of metabolic stress that activates the c-Jun NH(2)-terminal kinase (JNK). This FFA-stimulated JNK pathway is relevant to hallmarks of metabolic syndrome, including insulin resistance. Here we used gene ablation studies in mice to demonstrate a central role for mixed-lineage protein kinases (MLK) in this signaling pathway. Saturated FFA causes protein kinase C (PKC)-dependent activation of MLK3 that subsequently causes increased JNK activity by a mechanism that requires the MAP kinase kinases MKK4 and MKK7. Loss of PKC, MLK3, MKK4, or MKK7 expression prevents FFA-stimulated JNK activation. Together, these data establish a signaling pathway that mediates effects of metabolic stress on insulin resistance.
 ...
PMID:Metabolic stress signaling mediated by mixed-lineage kinases. 1767 97

The primary target receptor for thiazolidinediones (TZDs) or peroxisome proliferator-activated receptor gamma (PPARgamma) agonists is a transcription factor in the nucleus of adipocytes and other metabolically active cells, where they improve insulin sensitivity and glucose utilization. TZDs are also able to modify gene expression in macrophages, smooth muscle cells, and endothelial cells. Although PPARgamma is considered to be a nuclear receptor, enucleate platelets also highly express this receptor. The aim of this review is to present the current understanding of a direct or indirect effect of TZDs on platelet function. By means of a comprehensive literature search (January 1990-June 2006), publications were obtained that contained specific information about in vitro and in vivo effects of TZDs on platelet function. The effects were studied for different risk biochemical markers, i.e., proteins found to be elevated in the state of procoagulant inflammation and endothelial dysfunction. Improvement of platelet function was reported for all TZDs-troglitazone, pioglitazone, and rosiglitazone. The described effects included reduction of platelet aggregation, suppression of thrombin-induced protein kinase C-alpha and -beta activation, decrease in plasma P-selectin and platelet P-selectin expression, increase in nitric oxide production, inhibition of the Rho/Rho kinase pathway, and inhibition of tissue factor- and platelet-activating factor-induced morphological changes in macrophages. These findings appeared in parallel with reduction of the plasma concentrations of pro-inflammatory risk markers. TZDs seem to have a direct pleiotropic positive influence on platelet function and coagulation and may be helpful in treating the prothrombotic state observed in patients with type 2 diabetes and metabolic syndrome.
 ...
PMID:Review of the pleiotropic effects of peroxisome proliferator-activated receptor gamma agonists on platelet function. 1793 Oct 49

Recently we showed that the administration of intraperitoneal L-carnitine (CA) has insulin-sensitizing effects in the high fructose-fed Wistar rat, a widely used model of metabolic syndrome. The present study was conducted to examine the regulatory effects of CA on blood pressure (BP) and related pressor mechanisms. Fructose-fed rats (FFR) showed elevated BP, cardiac hypertrophy, glucose intolerance, and increases in plasma glucose, insulin, free fatty acids (FFA), and angiotensin-converting enzyme (ACE) activity. They also showed increased protein kinase C betaII (PKC betaII) expression and oxidative stress in cardiac tissue. In plasma, decreased kallikrein enzyme activity and nitric oxide metabolites were observed, compared to control. Simultaneous treatment with CA (300 mg/Kg) mitigated these alterations. PKC betaII expression was similar to that of control; the rats displayed normal BP and ACE activity, enhanced antioxidant protection, and close to normal values of metabolic parameters. The BP-lowering effect of CA was abolished when CA-treated rats were administered L-nitroarginyl methyl ester (L-NAME 6g/Kg). These observations suggest that the BP-lowering action of CA in this model could be attributed to multiple and interrelated mechanisms, such as an increase in NO and kinin availability, reduction in PKC action, and antioxidant protection.
 ...
PMID:Increase in nitric oxide and reductions in blood pressure, protein kinase C beta II and oxidative stress by L-carnitine: a study in the fructose-fed hypertensive rat. 1805 77


1 2 3 4 5 Next >>