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

According to the most recent classification of diabetes mellitus the latent autoimmune diabetes in adults belongs to the group of type 1 autoimmune diabetes mellitus, as a slowly progressive form. It is not clear whether LADA is a distinct clinical entity or it is a part of the clinical spectrum of type 1 diabetes mellitus. The authors compare the antropologic (body mass index, waist to hip ratio), immunologic (occurrence of islet cell cytoplasmic autoantibodies and autoantibodies against glutamic acid decarboxylase and tyrosin phosphatase), genetic (HLA DR and DQ alleles known to be associated to type 1 diabetes mellitus) characteristics and occurrence of the features of the metabolic syndrome in the groups of type 1 and type 2 diabetes and LADA. 81 type 1 and 190 type 2 diabetics and 38 LADA patients were involved into the study. Freshly diagnosed type 1 diabetics served for controls of the autoantibody study: 48 patients manifested < or = 16 years of age and 89 type 1 diabetics manifested above 16 years of age. The three main diabetic groups differed in age: the average age in the type 1, type 2 and LADA groups were 37, 63 and 58 years respectively. There was no difference among the three groups in gender. The duration of the disease differed significantly between the type 2 and LADA groups (4.0 and 8.0 years respectively). In spite of the shorter duration of the disease in the LADA group, compared to the type 2 diabetics the frequency of insulin dependency was significantly higher in the LADA (81.6%) than in the type 2 group (46.7%). The BMI and WHR were comparable between the type 1 and LADA patients (average values were 23 and 0.83 in type 1 patients and 23.25 and 0.89 in LADA). The type 2 group differed significantly from type 1 and LADA (average values were 29.1 and 0.5). The concentration of glycated hemoglobin was comparable in the three groups. But there was a significant difference in HbA1c concentration between the freshly diagnosed subgroups of type 1 and LADA patients: 10.85% and 8% respectively. The fasting C-peptid levels were significantly higher in the sera of type 2 diabetics (0.75 pmol/l) compared to type 1 (0.2 pmol/l) and LADA patients (0.29 pmol/l). There was a significant difference in C-peptid concentrations between the type 1 and LADA groups, too. The insulin deficiency in LADA seemed to be not as severe as in type 1 diabetes. The serum total cholesterol and triglyceride levels were significantly higher and the HDL cholesterol concentration significantly lower in type 2 diabetics comparing to type 1 and LADA patients and there was no significant difference in this respect between the type 1 and LADA groups. The frequency of occurrence of hypertension differed no significantly between type 2 and LADA, but that of in type 1 diabetes was significantly lower than both type 2 and LADA. The occurrence of multiple autoantibodies (ICA + GADA + anti-IA2) was much more frequent in type 1 diabetes compared to LADA. In the sera of LADA patients the occurrence of ICA and GADA alone or ICA + GADA was characteristic (31.5% - 21.1% - 15.8% respectively). There was no difference between type 1 diabetes and LADA in the occurrence of the alleles of the MHC kown to be associated with type 1 diabetes. The occurrence of the haplotypes HLA DQ2/DR3 and/or DQ8/DR4 was observed in two thirds of type 1 diabetic and LADA patients. Chronic diabetic complications were observed in all of the groups and there was only a secondary connection of the complications with the type of the diabetes. Based on the results the authors suggest that LADA is a part of the clinical spectrum of type 1 diabetes of autoimmune origin.
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PMID:[Latent autoimmune diabetes in adults(LADA): part of the clinical spectrum of type-1 diabetes mellitus of autoimmune origin]. 1177 Jan 76

Like hyperglycemia, postprandial (diet-induced) hypertriglyceridemia is thought to play crucial roles in the pathogenesis of insulin resistant/metabolic syndrome. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor to induce postprandial hypertriglyceridemia. We found that insulin-resistant rats fed a diet high in fructose showed an increased proteintyrosine phosphatase 1B (PTP1B) content with strong expression of SREBP-1 mRNA in the liver. To clarify the association of PTP1B with SREBP-1 gene expression, we overexpressed PTP1B in rat hepatocytes, which led to increased mRNA content and promoter activity of SREBP-1a and -1c, resulting in the increased mRNA expression of fatty-acid synthase, one of the SREBP-1-responsive lipogenic genes. Because PTP1B overexpression increased phosphatase 2A (PP2A) activity, we inhibited PP2A activity by expression of its selective inhibitor, SV40 small T antigen and found that this normalized the PTP1B-enhanced SREBP-1a and -1c mRNA expressions through activation of the Sp1 site. These results indicate that PTP1B may regulate gene expression of SREBP-1 via enhancement of PP2A activity, thus mediating hepatic lipogenesis and postprandial hypertriglyceridemia. We demonstrate here a unique serial activation of the PTP1B-PP2A axis as a novel mechanism for the regulation of gene expression in the biosynthesis of triglyceride.
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PMID:Protein-tyrosine phosphatase 1B as new activator for hepatic lipogenesis via sterol regulatory element-binding protein-1 gene expression. 1294 32

Type II SH2 domain-containing inositol 5-phosphatase (INPPL1, or SHIP2) plays an important role in the control of insulin sensitivity. INPPL1 mutations affecting gene function have been found in rat models of type 2 diabetes and hypertension and in type 2 diabetic patients. We investigated the influence of nucleotide variation in INPPL1 on components of the metabolic syndrome. Following comprehensive resequencing of the gene, we genotyped 12 informative polymorphisms in 1,304 individuals from 424 British type 2 diabetes families that were characterized for several metabolic phenotypes. We have found highly significant associations of single nucleotide polymorphisms (SNPs) and haplotypes of INPPL1 with hypertension as well as with other components of the metabolic syndrome. In a cohort of 905 French type 2 diabetic patients, we found evidence of association of INPPL1 SNPs with the presence of hypertension. We conclude that INPPL1 variants may impact susceptibility to disease and/or to subphenotypes involved in the metabolic syndrome in some diabetic patients.
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PMID:Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome. 1522 Feb 17

Insulin resistance has been described in several diseases that increase cardiovascular risk and mortality, such as diabetes, obesity, hypertension, metabolic syndrome, and heart failure. Abnormalities of insulin signaling account for insulin resistance. Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). Several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IR substrate (IRS) proteins, including proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. On the other hand, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation. Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. The characterization of molecular mechanisms involved in the pathogenesis of insulin resistance may help to design efficacious pharmacologic molecules to treat endothelial and metabolic dysfunction associated with insulin resistance states to reduce the cardiovascular risk and to ameliorate the prognosis of patients with cardiovascular diseases.
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PMID:Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology. 1683 60

Endothelial cell dysfunction and apoptosis are critical in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Both endothelial cell apoptosis and atherosclerosis are reduced by high-density lipoprotein (HDL). Low HDL levels increase the risk of CVD and are also a key characteristic of the metabolic syndrome. The apolipoprotein E4 (APOE4) allele also increases the risk of atherosclerosis and CVD. We previously demonstrated that the antiapoptotic activity of HDL is inhibited by APOE4 very-low-density lipoprotein (APOE4-VLDL) in endothelial cells, an effect similar to reducing the levels of HDL. Here we establish the intracellular mechanism by which APOE4-VLDL inhibits the antiapoptotic pathway activated by HDL. We show that APOE4-VLDL diminishes the phosphorylation of Akt by HDL but does not alter phosphorylation of c-Jun N-terminal kinase, p38, or Src family kinases by HDL. Furthermore APOE4-VLDL inhibits Akt phosphorylation by reducing the phosphatidylinositol 3-kinase product phosphatidylinositol-(3,4,5)-triphosphate (PI[3,4,5]P3). We further demonstrate that APOE4-VLDL reduces PI(3,4,5)P3, through the phosphoinositol phosphatase SHIP2, and not through PTEN. SHIP2 is already implicated as an independent risk factor for type II diabetes, hypertension and obesity, which are also all components of the metabolic syndrome and independent risk factors for CVD. Significantly, the association between CVD and type 2 diabetes or hypertension is further increased by the APOE4 allele. Therefore the activation of SHIP2 by APOE4-VLDL, with the subsequent inhibition of the HDL/Akt pathway, is a novel and significant biological mechanism and may be a critical intermediate by which APOE4 increases the risk of atherosclerotic CVD.
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PMID:APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2. 1697 5

The lipid phosphatase SH2 domain-containing lipid phosphatase (SHIP2) has been implicated in the regulation of insulin sensitivity, but its role in the therapy of insulin-resistant states remains to be defined. Here, we examined the effects of an antisense oligonucleotide (AS) therapy directed against SHIP2 on whole body insulin sensitivity and insulin action in liver and muscle tissue in a dietary rodent model of the metabolic syndrome, the high-fat-fed (HF) rat. Whole body insulin sensitivity was examined in vivo by insulin tolerance tests before and after the intraperitoneal application of an AS directed against SHIP2 (HF-SHIP2-AS) or a control AS (HF-Con-AS) in HF rats. Insulin action in liver and muscle was assayed by measuring the activation of protein kinase B (Akt) and insulin receptor substrate (IRS)-1/2 after a portal venous insulin bolus. SHIP2 mRNA and protein content were quantified in these tissues by real-time PCR and immunoblotting, respectively. In HF-SHIP2-AS, whole body glucose disposal after an insulin bolus was markedly elevated compared with HF-Con-AS. In liver, insulin activated Akt similarly in both groups. In muscle, insulin did not clearly activate Akt in HF-Con-AS animals, whereas insulin-induced Akt phosphorylation was sustained in SHIP2-AS-treated rats. IRS-1/2 activation did not differ between the experimental groups. SHIP2 mRNA and protein content were markedly reduced only in muscle. In standard diet-fed controls, SHIP2-AS reduced SHIP2 protein levels in liver and muscle, but it had no significant effect on insulin sensitivity. We conclude that treatment with SHIP2-AS can rapidly improve muscle insulin sensitivity in dietary insulin resistance. The long-term feasibility of such a strategy should be examined further.
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PMID:Antisense oligonucleotides against the lipid phosphatase SHIP2 improve muscle insulin sensitivity in a dietary rat model of the metabolic syndrome. 1732 70

Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions. Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirt1, increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin-triggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.
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PMID:FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. 1807 53

Phosphatidate phosphatase-1 (PAP1) enzymes have a key role in glycerolipid synthesis through the conversion of phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine. PAP1 activity in mammals is determined by the lipin family of proteins, lipin-1, lipin-2, and lipin-3, which each have distinct tissue expression patterns and appear to have unique physiological functions. In addition to its role in glycerolipid synthesis, lipin-1 also operates as a transcriptional coactivator, working in collaboration with known nuclear receptors and coactivators to modulate lipid metabolism gene expression. The requirement for different lipin activities in vivo is highlighted by the occurrence of lipodystrophy, insulin resistance, and neuropathy in a lipin-1-deficient mutant mouse strain. In humans, variations in lipin-1 expression levels and gene polymorphisms are associated with insulin sensitivity, metabolic rate, hypertension, and risk for the metabolic syndrome. Furthermore, critical mutations in lipin-2 result in the development of an inflammatory disorder in human patients. A key goal of future studies will be to further elucidate the specific roles and modes of regulation of each of the three lipin proteins in key metabolic processes, including triglyceride and phospholipid synthesis, fatty acid metabolism, and insulin sensitivity.
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PMID:Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. 1879 Oct 37

Oxidative myofibers, also known as slow-twitch myofibers, help maintain the metabolic health of mammals, and it has been proposed that decreased numbers correlate with increased risk of obesity. The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) plays a central role in maintaining levels of oxidative myofibers in skeletal muscle. Indeed, loss of PGC-1alpha expression has been linked to a reduction in the proportion of oxidative myofibers in the skeletal muscle of obese mice. MAPK phosphatase-1 (MKP-1) is encoded by mkp-1, a stress-responsive immediate-early gene that dephosphorylates MAPKs in the nucleus. Previously we showed that mice deficient in MKP-1 have enhanced energy expenditure and are resistant to diet-induced obesity. Here we show in mice that excess dietary fat induced MKP-1 overexpression in skeletal muscle, and that this resulted in reduced p38 MAPK-mediated phosphorylation of PGC-1alpha on sites that promoted its stability. Consistent with this, MKP-1-deficient mice expressed higher levels of PGC-1alpha in skeletal muscle than did wild-type mice and were refractory to the loss of oxidative myofibers when fed a high-fat diet. Collectively, these data demonstrate an essential role for MKP-1 as a regulator of the myofiber composition of skeletal muscle and suggest a potential role for MKP-1 in metabolic syndrome.
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PMID:MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice. 1992 Mar 56

Hypertension is a common complication of type 2 diabetes mellitus (T2DM), and is the main cause for T2DM-associated mortality. Although the stringent control of blood pressure is known to be beneficial in reducing the cardiovascular mortality of T2DM patients, drugs with both anti-hypertensive and anti-hyperglycemic effects are seldom reported. The traditional Chinese medicine danshen has long been used for lowering both blood pressure and blood glucose in T2DM patients, shedding lights on the development of such medication. However, the molecular mechanism and active component remain unclear. Here, we report that the lipophilic component, 15,16-dihydrotanshinone I (DHTH) from danshen potently antagonized both mineralocorticoid and glucocorticoid receptors, and efficiently inhibited the expression of their target genes like Na(+)/K(+) ATPase, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK). In addition, DHTH increased AMPKalpha phosphorylation and regulated its downstream pathways, including increasing acetyl-CoA carboxylase (ACC) phosphorylation, inhibiting transducer of regulated CREB activity 2 (TORC2) translocation and promoting glucose uptake. Such discovered multi-target effects of DHTH are expected to have provided additional understandings on the molecular basis of the therapeutic effects of danshen against the metabolic syndrome.
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PMID:Danshen extract 15,16-dihydrotanshinone I functions as a potential modulator against metabolic syndrome through multi-target pathways. 2038 Aug 78


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