Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is produced by adipose tissue and acts as a feedback signal to the hypothalamus controlling energy homeostasis, by reducing food consumption and increasing energy expenditure. Because serum leptin levels are highly correlated with body fat mass, they can be used as an index to predict obesity-related diseases. However, the identity of genetic factors that influence the obesity and the obesity-related metabolic disorders remains largely unknown. In this study, we performed a whole-genome scan search, using 382 F2 intercross progeny between the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model for obese type 2 diabetes in human, and F344 rat, in order to identify loci responsible for the regulation of leptin and other obesity-related plasma substances. We have identified two quantitative trait loci (QTLs) contributing to serum leptin levels. These two loci, designated Olep1 [Chromosome (Chr) 2] and Olep2 (Chr 6), were homologous to those of human genome regions containing several potential candidate genes for obesity. These are fatty acid-binding protein 2 (FABP2), FABP4, and FABP5 for Olep1, and proopiomelanocortin (POMC) and glucose regulatory protein (GCKR) for Olep2.
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PMID:Serum leptin concentration is linked to chromosomes 2 and 6 in the OLETF rat, an animal model of type 2 diabetes with mild obesity. 1472 32

Obesity and type 2 diabetes are closely related, multifactorial metabolic conditions characterized by alterations in energy metabolism and glucose homeostasis, respectively. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that regulates genes involved in lipid and glucose homeostasis, including the adipocyte-specific fatty acid-binding protein (FABP4). In turn, FABP4 binds fatty acids and transports them to the nucleus where the FABP4/fatty acid complex activates PPARgamma in a positive feedback loop. In this study, we tested the hypothesis that the polymorphisms, FABP4-376 and PPARgamma Pro12Ala, interactively influence insulin sensitivity and body composition in nondiabetic, Hispanic and non-Hispanic white males (n = 314) participating in the San Luis Valley Diabetes Study (SLVDS). Although the individual sites were not statistically significantly associated with any of the outcomes, we found statistically significant interaction terms in 2-way analysis of covariance (ANCOVA) models for homeostasis model assessment of insulin resistance (HOMA-IR) (P =.014) and lean mass (P =.019). While the PPARgamma Pro12Ala site was the only statistically significant predictor of fat mass in the 2-way model (P =.012), the FABP4 and PPARgamma main effect terms individually became stronger when considered in one model compared with the analysis of each polymorphism separately. These findings provide evidence that FABP4 and PPARgamma work together to influence a biologic pathway affecting insulin sensitivity and body composition, illustrating the importance of investigating the joint effect of genes in determining susceptibility for complex disease.
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PMID:Genetic variation in fatty acid-binding protein-4 and peroxisome proliferator-activated receptor gamma interactively influence insulin sensitivity and body composition in males. 1501 41

Fatty acid binding proteins (FABPs) are proteins that reversibly bind fatty acids and other lipids. So far, nine tissue-specific cytoplasmic FABPs have been identified. Adipose tissue FABP (FABP4) has been suggested to be a bridge between inflammation and other pathways related to the metabolic syndrome. In this regard, genetic variability at the FABP4 locus has been shown to be associated with plasma lipid levels, type 2 diabetes, and coronary heart disease risk.
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PMID:Identification of a functional polymorphism at the adipose fatty acid binding protein gene (FABP4) and demonstration of its association with cardiovascular disease: a path to follow. 1742 64

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.
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PMID:Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. 1755 40

Elevated circulating fatty acids are associated with impaired insulin action and inflammation. During intracellular transit, fatty acids use fatty acid-binding proteins (FABPs) as shuttles. A recent study (Furuhashi et al., 2007) explores inhibiting FABP4/aP2 as a strategy for treating atherosclerosis and type 2 diabetes.
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PMID:Blocking fatty acids' mystery tour: a therapy for metabolic syndrome? 1768 Nov 41

Diabetes mellitus is one of the most common endocrine disorders. It affects almost 6% of the world's population, and its prevalence continues to increase. The causes of diabetes mellitus are multifactorial, and in the general population both genetic and environmental factors contribute evenly to its development. Several genes have been consistently associated with type 2 diabetes mellitus; however, it is not clear how many of those translate into increased cardiovascular disease risk. Recent evidence suggests that genetic variation at the CALPN10, FABP4, GK, GST, PPARA, and PPARG loci may confer higher cardiovascular disease risk in patients with type 2 diabetes mellitus. However, the evidence is scattered and inconclusive and its translation into practical clinical testing will require studies properly designed to examine not only simple genetic associations but also gene-gene and gene-environment interactions.
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PMID:Genetic links between diabetes mellitus and coronary atherosclerosis. 1824 14

Green tea intake has been shown to confer various health benefits to patients suffering from metabolic disorders. Here, we studied the effect of several major green tea polyphenols on adipocyte differentiation in human bone marrow mesenchymal stem cells (hBM-MSCs) and compared it to the effect of representative antidiabetic drugs. (-)-Catechin was the most potent of the eight green tea polyphenols evaluated in promoting adipocyte differentiation in hBM-MSCs, and this effect was dose-dependent. (-)-Catechin increased the mRNA levels of various adipogenic markers, such as adiponectin, peroxisome proliferator-activated receptor gamma (PPARgamma), FABP4, and LPL, as measured during adipocyte differentiation in hBM-MSCs. In addition, (-)-catechin upregulated the secretion of adiponectin in hBM-MSC culture. Using a reporter gene assay and a competitive ligand binding study, (-)-catechin also significantly activated PPARgamma in a dose-dependent fashion; however, (+)-catechin, the enantiomer of (-)-catechin, was not effective as a PPARgamma agonist, which seems to imply that the effect of (-)-catechin on PPARgamma is stereospecific. In conclusion, our data suggest that (-)-catechin promotes adipocyte differentiation and increased sensitivity to insulin in part by direct activation of PPARgamma, which could be at the basis of the observed pharmacological benefits of green tea intake in reducing the risk of type 2 diabetes.
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PMID:(-)-Catechin promotes adipocyte differentiation in human bone marrow mesenchymal stem cells through PPAR gamma transactivation. 1895 82

Adipocypte fatty acid-binding protein-4 (FABP4/adipocyte P2) may play a central role in energy metabolism and inflammation. In animal models, defects of the aP2 gene (aP2(-/-)) partially protected against the development of obesity-related insulin resistance, dyslipidemia, and atherosclerosis. However, it is unclear whether common genetic variation in FABP4 gene contributes to risk of type 2 diabetes (T2D) or diabetes-related metabolic traits in humans. We comprehensively assess the genetic associations of variants in the FABP4 gene with T2D risk and diabetes-associated biomarkers in a prospective study of 1,529 cases and 2,147 controls among postmenopausal women aged 50-79 years who enrolled in the Women's Health Initiative Observational Study (WHI-OS). We selected and genotyped a total of 11 haplotype-tagging single-nucleotide polymorphisms (tSNPs) spanning 41.3 kb across FABP4 in all samples. None of the SNPs and their derived haplotypes showed significant association with T2D risk. There were no significant associations between SNPs and plasma levels of inflammatory and endothelial biomarkers, including C-reactive protein, tumor necrosis factor (TNF), interleukin-6 (IL-6), E-selectin, and intercellular adhesion molecule (ICAM-1). Among African-American women, several SNPs were significantly associated with lower levels of vascular cell adhesion molecule-1 (VCAM-1), especially among those with incident T2D. On average, plasma levels of VCAM-1 were significantly lower among carriers of each minor allele at rs1486004(C/T; -1.08 ng/ml, P = 0.01), rs7017115(A/G; -1.07 ng/ml, P = 0.02), and rs2290201(C/T; -1.12 ng/ml, P = 0.002) as compared with the homozygotes of the common allele, respectively. After adjusting for multiple testing, carriers of the rs2290201 minor allele remained significantly associated with decreasing levels of plasma VCAM-1 in these women (P = 0.02). In conclusion, our finding from a multiethnic cohort of postmenopausal women did not support the notion that common genetic variants in the FABP4 gene may trigger increased risk of T2D. The observed significant association between reduced VCAM-1 levels and FABP4 genotypes in African-American women warrant further confirmation.
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PMID:Common genetic variants in fatty acid-binding protein-4 (FABP4) and clinical diabetes risk in the Women's Health Initiative Observational Study. 2011 Oct 20

Fatty acid-binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.
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PMID:Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus. 2092 Jun 50

Adipocyte fatty acid binding protein-4 (A-FABP4) and retinol binding protein-4 (RBP4) have recently been linked to type 2 diabetes mellitus (DM). Serum A-FABP4 and RBP4 levels and their relationships with early diabetic nephropathy were examined in 87 type 2 diabetic patients. The patients with diabetic nephropathy showed high A-FABP4 levels compared to the patients without diabetic nephropathy (p=0.0001). Log A-FABP4 correlated positively with age (p=0.02), log duration of diabetes (p=0.04), log body mass index (BMI) (p=0.0001), log creatinine (p=0.007), log C-reactive protein (CRP) (p=0.01), log albumin excretion rate (AER) (p=0.001), and negatively with MDRD-GFR (p=0.0001). Serum RBP4 levels were similar between the patients with and without diabetic nephropathy. RBP4 correlated positively with triglycerides (p=0.001), log creatinine (p=0.009), and negatively with MDRD-GFR (p=0.04). In regression analysis, log A-FABP4 was associated with age, sex, log BMI, and log AER (r(2)=0.43) and RBP4 was associated with triglycerides and log creatinine (r(2)=0.22). In conclusion, we found high serum A-FABP4 but unchanged RBP4 concentrations and their associations with renal function and early diabetic nephropathy in type 2 DM.
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PMID:The relationship between adipocyte fatty acid binding protein-4, retinol binding protein-4 levels and early diabetic nephropathy in patients with type 2 diabetes. 2117 57


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