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)

Adiponectin is secreted from adipocytes, and low circulating levels have been epidemiologically associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. To investigate whether adiponectin could exert autocrine effects in adipocytes, we expressed the adiponectin gene in 3T3-L1 fibroblasts. We observed that 3T3-L1 fibroblasts expressing adiponectin have a fast growth phase and reach confluence more rapidly compared with control cells or LacZ-transduced cells. Furthermore, cells with overexpressed adiponectin were observed to differentiate into adipocytes more rapidly, and during adipogenesis, they exhibited more prolonged and robust gene expression for related transcriptional factors, CCAAT/enhancer binding protein alpha (C/EBP2), peroxisome proliferator-activated receptor gamma (PPARgamma), and adipocyte determination and differentiation factor 1/sterol-regulatory element binding protein 1c (ADD1/SREBP1c) and earlier suppression of PPARgamma coactivator-1alpha (PGC-1alpha). In fully differentiated adipocytes, adiponectin-overexpressing cells accumulated more and larger lipid droplets compared with control cells. Also, adiponectin increased insulin's ability to maximally stimulate glucose uptake by 78% through increased glucose transporter 4 (GLUT4) gene expression and increased GLUT4 recruitment to the plasma membrane. These data suggest a new role for adiponectin as an autocrine factor in adipose tissues: promoting cell proliferation and differentiation from preadipocytes into adipocytes, augmenting programmed gene expression responsible for adipogenesis, and increasing lipid content and insulin responsiveness of the glucose transport system in adipocytes.
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PMID:Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. 1583 18

Adiponectin, an adipose tissue-specific plasma protein, is involved in insulin sensitizing and has anti-atherosclerotic properties. Plasma levels of adiponectin are decreased in obese individuals and patients with type 2 diabetes with insulin resistance. Tumor necrosis factor-alpha (TNF-alpha) decreases the expression of adiponectin in adipocytes. The aims of the present study were: (1) to identify the promoter region responsible for basal transcription of the human adiponectin gene, and (2) to investigate the mechanism by which adiponectin was regulated by TNF-alpha. The human adiponectin promoter (2.1kb) was isolated and used for luciferase reporter analysis by transient transfection into 3T3-L1 adipocytes. Deletion analysis demonstrated that the promoter region from -676 to +41 was sufficient for basal transcriptional activity. Mutation analysis of putative response elements for sterol regulatory element binding protein (SREBP) (-431 to -423) and CCAAT/enhancer binding protein (C/EBP) (-230 to -224) showed that both elements were required for basal promoter activity. Adiponectin transcription was increased 3-fold in cells that over-expressed constitutively active C/EBP-beta. Electrophoretic mobility shift assay, using nuclear extract from 3T3-L1 cells and the -258 to -199 region as a probe, demonstrated specific DNA-protein binding, which was abolished by TNF-alpha treatment. The present data indicate that the putative response elements for SREBP and C/EBP are required for human adiponectin promoter activity, and that suppression by TNF-alpha may, at least in part, be associated with inactivation of C/EBP-beta.
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PMID:Identification of the promoter region required for human adiponectin gene transcription: Association with CCAAT/enhancer binding protein-beta and tumor necrosis factor-alpha. 1585 Jul 85

Obesity is not necessary to observe insulin resistance in humans since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART (highly-active antiretroviral therapy) - associated lipodystrophy. Both the obese and the lipodystrophic patients have, however, an increase in the amount of fat hidden in the liver. Liver fat content can be non-invasively accurately quantified by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. The causes of interindividual variation in liver fat content independent of obesity are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss. In addition, treatment of both lipodystrophic and type 2 diabetic patients with PPARgamma agonists but not metformin decreases liver fat and increases adiponectin levels. Markers of liver fat such as serum alanine aminotransferase activity have been shown to predict type 2 diabetes in several studies independent of obesity. The fatty liver thus may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease.
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PMID:The fatty liver and insulin resistance. 1589 48

Adiponectin is a plasma protein produced by the adipose tissue. Hypoadiponectinemia has been associated with insulin resistance and several components of the metabolic syndrome (MS): type 2 diabetes, obesity, and dyslipidemia. We investigated whether single nucleotide polymorphisms (SNPs) at positions 45 and 276 in the adiponectin gene were associated with features of the MS in 747 unrelated Spanish subjects. The G allele of SNP45 and the G/G genotype of SNP276 were associated with impaired glucose tolerance (p = 0.020 and 0.042, respectively). The G/G genotype for SNP276 was associated with lower serum adiponectin levels as compared with the G/T and T/T genotypes (G/G, 10.10 +/- 0.24 microg/mL; G/T, 10.98 +/- 0.32 microg/mL; T/T, 12.00 +/- 0.92 microg/mL; p = 0.015) even after adjustment for sex, age, BMI, waist-to-hip ratio, homeostasis model assessment index, and the degree of glucose tolerance (p = 0.040). We found a significant negative association of circulating adiponectin levels with waist-to-hip ratio (r = -0.42, p < 0.001), sagittal abdominal diameter (r = -0.24, p < 0.001), triglycerides (r = -0.32, p < 0.001), homeostasis model assessment index (r = -0.14, p = 0.001), and uric acid (r = -0.36, p < 0.001) and positive association with high-density lipoprotein-cholesterol (r = 0.41, p < 0.001). Our findings indicate that serum adiponectin levels are associated with several components of the MS. The SNP276 of the adiponectin gene may affect impaired glucose tolerance and hypoadiponectinemia.
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PMID:An SNP in the adiponectin gene is associated with decreased serum adiponectin levels and risk for impaired glucose tolerance. 1591 31

Adiponectin is an adipose tissue-specific protein and plays an important role in insulin sensitivity. On the other hand, intramyocellular lipid content and hepatic lipid content (HLC) are related to insulin resistance in humans. In the present study, the possible relations between the serum concentration of adiponectin and intracellular triglyceride content in skeletal muscle and in the liver were investigated in individuals with type 2 diabetes mellitus. Fifty Japanese sedentary subjects (34 men, 16 women) with type 2 diabetes who had neither been treated with insulin nor with thiazolidinediones were enrolled in the study. Insulin sensitivity in vivo was evaluated by measurement of the glucose infusion rate during a hyperinsulinemic-euglycemic clamp and of the homeostasis model of assessment-insulin resistance index. The intracellular triglyceride content in skeletal muscle and the liver was determined by nuclear magnetic resonance. The serum adiponectin concentration was inversely correlated with both HLC ( r = -0.39, P < .01) and the homeostasis model of assessment-insulin resistance index ( r = -0.32, P < .05), but it was not significantly related to either intramyocellular lipid content or glucose infusion rate during the hyperinsulinemic-euglycemic clamp in individuals with type 2 diabetes. These results suggest that adiponectin might play an important role in the regulation of HLC and basal insulin sensitivity in individuals with type 2 diabetes.
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PMID:Inverse correlation between serum adiponectin concentration and hepatic lipid content in Japanese with type 2 diabetes. 1593 13

The adipose-specific protein adiponectin has been recently discovered to improve insulin sensitivity. Angiotensin type-1 receptor (AT1R) blockers (ARBs) reduce the incidence of type 2 diabetes mellitus by mostly unknown molecular mechanisms. To identify new antidiabetic mechanisms of ARBs, we studied the regulation of adiponectin by angiotensin II (Ang II) and different ARBs in murine 3T3-L1 adipocytes and obese Zucker rats. Adiponectin protein expression was markedly stimulated by Ang II (5 nmol/L), which was inhibited by blockade of the AT2R, and further enhanced by the ARB irbesartan. Irbesartan-mediated adiponectin upregulation started beyond the concentrations needed for AT1R blockade and was also present in the absence of Ang II, implicating an AT1R-independent mechanism of action. Recently, certain ARBs (irbesartan, telmisartan) were identified as ligands of the peroxisome proliferator-activated receptor (PPAR)gamma. Telmisartan also stimulated adiponectin protein expression, whereas the non-PPARgamma-activating ARB eprosartan had no effect. Blockade of PPARgamma activation by the PPARgamma antagonist GW9662 markedly inhibited irbesartan-induced adiponectin expression. Cognate mRNA levels of adiponectin were not affected by ARBs. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that irbesartan prevented the cellular depletion of adiponectin protein. Finally, administration of irbesartan to obese Zucker rats improved insulin sensitivity and attenuated adiponectin serum depletion. The present study demonstrates that AT2R activation and certain ARBs induce adiponectin in adipocytes, which was associated with an improvement of parameters of insulin sensitivity in vivo. ARB-induced adiponectin stimulation is likely to be mediated via PPARgamma activation involving a post-transcriptional mechanism.
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PMID:PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. 1593 9

Adiponectin is secreted specifically by adipose tissue. It was reported that the serum adiponectin level was markedly increased in patients with end-stage renal disease and was positively associated with abnormal renal function in type 2 diabetes. Recently, we found that urinary adiponectin level was significantly increased in type 2 diabetic patients with overt diabetic nephropathy, but not in those without nephropathy. The aim of the present study was to evaluate whether the urinary adiponectin level is increased not only in diabetic patients with macroalbuminuria but also in IgA-nephropathy patients with macroalbuminuria. We measured urinary adiponectin levels in 24 healthy control subjects, 12 IgA-nephropathy patients, and 19 type 2 diabetic nephropathy patients, and they were, in medians, 2.24 microg/g creatinine (ranges of 0.85 to approximately 3.70), 59.2 microg/g creatinine (4.95 to approximately 186), and 33.1 microg/g creatinine (4.69 to approximately 114), respectively. In the two patient groups, urinary adiponectin levels were significantly higher than in control subjects (P<0.01). Moreover, positive correlations between urinary adiponectin levels and albumin-to-creatinine ratios were observed in IgA-nephropathy (R2=0.53, P<0.01) and diabetic nephropathy patients (R2=0.61, P<0.01), but not in control subjects. Serum adiponectin levels were unchanged in these three groups. These findings suggested that the increase of urinary adiponectin levels partly results from enhanced filtration of circulating adiponectin through the changes of glomerular permselectivity and intraglomerular hydruric pressure. However, clinical implication of urinary adiponectin excretion in healthy control remains to be elucidated.
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PMID:Enhanced urinary adiponectin excretion in IgA-nephropathy patients with proteinuria. 1595 50

Adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) are newly identified receptors for adiponectin, an adipocytokine with anti-inflammatory and insulin-sensitizing properties. We screened for polymorphisms by performing sequence analysis on all eight exons, splice junctions, and approximately 2 kb of the 5' flanking regions of each receptor. We detected 5 single nucleotide polymorphisms (SNPs) in ADIPOR1 and 16 SNPs in ADIPOR2. We genotyped these SNPs in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) to test for association with type 2 diabetes. Three intronic SNPs in ADIPOR1 were significantly associated with type 2 diabetes (P = 0.014-0.007; odds ratio [OR] 1.61-1.65) and in high linkage disequilibrium (r2 = 0.97-1.0). In ADIPOR2, we found that five SNPs delineated one large haplotype block (r2= 0.9-1.0) spanning >98 kb of the gene and promoter region, which was strongly associated with the combined type 2 diabetes/IGT trait (P < or = 0.001; OR 1.64-1.71). To our knowledge, these data provide the first evidence for association between variation in the adiponectin receptors and type 2 diabetes.
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PMID:Genetic variation in adiponectin receptor 1 and adiponectin receptor 2 is associated with type 2 diabetes in the Old Order Amish. 1598 28

Circulating level of adiponectin, an adipocyte-derived protein, is reduced in states of insulin resistance such as obesity and type 2 diabetes. We have previously shown that hypoadiponectinemia is related to insulin resistance in essential hypertension. Recent studies have shown that normotensive subjects with a positive family history of essential hypertension (FH+) have decreased insulin sensitivity compared to subjects with a negative family history of essential hypertension (FH-). We here examined the association between adiponectin concentration and insulin sensitivity in FH+ and FH-. Thirty young, non-obese and normotensive men without a family history of diabetes mellitus were enrolled. A total of 15 subjects were FH+, and the remaining 15 subjects were FH-. Insulin sensitivity index (ISI) was evaluated by the euglycemic hyperinsulinemic glucose clamp technique. Concentrations of adiponectin and other metabolic variables were measured. The FH+ group had significantly lower levels of ISI and adiponectin than did the FH- group. In all of the subjects, ISI was positively correlated with adiponectin concentration and high-density lipoprotein (HDL) cholesterol level and was negatively correlated with insulin level. Adiponectin concentration was the only independent determinant of ISI in a multiple regression analysis. Our results showed that adiponectin level was significantly decreased and that this was accompanied by reduced insulin sensitivity in young, nonobese and normotensive men with a family history of essential hypertension. Phenotype of reduced adiponectin level as an earlier penetrance may be especially useful in genetic analyses of insulin resistance and essential hypertension.
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PMID:Low adiponectin level in young normotensive men with a family history of essential hypertension. 1602 41

Adipose tissue, in addition to the storage of lipids function for lipids, plays active roles in normal metabolic homeostasis and in the development of several diseases, such as type 2 diabetes, dyslipaemia and atherosclerosis. These roles are mediated by adipocytokines, factors secreted by adipose tissue. These include tumor necrosis factors (TNF)-alpha, leptin, resistin, adiponectin or visfatin. Adipocytokines act in an autocrine, paracrine and endocrine manner. Adiponectin is a peculiar adipocytokine because in contrast to the markedly increased levels of leptin, resistin or TNF-alpha in obesity, its level is negatively correlated with body mass index, and is decreased in presence of insulin resistance and in type 2 diabetes. Adiponectin may play a crucial role in the development of diabetes mellitus and high adiponectin levels should protect against impairment of glucose metabolism. Moreover, adipocytokines are involved in the pathogenesis of vascular diseases and may represent a link between obesity, diabetes, inflammation and atherosclerosis. Weight loss, exercise and some antidiabetic drugs also influence plasma adipocytokines levels. For instance, thiazolidinediones treatment in patients with type 2 diabetes resulted in an increased in plasma adiponectin levels and a decrease in circulating TNF-alpha concentrations.
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PMID:[Adipocytokines: link between obesity, type 2 diabetes and atherosclerosis]. 1603 96


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