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)

Adiponectin is one of the adipokines secreted by adipocytes and regulates energy homeostasis associated with insulin sensitivity, suggesting a possibility of nutritional regulation of adiponectin gene expression. In this study, we showed that the transcription of adiponectin gene was induced 4-6 h after refeeding of mice. Also, differentiated 3T3-L1 adipocytes that were treated with high glucose expressed significantly increased adiponectin mRNA. Promoter analysis using nuclear extracts from white adipose tissue revealed that CCAAT/enhancer binding protein (C/EBP) and nuclear factor-Y (NF-Y) bound on the -117/-73 region of the adiponectin promoter. This region was critical for the activity of the adiponectin promoter as the deletion or mutation of this region markedly diminished the promoter activity to a basal level. Furthermore, the C/EBP binding increased in both refed animal and high glucose-treated 3T3-L1 adipocytes in an electrophoretic mobility shift assay, suggesting that C/EBP is responsible for the dietary response of the adiponectin gene expression. Chromatin immunoprecipitation studies demonstrated the binding of C/EBP and NF-Y in both mouse and differentiated 3T3-L1 adipocytes and also that C/EBP binding increased in response to high glucose. These findings demonstrated that C/EBP and NF-Y are critical for the regulation of the adiponectin expression in response to nutrients and in the course of adipocyte differentiation.
Diabetes 2004 Nov
PMID:CCAAT/enhancer binding protein and nuclear factor-Y regulate adiponectin gene expression in adipose tissue. 1550 55

To learn more about the factors that regulate adipokines in diabetes, we examined fasting plasma concentrations of adiponectin and C-reactive protein (CRP) in well-characterized groups of age-matched individuals classified as: (1) type 2 diabetes; (2) impaired fasting glucose or mild diabetes (IFG/mild DM); (3) obese, matched for body mass index (BMI); and (4) non-obese. Diabetic subjects were also studied on no phamacologic treatment, after 3 months randomization to metformin or glyburide, and after 3 months crossover to the opposite drug. CRP decreased and adiponectin increased progressively between subjects in groups 1 through 4. CRP was significantly associated with percent (r = 0.45) and total (r = 0.50) fat, insulin sensitivity as S(I) (r = -0.39) or homeostasis model assessment of insulin resistance [HOMA (IR)] (r = -0.36), and hemoglobin A(1c) (HbA(1c)) (r = 0.41). The relationship of CRP to percent fat appeared to be logarithmic and log CRP varied with percent fat independent of gender. Adiponectin concentration was significantly associated with insulin sensitivity as S(I) (r = 0.55) or HOMA (IR) (r = -0.46). Adiponectin concentrations were higher among women overall (all groups included) but not in women classified as type 2 diabetes. Although mean adiponectin was higher in subjects classified as non-obese compared to obese, adiponectin, in sharp contrast to leptin (previously reported data) and to CRP, varied markedly when expressed as a function of adiposity. Multiple regression models confirmed the strong relationship of adiponectin to insulin sensitivity, as well as the relationships of CRP to adiposity and insulin sensitivity. Glyburide treatment of diabetes decreased CRP and did so even though body weight increased. We conclude that both CRP and adiponectin correlate strongly to S(I). CRP, in contrast to adiponectin, is far more dependent on adiposity. The relationship between CRP (like leptin) and gender depends on how CRP is expressed relative to adiposity. Our data raise the possibility that gender differences in adiponectin may be lost in diabetes. Finally, pharmacologic treatment of diabetes may modulate CRP independent of adiposity.
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PMID:Adiponectin and C-reactive protein in obesity, type 2 diabetes, and monodrug therapy. 1553 1

Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders. The adipocytokine adiponectin is decreased in patients with obesity-linked diseases. Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.
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PMID:Adiponectin-mediated modulation of hypertrophic signals in the heart. 1555 58

Adiponectin, an adipocyte-secreted protein encoded by the ACDC gene (also known as APM1), has been shown to play an important role in the regulation of fatty acid and glucose metabolism in liver and muscle, where it modulates insulin sensitivity. Adiponectin enhances fatty acid oxidation in liver and muscle, thus reducing triglyceride content in these tissues. Moreover, it stimulates glucose utilization in muscle and inhibits glucose production by the liver, consequently decreasing blood glucose levels. Plasma adiponectin levels are positively correlated with insulin sensitivity in humans. Circulating adiponectin forms a wide range of multimers. Mutations in the ACDC gene result in an impaired multimerization and/or impaired secretion of adiponectin from adipocytes, both linked to the development of insulin resistance and type II diabetes. This review focuses on the molecular mechanisms underlying hypoadiponectinemia associated with the diabetic phenotype. We further discuss the more recent findings that implicate adiponectin multimer formation as an important feature of the biological function of this adipocyte-derived hormone.
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PMID:[Adiponectin gene polymorphism and protein dysfunction in the development of insulin resistance]. 1559 38

Adiponectin is an abundant adipose tissue-derived protein with important metabolic effects. Plasma adiponectin levels are decreased in obese individuals, and low adiponectin levels predict insulin resistance and type 2 diabetes. Two variants in the adiponectin gene ACDC have been previously associated with plasma adiponectin levels, obesity, insulin resistance, and type 2 diabetes. To determine the role of genetic variation in ACDC in susceptibility to obesity and type 2 diabetes in Pima Indians, we screened the promoter, exons, and exon-intron boundaries of the gene to identify allelic variants. We identified 17 informative polymorphisms that comprised four common (minor allele frequency >15%) linkage disequilibrium clusters consisting of 1-4 variants each. We genotyped one representative polymorphism from each cluster in 1,338 individuals and assessed genotypic association with type 2 diabetes, BMI, serum lipid levels, serum adiponectin levels, and measures of insulin sensitivity and secretion. None of the ACDC variants were associated with type 2 diabetes, BMI, or measures of insulin sensitivity or secretion. One variant, single nucleotide polymorphism (SNP)-12823, was associated with serum adiponectin levels (P = 0.002), but this association explained only 2% of the variance of serum adiponectin levels. Our findings suggest that these common ACDC polymorphisms do not play a major role in susceptibility to obesity or type 2 diabetes in this population.
Diabetes 2005 Jan
PMID:Common Polymorphisms in the Adiponectin Gene ACDC Are Not Associated With Diabetes in Pima Indians. 1561 40

Adiponectin, predominantly synthesized in the adipose tissue, seems to have substantial anti-inflammatory properties and to be a major modulator of insulin resistance and dyslipidemia, mechanisms that are associated with an increased atherosclerotic risk in diabetic patients. However, it is unknown whether higher levels of adiponectin are associated with a reduced risk for coronary heart disease (CHD) among diabetic individuals. We investigated the association between plasma adiponectin levels and incidence of CHD among 745 men with confirmed type 2 diabetes in the Health Professionals Follow-up Study. Participants were aged 46-81 years and were free of diagnosed cardiovascular disease at the time of blood draw in 1993/1994. During an average of 5 years of follow-up (3,980 person-years), we identified 89 incident cases of CHD (19 myocardial infarction and 70 coronary artery bypass surgery), confirmed by medical records. Levels of adiponectin were inversely associated with BMI and directly associated with age, alcohol intake, and duration of diabetes (P < 0.05). After adjustment for age, BMI, smoking, alcohol consumption, duration of diabetes, and other lifestyle factors, adiponectin was associated with a decreased risk for CHD events. The multivariate relative risk for CHD for a doubling of adiponectin was 0.71 (95% CI 0.53-0.95). Further adjustment for HDL cholesterol attenuated this association (0.78 [0.57-1.06]). The inverse association between adiponectin and CHD was consistent across strata of aspirin use, family history of myocardial infarction, alcohol consumption, insulin use, duration of diabetes, and levels of HbA(1c), triglycerides, C-reactive protein, and HDL cholesterol. Our study suggests that increased adiponectin levels are associated with a moderately decreased CHD risk in diabetic men. This association seems to be mediated in part by effects of adiponectin on HDL cholesterol levels.
Diabetes 2005 Feb
PMID:Adiponectin and future coronary heart disease events among men with type 2 diabetes. 1567 12

Adiponectin is a protein secreted exclusively by white adipose tissues and is abundantly present in human plasma. Adiponectin was found decreased in obese and diabetes mellitus type 2 patients and increased with weight reduction. A negative correlation between circulating adiponectin levels and body mass index and insulin resistance has been demonstrated. Plasma adiponectin concentrations were found lower in diabetes mellitus type 2 patients with coronary artery disease. Moreover, studies in aortic endothelial cells revealed that the protein exerts a dose-dependent decrease of the surface expression of vascular adhesion molecules and cytokine production from macrophages, suggesting the implication of adiponectin in atherosclerosis and inflammation. Weight loss and treatment with thiazolidinediones stimulate endogenous adiponectin production. Peripheral administration of adiponectin leads to reduction of visceral adiposity and increase of free fatty acid oxidation and insulin resistance. Furthermore, it enhances the expression of uncoupling proteins and sympathetic nerve activity in adipose tissues. Experimental studies in mice have shown that intraperitoneal administration of adiponectin lowers plasma glucose. These data show adiponectin to be an important factor in the issue of obesity and its associated disorders, and indicate a potential future utilization of adiponectin as a drug in the treatment of metabolic syndrome.
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PMID:Adiponectin: novelties in metabolism and hormonal regulation. 1568 45

Adiponectin, which is produced by adipose tissue, is thought to play an important role in inflammation. On the other hand, adiposity, or the hypertrophy of adipose tissue, has been reported to increase oxidative stress. Accordingly, the possibility exists that adiponectin, as well as leptin, influences oxidative stress, resulting in a proinflammatory state. However, the relationship between adiponectin and oxidative stress is unclear. We examined 259 Japanese Americans living in Hawaii who were diagnosed as having normal glucose tolerance (NGT), impaired glucose tolerance, or diabetes by a 75-g oral glucose tolerance test. First, we measured their serum adiponectin, leptin, and high-sensitivity C-reactive protein levels as markers of inflammation, and urinary 8-iso-protaglandin F(2 alpha) (isoprostane) as a relevant marker of oxidative stress. We investigated the relationship between adiponectin or leptin and isoprostane among these subjects. In the diabetic subjects, the adiponectin and leptin levels were significantly lower and higher, respectively, than among the NGT subjects. Urinary isoprostane levels tended to decrease significantly after a rise in adiponectin levels (P = .014) among the NGT subjects. Next, we investigated the association between the 2 adipocytokines and isoprostane by regression models. Adiponectin was negatively but significantly associated with urinary isoprostane levels adjusted for age, gender, and smoking status, whereas leptin was positively and significantly correlated with urinary isoprostane levels (P = .014 and .004, respectively). With respect to adiponectin, this association was attenuated but still significant when further adjustments were made for waist-to-hip ratio, body mass index, percent body fat, C-reactive protein levels, glucose tolerance status, or homeostasis model assessment. In conclusion, this study suggests that adiponectin and leptin might be associated with oxidative stress levels. These results also suggest the possibility that adiponectin might modulate oxidative stress, leading to antidiabetic and anti-arteriosclerotic effects.
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PMID:A protective effect of adiponectin against oxidative stress in Japanese Americans: the association between adiponectin or leptin and urinary isoprostane. 1569 Mar 13

Obesity is defined as increased mass of adipose tissue, conferring a higher risk of cardiovascular and metabolic disorders such as diabetes, hyperlipidemia, and coronary heart disease. To investigate the role of transcriptional factors, which are involved in adipocytes differentiation and adiposity, we have generated peroxisome proliferator-activated receptor (PPAR) gamma or CREB-binding protein (CBP)-deficient mice by gene targeting. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. Heterozygous CBP-deficient mice showed increased insulin sensitivity and were completely protected from body weight gain induced by a high-fat diet. PPARgamma or CBP deficiency results in increased effects of hormones such as adiponectin and leptin. Adiponectin was decreased in obesity and lipoatrophy, and replenishment of adiponectin ameliorated insulin resistance. Moreover, adiponectin-deficient mice showed insulin resistance and atherogenic phenotype. Finally, cDNA encoding adiponectin receptors (AdipoR1/R2) have been identified by expression cloning. The expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyperinsulinemia models, and it is correlated with adiponectin sensitivity. These results facilitate the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and propose the molecular targets for anti-diabetic and anti-atherogenic drugs.
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PMID:Nuclear receptors as targets for drug development: molecular mechanisms for regulation of obesity and insulin resistance by peroxisome proliferator-activated receptor gamma, CREB-binding protein, and adiponectin. 1572 3

Adiponectin is an adipose tissue-specific protein with insulin-sensitizing and antiatherogenic properties. Therefore, the adiponectin gene is a promising candidate gene for type 2 diabetes. We investigated the single nucleotide polymorphisms (SNPs) +45T/G and +276G/T of the adiponectin gene as predictors for the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial, which aimed to investigate the effect of acarbose compared with placebo on the prevention of type 2 diabetes. Compared with the TT genotype, the G-allele of SNP +45 was associated with a 1.8-fold risk for type 2 diabetes (95% CI 1.12-3.00, P = 0.015) in the placebo group. Subjects treated with placebo and simultaneously having the G-allele of SNP +45 and the T-allele of SNP +276 (the risk genotype combination) had a 4.5-fold (1.78-11.3, P = 0.001) higher risk of developing type 2 diabetes compared with subjects carrying neither of these alleles. Women carrying the risk genotype combination had an especially high risk of conversion to diabetes (odds ratio 22.2, 95% CI 2.7-183.3, P = 0.004). In conclusion, the G-allele of SNP +45 is a predictor for the conversion to type 2 diabetes. Furthermore, the combined effect of SNP +45 and SNP +276 on the development of type 2 diabetes was stronger than that of each SNP alone.
Diabetes 2005 Mar
PMID:The common polymorphisms (single nucleotide polymorphism [SNP] +45 and SNP +276) of the adiponectin gene predict the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial. 1573 70


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