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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance in humans is not always accompanied by obesity, since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART- (highly-active antiretroviral therapy)-associated lipodystrophy. Both obese and lipodystrophic patients, however, have an increase in the amount of fat hidden in the liver. Liver fat content can be accurately quantified non-invasively by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin concentrations and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. An increase in liver fat content has been shown to predict type 2 diabetes, independently of other cardiovascular risk factors. This is easily explained by the fact that the liver, once fatty, overproduces most of the known cardiovascular risk factors such as very low density lipoprotein (VLDL), glucose, C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), fibrinogen and coagulation factors. The causes of inter-individual 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 and by a low as compared to a high fat diet. In addition, treatment of both lipodystrophic and type 2 diabetic patients with peroxisome proliferators activator receptor-gamma (PPARgamma) agonists, but not metformin, decreases liver fat and markedly increases adiponectin levels. The fatty liver 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:Fat in the liver and insulin resistance. 1617 70

Adiponectin is a 30kDa protein exclusively produced and secreted from adipocytes and as a cytokine has been found to link obesity, insulin resistance, and type 2 diabetes. Production of biologically active adiponectin in large scale is desirable for pharmaceutical applications. Mouse adiponectin cDNA was used for developing transgenic sweet potato plants via Agrobacterium-mediated transformation. The presence of the transgene was verified by PCR and DNA gel blot analysis. Further investigated were five independent transgenic lines, all of which expressed high levels of adiponectin mRNA. Immuno blot analysis with a mouse adiponectin antiserum revealed that, in addition to a 29 kDa-protein which co-migrates with the adiponectin protein produced in Escherichia coli cells, a 31 kDa-protein was produced, indicative of a post-translational modification of the protein. The transgenic plants did not show obvious differences in growth rate and morphology in response to adiponectin production.
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PMID:Production of mouse adiponectin, an anti-diabetic protein, in transgenic sweet potato plants. 1625 75

Adiponectin is a protein hormone produced exclusively by adipocytes. Its circulating levels are decreased in individuals with obesity, atherosclerosis and insulin resistance, suggesting that its deficiency may have a causal role in the etiopathogenesis of these diseases. Studies have shown that adiponectin administration in rodents has insulin-sensitizing, anti-atherogenic and anti-inflammatory effects and under certain settings also decreases body weight. Therefore, adiponectin replacement in humans may represent a promising approach to prevent and/or treat obesity, insulin resistance and type 2 diabetes; however, clinical studies with adiponectin administration need to be conducted to confirm this hypothesis. Current experimental and clinical data regarding adiponectin physiology and pathophysiology are detailed in this review.
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PMID:Adiponectin and its potential in the treatment of obesity, diabetes and insulin resistance. 1625 19

Adipocyte cell proliferation is an important process in body fat mass development in obesity. Adiponectin or Acrp30 is an adipocytokine exclusively expressed and secreted by adipose tissue that regulates lipid and glucose metabolism and plays a key role in body weight regulation and homeostasis. Adiponectin mRNA expression in adipose tissue and plasma level of adiponectin are decreased in obesity and type 2 diabetes. In obese rodents, the selective CB(1) receptor antagonist rimonabant reduces food intake and body weight and improves lipid and glucose parameters. We have reported previously that rimonabant stimulated adiponectin mRNA expression in adipose tissue of obese fa/fa rats, by a direct effect on adipocytes. We report here that rimonabant (10-400 nM) inhibits cell proliferation of cultured mouse 3T3 F442A preadipocytes in a concentration-dependent manner. In parallel to this inhibitory effect on preadipocyte cell proliferation, rimonabant (25-100 nM) stimulates mRNA expression and protein levels of two late markers of adipocyte differentiation (adiponectin and glyceraldehyde-3-phosphate dehydrogenase) with a maximal effect at 100 nM, without inducing the accumulation of lipid droplets. Furthermore, treatment of mouse 3T3 F442A preadipocytes with rimonabant (100 nM) inhibits basal and serum-induced p42/44 mitogen-activated protein (MAP) kinase activity. These results suggest that inhibition of MAP kinase activity by rimonabant may be one of mechanisms involved in the inhibition of 3T3 F442A preadipocyte cell proliferation and stimulation of adiponectin and GAPDH expression. The inhibition of preadipocyte cell proliferation and the induction of adipocyte late "maturation" may participate in rimonabant-induced antiobesity effects, particularly the reduction of body fat mass.
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PMID:The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. 1628 21

Adiponectin is a serum protein secreted by adipocytes and accounts for approximately 0.01% of total plasma protein. In healthy patient populations adiponectin can be found in concentrations of 7-12 mg/l. Unlike other adipocyte products, adiponectin correlates with decreased free fatty acid blood concentrations and reduced body mass index or body weight. Adiponectin protects from vascular diseases by inhibiting local proinflammatory signals, preventing preatherogenic plaque formation, and by impeding arterial wall thickening. Proinflammatory state and endothelial dysfunction are nominators of the metabolic syndrome, a complex set of risk factors including vascular and metabolic insulin resistance with hyperglycemia, hypertension, and dyslipidemia. Over the past years, thiazolidinediones, like rosiglitazone or pioglitazone, became known as a therapeutic option for patients suffering from the metabolic syndrome. It is considered that insulin sensitizers exert their benefit through indirect induction of adiponectin expression. Clinical studies have confirmed that treatment with thiazolidinediones may increase adiponectin concentrations in patients with type 2 diabetes independent from improvements in blood glucose control or parallel treatment with insulinotropic drugs. These findings suggest that adiponectin may have a diagnostic value and can be used especially for monitoring treatment success. This review summarizes recent biological and clinical data indicating that adiponectin may be the molecular link between obesity and insulin resistance and may serve as a biomarker for the metabolic syndrome.
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PMID:Biological background and role of adiponectin as marker for insulin resistance and cardiovascular risk. 1628 70

Adiponectin, an adipose-derived plasma protein, has been well established to be an important biomarker for metabolic syndrome and its complications after exhausted studies in humans. Animal and cell culture experiments also support most claims from human observations of its roles in the metabolic syndrome. Reproducible results of human genetic studies of diverse ethnic origin and by different investigators may provide the evidence for its causative roles in the pathogenesis of the metabolic syndrome and further insight into the genetic constitutions of the metabolic syndrome. Some of the common polymorphisms in the promoter region, exon and intron 2, and the rare nonsynonymous mutations in exon 3 of the human adiponectin gene were repeatedly shown in many studies from many different ethnic populations to associate with the phenotypes related to body weight, glucose metabolism, insulin sensitivity, and risk of type 2 diabetes mellitus and coronary artery disease. The association of adiponectin genetic variations with dyslipidemia and blood pressure was less explored. The common polymorphisms and rare mutations of the human adiponectin gene itself were demonstrated to associate with differential expression of adiponectin at the plasma protein level and mRNA level in adipose tissue. The PPARgamma2 Pro12Ala variants were also shown to influence insulin sensitivity in interaction with adiponectin genotype or to influence plasma adiponectin levels. However, the results were not consistent. Three genome-wide scans for the loci that regulate plasma adiponectin concentration suggest further exploration on chromosomes 5, 9, 14, 15, and 18 is required. These human genetic studies on adiponectin and the metabolic syndrome strongly suggest that adiponectin is one of the causative factors in its pathogenesis and provide significant insights into the genetic makeup of the metabolic syndrome. Extension from these studies may accelerate the discovery of new molecular targets for future therapeutic interventions.
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PMID:Human genetics of adiponectin in the metabolic syndrome. 1638 53

Adiponectin is a metabolic link between adipose tissue and insulin action, mediating part of obesity-associated insulin resistance and type 2 diabetes. Two adiponectin receptors have been identified, and we investigated whether sequence variations in adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) genes could contribute to the genetic risk for type 2 diabetes in a case-control study of 1,498 Caucasian subjects. We sequenced the putative functional regions of the two genes in 48 subjects and selected single nucleotide polymorphisms (SNPs) from the public database. Five SNPs in ADIPOR1 and 12 in ADIPOR2 were tested for association with type 2 diabetes. No SNP of ADIPOR1 showed association in any of the samples from the French population. In contrast, three SNPs of ADIPOR2 showed nominal evidence for association with type 2 diabetes before correction for multiple testing (odds ratio [OR] 1.29-1.37, P = 0.034-0.014); only rs767870, located in intron 6, was replicated in an additional diabetes dataset (n = 636, OR 1.29, P = 0.020) with significant allelic association from the overall meta-analysis of 2,876 subjects (adjusted OR 1.25 [95% CI 1.07-1.45], P = 0.0051). In conclusion, our data suggest a modest contribution of ADIPOR2 variants in diabetes risk in the French population.
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PMID:Genetic analysis of ADIPOR1 and ADIPOR2 candidate polymorphisms for type 2 diabetes in the Caucasian population. 1650 55

Several studies have reported an association between markers of liver injury, including elevated concentrations of alanine aminotransferase (ALT) aspartate aminotransferase (AST), and prospective risk of type 2 diabetes. We therefore examined the relationship between ALT and AST on the one hand, and serum adiponectin and highly sensitive CRP on the other, both of which have been reported to be associated with prospective risk of type 2 diabetes; we also tested for variable components of metabolic syndrome in 198 male college students aged 18-20 years. ALT showed a positive relationship with percentage body fat (r = 0.19, p = 0.02), serum leptin (r = 0.21, p = 0.01), LDL cholesterol (r = 0.29, p = 0.0003), triglyceride (r = 0.28, p = 0.0004) and apolipoprotein B (r = 0.35, p < 0.0001) even after adjustment for body mass index (BMI). Although there was a significant relationship with serum insulin, adiponectin (inversely), homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure, HDL cholesterol (inversely) and LDL particle diameter in simple regression analysis, significance disappeared after adjustment for BMI. In contrast, CRP (r = 0.16, p = 0.04) was associated with ALT after adjustment for BMI, although simple regression analysis revealed no association between the two. Relationships were smaller for AST, and significance disappeared after adjustment for BMI. Multiple regression analysis excluding lipid variables revealed significant and independent associations of ALT with adiponectin and percentage body fat. In a model including lipid variables, apolipoprotein B emerged as an independent predictor of ALT in addition to adiponectin and percentage body fat. These variables explained 29 % of ALT variability. In conclusion, serum ALT levels were associated with leptin and CRP as well as many components of the insulin resistance syndrome in young healthy men. Adiponectin, apolipoprotein B and percentage body fat emerged as significant and independent predictors of ALT. Since adiponectin and chronic subclinical inflammation have been reported to predict the development of type 2 diabetes and since abnormalities in apolipoprotein B metabolism occur in the early course of insulin resistance, these findings may be compatible with the association between liver markers and risk of diabetes.
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PMID:Serum alanine aminotransferase is associated with serum adiponectin, C-reactive protein and apolipoprotein B in young healthy men. 1652 13

The increasing prevalence of obesity and metabolic syndrome/insulin resistance has attracted considerable interest due to their identification as risk factors for cardiovascular disease and, hence, targets for cardiovascular disease prevention. This review focuses on adiponectin, the most profusely secreted protein from adipose tissue, which itself is being increasingly recognised as an important and very active endocrine organ, secreting a wide range of biologically active substances known as adipokines or adipocytokines. Adiponectin has been demonstrated to have insulin sensitising effects, and secretion of adiponectin is reduced as adipose tissue mass increases. Adiponectin has also been demonstrated to have anti-inflammatory and anti-atherogenic properties, and is independently associated with cardiovascular disease. The evidence that suggests adiponectin plays a role in the relationship between obesity and insulin resistance, and also insulin resistance and cardiovascular disease, is examined. Variation in the adiponectin gene is one tool to determine whether this relationship is causal. The association of identified variants with human disease, specifically obesity and its consequences, type 2 diabetes and cardiovascular disease is reviewed. This data may enable patients at greater risk of the adverse effects of obesity to be identified and, as such, benefit from more targeted therapy of its consequences.
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PMID:Adiponectin and its gene variants as risk factors for insulin resistance, the metabolic syndrome and cardiovascular disease. 1658 Oct 78

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.
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PMID:Recent advances in the relationship between obesity, inflammation, and insulin resistance. 1661 57


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