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)

Soluble protein hormones are key regulators of a number of metabolic processes, including food intake and insulin sensitivity. We have used a signal sequence trap to identify genes that encode secreted or membrane-bound proteins in Psammomys obesus, an animal model of obesity and type 2 diabetes (T2D). Using this signal sequence trap, we identified the chemokine chemerin as being a novel adipokine. Gene expression of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), was significantly higher in adipose tissue of obese and type 2 diabetic P. obesus compared with lean, normoglycemic P. obesus. Fractionation of P. obesus adipose tissue confirmed that chemerin was predominantly expressed in adipocytes, whereas CMKLR1 was expressed in both adipocytes and stromal-vascular cells of adipose tissue. In 3T3-L1 adipocytes, chemerin was markedly induced during differentiation, whereas CMKLR1 was down-regulated during differentiation. Serum chemerin levels were measured by ELISA in human plasma samples from 114 subjects with T2D and 142 normal glucose tolerant controls. Plasma chemerin levels were not significantly different between subjects with T2D and normal controls. However, in normal glucose tolerant subjects, plasma chemerin levels were significantly associated with body mass index, circulating triglycerides, and blood pressure. Here we report, for the first time, that chemerin is an adipokine, and circulating levels of chemerin are associated with several key aspects of metabolic syndrome.
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PMID:Chemerin is a novel adipokine associated with obesity and metabolic syndrome. 1764 Sep 97

Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF-kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C-terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells.
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PMID:Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. 1770 46

Beyond glycemic control, the thiazolidinediones (TZDs) provide numerous cardiovascular benefits. Clinical data support a role for the TZDs in lowering blood pressure, correcting dyslipidemia, improving vascular structure and function, decreasing inflammation, improving the adipokine profile, reducing systemic oxidative stress, and possibly in stabilizing coronary plaques that may be prone to rupture. Data from the first outcomes trial assessing a TZD in reducing cardiovascular morbidity and mortality have recently been reported. Results were promising, but not conclusive. Therefore, other large studies currently underway should provide greater insight into the role of the TZDs in modifying cardiovascular risk in patients with type 2 diabetes. Reported side effects of the TZDs include fluid retention, worsening of heart failure, and weight gain. Recent research is beginning to clarify the mechanisms associated with these potential side effects and may result in the expanded use of this drug class in patients with heart failure. Because of the unique mechanism of action of this drug class that addresses a fundamental pathophysiolgical phenomenon in type 2 diabetes, namely, improving insulin resistance, and the growing body of evidence supporting cardiovascular benefits, strong consideration should be given to utilizing the TZDs early in the clinical course of diabetes.
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PMID:The cardiovascular effects of the thiazolidinediones: a review of the clinical data. 1782 58

Both ectopic fat accumulation and changes of the amount of several adipocyte secreting proteins (adipokines) are thought to contribute to the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now investigated the effects of 2 insulin-sensitizing drugs, pioglitazone and metformin, on body fat composition and serum adipokine concentrations in individuals with type 2 diabetes mellitus. A total of 41 diabetic patients were treated with pioglitazone (n =21) or metformin (n =20) for 6 months. Intramyocellular lipid content (IMCL) and hepatic lipid content as well as the areas of subcutaneous and visceral fat deposits in the abdomen were determined by nuclear magnetic resonance spectroscopy before and after drug treatment. The serum concentrations of adiponectin and retinol binding protein 4 were also determined by enzyme-linked immunosorbent assays. Pioglitazone treatment reduced both hepatic lipid content (12.0 +/- 6.1 vs 8.4 +/- 3.7 arbitrary units [AU], P < .01) and IMCL (8.4 +/- 3.6 vs 6.3 +/- 2.4 AU/creatine, P < .01), whereas metformin reduced only IMCL (7.0 +/- 3.6 vs 5.8 +/- 2.0 AU/creatine, P < .05). Although the areas of visceral and subcutaneous fat were not significantly affected by treatment with either drug, pioglitazone induced a significant reduction in the ratio of visceral to subcutaneous fat area (0.92 +/- 0.41 vs 0.85 +/- 0.41, P < .05). Pioglitazone treatment also resulted in a marked increase in serum adiponectin concentration (5.6 +/- 4.1 vs 16.2 +/- 9.9 microg/mL, P < .0001) and a small but significant decrease in serum retinol binding protein 4 concentration (73.4 +/- 25.1 vs 65.1 +/- 23.7 microg/mL, P < .05). These results suggest that pioglitazone may improve insulin sensitivity both by affecting serum adipokine concentrations and by reducing the intracellular triglyceride content of liver and skeletal muscle in individuals with type 2 diabetes mellitus.
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PMID:Effects of pioglitazone and metformin on intracellular lipid content in liver and skeletal muscle of individuals with type 2 diabetes mellitus. 1788 55

Visfatin, is a new adipokine, highly expressed in the visceral fat of both mice and humans. To examine whether visfatin is expressed in human peripheral monocyte-enriched mononuclear cells and whether its expression is altered in type 2 diabetes (DM2), we compared 24 DM2 women [17 overweight (BMI >25) and 7 lean (BMI<25)] to 26 healthy women (14 overweight and 12 lean), all premenopausal. Relative visfatin mRNA levels were significantly higher (approximately 3-fold) in DM2 compared to healthy control women (p<0.02), independently of the presence of overweight/obesity. Mononuclear TNF-alpha and IL-6 mRNA expression was also elevated in DM2 compared to control women (p=0.001 and p=0.004, respectively), an increase observed in both lean and overweight DM2 women. By contrast, circulating visfatin, TNF-alpha, and IL-6 levels showed no difference between DM2 and control women, while adiponectin plasma levels were significantly decreased in the DM2 women (p<0.001). Circulating visfatin and TNF-alpha levels did not differ either between the lean and the overweight subgroups of DM2 and control women, while IL-6 plasma levels were significantly higher in both overweight subgroups compared to their lean counterparts. In conclusion, visfatin, TNF-alpha, and IL-6 mRNA expressions are increased in peripheral mononuclear-monocytic cells from women with type 2 diabetes, independent of their BMI, which may enhance the effects of their adipose-derived levels and may contribute to the increased insulin resistance and atherogenic risk of these patients.
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PMID:Visfatin, TNF-alpha and IL-6 mRNA expression is increased in mononuclear cells from type 2 diabetic women. 1795 40

Type 2 diabetes is widespread and its prevalence is increasing rapidly. In the US alone, approximately 41 million individuals have prediabetes, placing them at high risk for the development of diabetes. The pathogenesis of type 2 diabetes involves inadequate insulin secretion and resistance to the action of insulin. Suggestive data link insulin resistance and accompanying hyperglycemia to an excess of abdominal adipose tissue, a link that appears to be mediated partially by adipocyte secretion of multiple adipokines that mediate inflammation, thrombosis, atherogenesis, hypertension, and insulin resistance. The adipokine adiponectin has reduced expression in obesity and appears to be protective against the development of type 2 diabetes. Current recommendations to prevent type 2 diabetes center on lifestyle modifications, such as diet and exercise. Clinical trials have established the efficacy of lifestyle intervention, as well as pharmacologic interventions that target glycemic control or fat metabolism. However, diabetes did develop in a substantial percentage of individuals who received intensive intervention in these trials. Thus there is an unmet need for additional strategies in high-risk individuals. Recent data suggest thiazolidinediones and blockade of the endocannabinoid system represent novel therapeutic approaches that may be used for the prevention of diabetes.
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PMID:The burden of type 2 diabetes: strategies to prevent or delay onset. 1796 81

Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic conditions (such as cancer and sepsis) and with pathological states of nutritional overload (such as obesity-related type 2 diabetes). Two common features of these metabolic disorders are adipose tissue dysfunction and elevated levels of tumour necrosis factor-alpha (TNF-alpha). Herein, we review the multiple actions of this pro-inflammatory adipokine on adipose tissue biology. These include inhibition of carbohydrate metabolism, lipogenesis, adipogenesis and thermogenesis and stimulation of lipolysis. TNF-alpha can also impact the endocrine functions of adipose tissue. Taken together, TNF-alpha contributes to metabolic dysregulation by impairing both adipose tissue function and its ability to store excess fuel. The molecular mechanisms that underlie these actions are discussed.
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PMID:TNF-alpha and adipocyte biology. 1803 76

Adiponectin is an abundantly expressed adipokine in adipose tissue and has direct insulin sensitizing activity. A decrease in the circulating levels of adiponectin by interactions between genetic factors and environmental factors causing obesity has been shown to contribute to the development of insulin resistance, type 2 diabetes, metabolic syndrome and atherosclerosis. In addition to its insulin sensitizing actions, adiponectin has central actions in the regulation of energy homeostasis. Adiponectin enhances AMP-activated protein kinase activity in the arcuate hypothalamus via its receptor AdipoR1 to stimulate food intake and decreases energy expenditure. We propose a hypothesis on the physiological role of adiponectin: a starvation gene in the course of evolution by promoting fat storage on facing the loss of adiposity.
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PMID:The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. 1805 35

Adiponectin is an abundantly expressed adipokine in adipose tissue and has direct insulin sensitizing activity. We have proposed the following adiponectin hypothesis. Interactions of genetic factors such as single nucleotide polymorphisms (SNPs) in the Adiponectin gene and environmental factors causing obesity result in hypoadiponectinaemia, which appears to play an important causal role in obesity-linked insulin resistance, type 2 diabetes and the metabolic syndrome. We have cloned the adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin. AdipoR1 and AdipoR2 are down-regulated in obesity-linked insulin resistance. Up-regulation of adiponectin or adiponectin receptors may represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance.
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PMID:Adiponectin and adiponectin receptors in obesity-linked insulin resistance. 1826 82

Visfatin was recently identified as a novel adipokine highly enriched in visceral adipose tissue and suggested to play a role in the pathophysiology of obesity and type 2 diabetes mellitus. However, the biological role of visfatin remains elusive since subsequent studies failed to repeat some of the original findings. We report here the cloning of six porcine visfatin transcript variants, resulting from alternate polyadenylation or alternate splicing of exons. It is further demonstrated that the porcine visfatin gene and protein expression measured in fat tissues correlate negatively with subcutaneous (s.c.), visceral and total body fat tissue weights. Moreover, there was no correlation between visfatin mRNA or protein levels and fasting glucose or insulin. No correlation could be found between circulating visfatin and any of the carcass and metabolic parameters. Our results also demonstrate that the tumor necrosis factor (TNF)alpha increases porcine visfatin gene expression in stromal-vascular (SV) cell cultures, thus suggesting an intermediary role for TNFalpha in visfatin response. In conclusion, our results demonstrate that the porcine visfatin gene cannot be considered as a marker of fat accumulation since the highest visfatin expression levels were associated with the leaner animals.
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PMID:Visfatin expression is not associated with adipose tissue abundance in the porcine model. 1834 25


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