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)

Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.
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PMID:The hormone resistin links obesity to diabetes. 1120 21

A 12.5-kDa cysteine-rich adipose tissue-specific secretory factor (ADSF/resistin) is a novel secreted protein rich in serine and cysteine residues with a unique cysteine repeat motif of CX(12)CX(8)CXCX(3)CX(10)CXCXCX(9)CC. A single 0.8-kilobase mRNA coding for this protein was found in various murine white adipose tissues including inguinal and epididymal fats and also in brown adipose tissue but not in any other tissues examined. Two species of mRNAs with sizes of 1.4 and 0.8 kilobases were found in rat adipose tissue. Sequence analysis indicates that this is because of two polyadenylation signals, the proximal one with the sequence AATACA with a single base mismatch from murine AATAAA and the distal consensus sequence AATAAA. The mRNA level was markedly increased during 3T3-L1 and primary preadipocyte differentiation into adipocytes. Its expression in adipose tissue is under tight nutritional and hormonal regulation; the mRNA level was very low during fasting and increased 25-fold when fasted mice were refed a high carbohydrate diet. It was also very low in adipose tissue of streptozotocin-diabetes and increased 23-fold upon insulin administration. Upon treatment with the conditioned medium from COS cells transfected with the expression vector, conversion of 3T3-L1 cells to adipocytes was inhibited by 80%. The regulated expression pattern suggesting this factor as an adipose sensor for the nutritional state of the animals and the inhibitory effect on adipocyte differentiation implicate its function as a feedback regulator of adipogenesis.
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PMID:A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. 1127 54

Resistin was recently identified as a hormone secreted by adipocytes which leads to insulin resistance in vivo and in vitro and might therefore be an important link between obesity and diabetes. To clarify the regulation of resistin gene expression, 3T3-L1 adipocytes were treated with various agents known to modulate insulin sensitivity, and resistin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, isoproterenol treatment reduced the level of resistin mRNA to 20% of non-treated control cells. This effect was dose-dependent with significant inhibition occurring at concentrations as low as 10 nM isoproterenol. Moreover, pretreatment of adipocytes with the beta-adrenergic antagonist propranolol almost completely reversed the inhibitory effect of isoproterenol, whereas addition of the alpha-adrenergic antagonist phentolamine did not have any effect. Furthermore, the effect of isoproterenol could be mimicked by activation of G(S)-proteins and adenylyl cyclase. Thus, both cholera toxin and forskolin decreased resistin mRNA expression in a dose-dependent fashion by up to 90% of control levels. Taken together, these results suggest that resistin gene expression is regulated by a protein kinase A-dependent pathway in 3T3-L1 adipocytes.
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PMID:Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in 3T3-L1 adipocytes. 1143 27

Obesity is a growing public health problem worldwide. It is a particularly common problem among individuals with type 2 diabetes mellitus. The magnitude of obesity, the central location of fat, and a history of weight gain are independent risks for developing diabetes mellitus. Potential factors implicated in the pathogenesis of diabetes mellitus in obese patients include increased plasma free fatty acid concentrations, increased production of cytokines, increased leptin levels, and increased levels of a recently discovered protein called resistin. Epidemiological and interventional studies suggest that even modest loss of body weight, either by changes in lifestyle or pharmacological means is associated with significant amelioration of insulin resistance and improvement in diabetes mellitus control. Treatment of obesity is an important therapeutic goal in the management of patients with type 2 diabetes mellitus.
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PMID:Obesity: a rational target for managing diabetes mellitus. 1152 93

Type 2 diabetes mellitus is a complex phenotype that is frequently associated with central obesity and insulin resistance. Recently, a protein named resistin, encoded by RSTN (OMIM #605565), was identified in adipose tissue. Serum resistin was elevated in obese and diabetic mice, and administration of resistin to normal mice was found to interfere with glucose tolerance and insulin action. Because of these functions, resistin is a candidate gene for diabetes and obesity. Through the use of DNA sequencing, we thus developed amplification primers for rapid screening of the RSTN gene that encodes resistin. No putative mutations were found, but two noncoding single-nucleotide polymorphisms (SNPs) were identified, and these were found to vary in frequency across various ethnic groups. The identification of amplification primers and SNPs provides tools to investigate resistin for association with other phenotypes.
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PMID:Single nucleotide polymorphisms of the resistin (RSTN) gene. 1155 7

Recent studies in murine models suggest that resistin (also called Fizz3 [1]), a novel cysteine-rich protein secreted by adipocytes, may represent the long-sought link between obesity and insulin resistance (2). Furthermore, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists appear to inhibit resistin expression in murine adipocytes, providing a possible explanation for the mode of action of this class of insulin sensitizers (2). Using a fluorescent real-time reverse transcriptase-polymerase chain reaction-based assay, we found that resistin mRNA levels in whole adipose tissue samples were increased in morbidly obese humans compared with lean control subjects. However, in freshly isolated human adipocytes, resistin mRNA levels were very low and showed no correlation with BMI. Resistin mRNA was undetectable in preadipocytes, endothelial cells, and vascular smooth muscle cells, but it was readily detectable in circulating mononuclear cells. Although exposure of human mononuclear cells to PPAR-gamma agonists markedly upregulated fatty acid-binding protein-4 expression, these agents had no effect on mononuclear cell resistin expression. Finally, resistin mRNA was undetectable in adipocytes from a severely insulin-resistant subject with a dominant-negative mutation in PPAR-gamma (3). We conclude that the recently described relationships of murine resistin/Fizz3 expression with obesity, insulin resistance, and PPAR-gamma action may not readily translate to humans. Further studies of this novel class of proteins are needed to clarify their roles in human metabolism.
Diabetes 2001 Oct
PMID:Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. 1157 98

The traditional role attributed to white adipose tissue is energy storage, fatty acids being released when fuel is required. The metabolic role of white fat is, however, complex. For example, the tissue is needed for normal glucose homeostasis and a role in inflammatory processes has been proposed. A radical change in perspective followed the discovery of leptin; this critical hormone in energy balance is produced principally by white fat, giving the tissue an endocrine function. Leptin is one of a number of proteins secreted from white adipocytes, which include angiotensinogen, adipsin, acylation-stimulating protein, adiponectin, retinol-binding protein, tumour neorosis factor a, interleukin 6, plasminogen activator inhibitor-1 and tissue factor. Some of these proteins are inflammatory cytokines, some play a role in lipid metabolism, while others are involved in vascular haemostasis or the complement system. The effects of specific proteins maybe autocrine or paracrine, or the site of action maybe distant from adipose tissue. The most recently described adipocyte secretory proteins are fasting-induced adipose factor, a fibrinogen-angiopoietin-related protein, metallothionein and resistin. Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity. Metallothionein is a metal-binding and stress-response protein which may have an antioxidant role. The key challenges in establishing the secretory functions of white fat are to identify the complement of secreted proteins, to establish the role of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production with alterations in adiposity (obesity, fasting, cachexia). There is already considerable evidence of links between increased production of some adipocyte factors and the metabolic and cardiovascular complications of obesity. In essence, white adipose tissue is a major secretory and endocrine organ involved in a range of functions beyond simple fat storage.
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PMID:Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. 1168 7

Expression of the gene encoding resistin, a low molecular weight protein secreted from adipose tissue postulated to link obesity and type II diabetes, was examined in 3T3-L1 adipocytes. Resistin mRNA was detected in 3T3-L1 cells by day 3 following induction of differentiation into adipocytes; by day 4 the level of resistin mRNA peaked and remained high. The PPARgamma activators, rosiglitazone or darglitazone, reduced the level of resistin mRNA. Dexamethasone upregulated resistin mRNA level, but no effect was observed with the beta(3)-adrenoceptor agonist, BRL 37344. A substantial reduction in resistin mRNA level was observed with insulin, which induced decreases at physiological concentrations. Insulin may be a major inhibitor of resistin production, and this does not support a role for resistin in insulin resistance.
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PMID:Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. 1168 67

Resistin has recently been implicated as an adipocytokine leading to insulin resistance and, therefore, potentially linking obesity and diabetes. To further characterize the regulation of this fat-secreted protein by insulin sensitivity-modulating hormones, 3T3-L1 adipocytes were treated with tumor necrosis factor (TNF) alpha, angiotensin (AT) 2, as well as growth hormone (GH), and resistin gene expression and protein secretion were determined by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. Interestingly, both, resistin mRNA expression and protein secretion, were inhibited by 70-90% after TNFalpha-treatment whereas AT2 and GH did not have any effect. The inhibitory effect of TNFalpha was time- and dose-dependent with significant inhibition occurring as early as 4 h after effector addition and at concentrations as low as 1 ng/ml TNFalpha. Pharmacological inhibition of protein kinase A (PKA), p44/42, and p38 mitogen-activated protein (MAP) kinase did not reverse the inhibitory effect of TNFalpha suggesting that neither of these signaling molecules is involved in suppression of resistin gene expression by TNFalpha. Furthermore, suppression of resistin mRNA levels could be completely reversed to control levels by withdrawal of TNFalpha for 24 h. Taken together, these results suggest that TNFalpha is a pivotal negative regulator of resistin gene expression. This may have important implications for the pathogenesis of insulin resistance and its link to obesity.
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PMID:Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. 1168 13

Resistin, the peptide specifically secreted from adipocytes, is a hormone antagonistic to insulin action and, thus, may serve as a link between human obesity due to adiposity and insulin resistance associated with type 2 diabetes. To test this hypothesis, we studied the gene expression of resistin in adipocytes isolated from rats fed with a fructose diet which induced insulin resistance. Compared to the control rats (C) on a normal chow diet, the fructose-fed rats (F) developed hyperinsulinemia, glucose intolerance, hypertriglyceridemia and hypertension, a profile reminiscent of the syndrome X of patients with non-insulin-dependent diabetes mellitus (NIDDM). The F rats had significantly elevated plasma free fatty acids (FFA), enlarged epididymal fat pads, and increased adipocyte size compared with the C rats. We examined the glucose transport and the relative quantity of resistin mRNA produced in the adipocytes of these two groups of rats. Compared to the C rats, the F rats had a clearly reduced insulin-stimulated glucose transport. The gene expression of resistin and other adipocyte peptides was measured on the mRNA by semiquantitative RT-PCR; the validity of this technique was established in advance with a rat-fasting and then refeeding experiment. The F rats showed a decreased expression of the resistin gene, whereas gene expression of leptin and angiotensinogen in contrast increased. Free fatty acids were found to suppress the expression of resistin gene in normal rat adipocytes. These results demonstrate that an insulin-resistant instance in the fructose diet rat model exists with the decreased gene expression of resistin.
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PMID:Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids. 1174 41


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