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)

The human adipocyte-specific apM-1 gene encodes a secretory protein of the adipose tissue that has been suggested to play a role in the pathogenesis of obesity. The regulation of apM-1 was studied along adipocyte differentiation. While apM-1-mRNA and apM-1 protein were absent in preadipocytes and in 48 h differentiated adipocytes, they were found upregulated from day 4 to day 9 of adipocyte differentiation as shown by RNase protection assay and Western blot analysis. These data indicate that apM-1 may be a late marker of adipocyte differentiation. In human sera apM-1 protein is also detectable by Western blots using a polyclonal antibody raised against a synthetic peptide sequence of the human apM-1. The genomic structure of the human apM-1 gene together with a total of 2.7 kb of the 5'-flanking region with putative transcription factor binding sites is presented. Interestingly, sequence comparisons link the apM-1 gene to the family of TNF's and to genes expressed in activated T-cells. The chromosomal localization of apM-1 was investigated by FISH and mapped to human chromosome 1q21.3-1q23, a region that was identified as a susceptibility locus for Familial Combined Hyperlipidaemia (FCH) and polygenic NIDDM. These data and the chromosomal localization on chromosome 1q21.3-q23 raises the possibility that apM-1 as an adipocyte-specific secretory protein may play a role in the pathogenesis of FCH and associated insulin resistance. Exon- and intron-specific primer sequences are presented as a basis for mutation screening of patients affected with FCH.
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PMID:The human apM-1, an adipocyte-specific gene linked to the family of TNF's and to genes expressed in activated T cells, is mapped to chromosome 1q21.3-q23, a susceptibility locus identified for familial combined hyperlipidaemia (FCH). 1040 84

Adiponectin and resistin are recently described secretory products of adipose tissue. Adiponectin is secreted by fat cells and circulates in the blood. Plasma adiponectin concentration is reduced in obese animals and humans and in patients with type 2 diabetes mellitus. Adiponectin stimulates fatty acids oxidation, decreases plasma triglycerides, and improves glucose metabolism by increasing insulin sensitivity. In addition, adiponectin inhibits the inflammatory process and possibly atherogenesis by suppressing the migration of monocytes/macrophages and their transformation into foam cells. Plasma adiponectin is lower in patients with ischemic heart disease than in body mass index-matched healthy individuals. Hypoadiponectinemia may contribute to insulin resistance and accelerated atherogenesis associated with obesity. Resistin/FIZZ3 is a member of the newly discovered cysteine-reach secretory protein family, referred to as 'resistin-like molecules' (RELM) or 'found in inflammatory zone' (FIZZ), together with FIZZ1/RELMalpha and FIZZ2/RELMbeta. Each of these has unique tissue distribution. Both resistin and FIZZ1/RELMalpha are expressed in adipose tissue. Initial studies in rodents suggested that resistin is upregulated in obesity and may be involved in the development of insulin resistance. Later studies failed to confirm this hypothesis and demonstrated reduced resistin expression in adipose tissue of obese animals. In human adipose tissue resistin is detectable at a very low level, and there is no relationship between resistin expression and obesity. Although the role of resistin in linking human obesity with type 2 diabetes is thus questionable, this protein is detected in peripheral blood monocytes,
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PMID:Adiponectin and resistin--new hormones of white adipose tissue. 1458 85

The fattening of the human species and the accompanying emergence of the metabolic syndrome and of type 2 diabetes as remarkably frequent clinical entities are among the major epidemiologic events of our time. Control of the diabetes epidemic requires a greater understanding of the pathophysiologic processes underlying these phenomena. Many epidemiologic studies have now shown associations between inflammation markers and diabetes, with the most consistent being for leukocytes and the strongest being for C-reactive protein. Consistent protective associations have also been reported for adiponectin, an adipocyte secretory protein with antiinflammatory actions. Although great variability is seen between reported associations, as a whole these studies suggest a role for inflammation linked to obesity. The variability reported is in part due to differences in model adjustment, in how diabetes was ascertained, and in the different means used to operationalize the concept of low-grade chronic systemic inflammation. It is also due, in part, to sample characterization, as findings are heterogeneous across some subgroups, such as those defined by smoking. Consistent with their association with type 2 diabetes, inflammation markers have also be shown to predict conditions present in the prediabetes state such as weight gain, hypertension, gestational diabetes, and decline in insulin sensitivity.
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PMID:The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes. 1647 45

Central (visceral) obesity is more closely associated with insulin resistance, type 2 diabetes, and cardiovascular disease than is peripheral [subcutaneous (sc)] obesity, but the underlying mechanism for this pathophysiological difference is largely unknown. To understand the molecular basis of this difference, we sequenced 10,437 expressed sequence tags (ESTs) from a human omental fat cDNA library and discovered a novel visceral fat depot-specific secretory protein, which we have named omentin. Omentin ESTs were more abundant than many known adipose genes, such as perilipin, adiponectin, and leptin in the cDNA library. Protein sequence analysis indicated that omentin mRNA encodes a peptide of 313 amino acids, containing a secretory signal sequence and a fibrinogen-related domain. Northern analysis demonstrated that omentin mRNA was predominantly expressed in visceral adipose tissue and was barely detectable in sc fat depots in humans and rhesus monkeys. Quantative real-time PCR showed that omentin mRNA was expressed in stromal vascular cells, but not fat cells, isolated from omental adipose tissue, with >150-fold less in sc cell fractions. Accordingly, omentin protein was secreted into the culture medium of omental, but not sc, fat explants. Omentin was detectable in human serum by Western blot analysis. Addition of recombinant omentin in vitro did not affect basal but enhanced insulin-stimulated glucose uptake in both sc (47%, n = 9, P = 0.003) and omental (approximately 30%, n = 3, P < 0.05) human adipocytes. Omentin increased Akt phosphorylation in the absence and presence of insulin. In conclusion, omentin is a new adipokine that is expressed in omental adipose tissue in humans and may regulate insulin action.
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PMID:Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. 1653 7

Both major forms of diabetes involve a decline in beta-cell mass, mediated by autoimmune destruction of insulin-producing cells in type 1 diabetes and by increased rates of apoptosis secondary to metabolic stress in type 2 diabetes. Methods for controlled expansion of beta-cell mass are currently not available but would have great potential utility for treatment of these diseases. In the current study, we demonstrate that overexpression of trefoil factor 3 (TFF3) in rat pancreatic islets results in a 4- to 5-fold increase in [(3)H]thymidine incorporation, with full retention of glucose-stimulated insulin secretion. This increase was almost exclusively due to stimulation of beta-cell replication, as demonstrated by studies of bromodeoxyuridine incorporation and co-immunofluorescence analysis with anti-bromodeoxyuridine and antiinsulin or antiglucagon antibodies. The proliferative effect of TFF3 required the presence of serum or 0.5 ng/ml epidermal growth factor. The ability of TFF3 overexpression to stimulate proliferation of rat islets in serum was abolished by the addition of epidermal growth factor receptor antagonist AG1478. Furthermore, TFF3-induced increases in [3H]thymidine incorporation in rat islets cultured in serum was blocked by overexpression of a dominant-negative Akt protein or treatment with triciribine, an Akt inhibitor. Finally, overexpression of TFF3 also caused a doubling of [3H]thymidine incorporation in human islets. In summary, our findings reveal a novel TFF3-mediated pathway for stimulation of beta-cell replication that could ultimately be exploited for expansion or preservation of islet beta-cell mass.
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PMID:Trefoil factor 3 stimulates human and rodent pancreatic islet beta-cell replication with retention of function. 1825 87

Adiponectin is a secretory protein predominantly expressed by adipocytes and released at a high rate into circulation. The ease with which the levels of adiponectin can be measured owing to its high abundance, small diurnal variation and high stability in plasma have made it a popular target for measurements in many clinical studies. It has emerged as a valuable biomarker for insulin sensitivity, cardiovascular risk and inflammation. However, adiponectin levels have been measured in many additional disease states. Preclinical studies not only have implicated adiponectin as an outstanding biomarker but also have demonstrated direct cardio-protective and insulin-sensitizing properties to be associated with the protein. Adiponectin might, therefore, be a viable protein therapeutic that could be supplied in a recombinant form in the context of type 2 diabetes and cardiovascular disease. However, the high abundance, complex tertiary and quaternary structure and rapid turnover might make chronic administration of the protein rather challenging.
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PMID:Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. 1935 49

White adipose tissue is an endocrine organ producing numerous proteins known as adipokines, which include leptin, adiponectin, resistin, visfatin, and other factors, which are involved in most metabolic disorders. In obesity, plasma leptin concentrations are high due to leptin resistance that may result from the attenuation of leptin signaling in the hypothalamus. Leptin acts to inhibit appetite, stimulate thermogenesis, enhance fatty acid oxidation, decrease glucose, and reduce body weight, and fat. A reduced adiponectin level has been associated with insulin resistance, dyslipidemia, and atherosclerosis, and its low level is a predictor of later development of type 2 diabetes. Resistin expression is low in adipose tissue and high in bone marrow and lungs, its role in glucose homeostasis remains controversial, it has been associated with insulin resistance and obesity. Visfatin is a secretory protein highly enriched in visceral adipocytes, liver, muscle, and lymphocytes. An increase of visfatin levels in obesity was related to preservation of insulin sensitivity, it enhances glucose uptake by adipocytes and inhibits hepatocyte glucose release, it induces tyrosine phosphorylation, and interacts with insulin receptors. Many studies are still being conducted to highlight the role of adipokines in metabolic disorders.
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PMID:Adipokines and etiopathology of metabolic disorders. 1975 Feb 55

The phenotypic stability of somatic cells is essential for the maintenance of both structural and functional organ integrity of the adult human body. Deregulated cell plasticity could result in the development of debilitating diseases such as cancer, fibrosis, atherosclerosis, obesity, and type 2 diabetes. We have previously demonstrated that a nonsense mutation in the NPC2 gene, which encodes ubiquitous, highly conserved, secretory protein with unknown function, leads to activation of human skin fibroblasts. The activated fibroblasts, also known as myofibroblasts, have the properties of mesenchymal stem cells and are able to differentiate along the mesodermal and endodermal lineages. Here we show that NPC2-null, but not the normal skin fibroblasts, possess characteristics of adipogenic progenitors as demonstrated by their specific gene expression pattern as well as the ability for efficient differentiation into white adipocytes. The presence of NPC2 in mature white adipocytes was also necessary for their maintenance because silencing NPC2 in differentiated cells by siRNA stimulated PPARG expression, which was followed by a shift toward a more favorable, brown adipocyte-like metabolic state characterized by up-regulated lipolysis and increased insulin sensitivity. It appears that NPC2 controls both the adipogenesis and the metabolic state of mature white adipocytes through a common mechanism that is linked to activation of FGFR2 that could be followed by induction of PPARG expression. Altogether, the current study highlights NPC2 as a novel intracrine/autocrine factor that controls adipocyte differentiation and function as well as potential therapeutic target for the treatment of type 2 diabetes and related metabolic disorders.
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PMID:Somatic cell plasticity and Niemann-pick type C2 protein: adipocyte differentiation and function. 2065 Aug 96

The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes.
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PMID:A liver-derived secretory protein, selenoprotein P, causes insulin resistance. 2103 59

Selenoprotein P (SeP; encoded by SEPP1 in humans) is a liver-derived secretory protein that induces insulin resistance in type 2 diabetes. Suppression of SeP might provide a novel therapeutic approach to treating type 2 diabetes, but few drugs that inhibit SEPP1 expression in hepatocytes have been identified to date. The present findings demonstrate that metformin suppresses SEPP1 expression by activating AMP-activated kinase (AMPK) and subsequently inactivating FoxO3a in H4IIEC3 hepatocytes. Treatment with metformin reduced SEPP1 promoter activity in a concentration- and time-dependent manner; this effect was cancelled by co-administration of an AMPK inhibitor. Metformin also suppressed Sepp1 gene expression in the liver of mice. Computational analysis of transcription factor binding sites conserved among the species resulted in identification of the FoxO-binding site in the metformin-response element of the SEPP1 promoter. A luciferase reporter assay showed that metformin suppresses Forkhead-response element activity, and a ChIP assay revealed that metformin decreases binding of FoxO3a, a direct target of AMPK, to the SEPP1 promoter. Transfection with siRNAs for Foxo3a, but not for Foxo1, cancelled metformin-induced luciferase activity suppression of the metformin-response element of the SEPP1 promoter. The overexpression of FoxO3a stimulated SEPP1 promoter activity and rescued the suppressive effect of metformin. Metformin did not affect FoxO3a expression, but it increased its phosphorylation and decreased its nuclear localization. These data provide a novel mechanism of action for metformin involving improvement of systemic insulin sensitivity through the regulation of SeP production and suggest an additional approach to the development of anti-diabetic drugs.
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PMID:Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. 2425 50


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