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)

Many species of monocellular eukaryots as well as the majority of animal cell and plant tissues show the presence of peroxisomes or microperoxisomes. Their size, shape and internal organization may differ in various cellular types significantly. Typical components of animal cell peroxisomes are the membrane, matrix, low density compartment enriched in lipids, and the compartment containing D-amino acid oxidase. The group of four enzymes (catalase, D-amino acid oxidase, L-alpha-OH-acid oxidase) the location of which had been originally discovered in peroxisomes of hepatocytes of rodents was later widened by approximately forty further enzymes. It is though probable that evolution brought along a reduction and loss of various metabolic functions of peroxisomes and a decrease in the number of enzymes. Peroxisomes are characterized by high variability of the enzymatic content in dependence on the nutritional conditions and the effect of xenobiotics. Fasting, diabetes mellitus, high-lipid diet, peroxisome proliferators induce several peroxisomal enzymes, especially fatty acids beta-oxidation. The mechanism of the impact of heterogeneous substances on the gene transcription has been clarified recently. Substances as fibrates, retinoic acid, polyunsaturated fatty acids activate specific types of receptors-PPAR (peroxisome proliferators activated receptors) belonging to the superfamily of receptors activated by steroid hormones, thyroid hormones, and D-vitamins. A simultaneous induction of several peroxisomal enzymes can be achieved by the linkage between PPAR and specific areas of promotors of particular genes. Such areas-PPREs (peroxisomal proliferator response elements) with five repeated TGA(A/C/T)CT hexanucleotide sequences separated by one nucleotide were discovered in several peroxisomal genes. It is assumed that the stimulation of transcription can be achieved by the linkage between homodimers, and heterodimers of nuclear receptors on these DNA sections. The majority of peroxisomal proteins is synthesised in the cytoplasm, namely on polysomes being in matured forms. Unimpaired biogenesis of peroxisomes requires membrane transport proteins and presence of signal in polypeptide chain of imported proteins (PTS-peroxisomal targeting signal). The function of PTS in many peroxisomal proteins is fulfilled by the C-terminal tripeptide which is composed of amino acids, namely serine, lysine, and leucine (SKL-tripeptide), respectively by a tripeptide with a very similar composition in amino acids. Aside from this signal, still another signal exists, which is located at the N-end of peroxisomal proteins. The role of membrane proteins 70, 35, 256, 22, 15 kDa, is being discussed in relationship to the functions and diseases caused by impaired biogenesis of peroxisomes. (Fig. 4, Ref. 128.)
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PMID:Properties and biogenesis of peroxisomes. 773 95

Thiazolidinedione derivatives are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the molecular basis for this adipogenic effect has remained unclear. Here, we report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPAR gamma with a Kd of approximately 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPAR gamma is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPAR gamma is a target for the therapeutic actions of this class of compounds.
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PMID:An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). 776 81

The identification of high-affinity ligands for PPAR gamma has revealed the role of this receptor as the molecular target for the antidiabetic activity of the thiazolidinediones. The surprising observation that agonists of an adipogenic transcription factor reverse the obesity-associated disease of diabetes highlights the power of using potent and selective ligands to study receptor-mediated biology. Similarly, the observation that PGD2 and its cyclopentenone metabolites compounds are microM PPAR ligands suggests that these receptors may have a physiological role in mediating prostaglandin signaling in the spleen.
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PMID:Discovery of ligands for the nuclear peroxisome proliferator-activated receptors. 899 50

We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.
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PMID:Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR gamma) gene. 916 28

Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabetic agents that are agonists for the peroxisome proliferator-activated nuclear receptor (PPAR-gamma2). In vivo, TZDs reduce circulating levels of free fatty acids (FFAs) and ameliorate insulin resistance in individuals with obesity and NIDDM. Adipocyte production of TNF-alpha is proposed to play a role in the development of insulin resistance, and because BRL 49653 has been shown to antagonize some of the effects of TNF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipocyte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T3-L1 adipocytes, glycerol release increased by approximately 7-fold, and FFA release increased by approximately 44-fold. BRL 49653 (10 pmol/l) reduced TNF-alpha-induced glycerol release by approximately 50% (P < 0.001) and FFA release by approximately 90% (P < 0.001). BRL 49653 also reduced glycerol release by approximately 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma2 agonist, 15-d delta-12,14-prostaglandin J2 (15-d deltaPGJ2), blocked TNF-alpha-induced glycerol release by approximately 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaffected by BRL 49653 and 15-d deltaPGJ2. BRL 49653 partially blocked the TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity.
Diabetes 1998 Apr
PMID:BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new insulin-sensitizing mechanism for thiazolidinediones. 956 6

Diabetes mellitus is a still growing disease. New diagnostic criteria lowered the cut off value to 126 mg/dl, in order to detect more rapidly diabetes and its complications. The treatment of diabetes 2 by the classic oral antidiabetic drugs (sulfamides and biguanides) is completed by intestinal glycosidases inhibitors and thiazolidendiones. These last drugs seem very attractive because they decrease insulin resistance in obese, diabetics. Their hepatic side effects must be however under control. Better knowledge of non lipidic effects of statins on the arterial wall and the discovery of the action of fibrates on PPAR (Peroxisome Proliferator Activated Receptors) improved strongly the therapeutic management of hyperlipidemias. Recent intervention studies have demonstrated the necessity to treat vigorously dysipidemias.
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PMID:[New developments in the treatment of diabetes and hyperlipidemias]. 980 78

Apolipoprotein CIII (ApoCIII) appears to play a key role in triglyceride-rich lipoprotein (TRL) metabolism. This 8.8 kDa polypeptide is mainly synthesized by the liver in 3 isoforms. The gene involved has been mapped on chromosome 11, and several polymorphisms associated with hypertriglyceridaemia and/or coronary artery disease (CAD) have been described. In normolipidaemic individuals, the total plasma ApoCIII level (0.10 g/l) is mainly HDL-linked. Plasma levels are increased in hyper-triglyceridaemic subjects in whom ApoCIII is VLDL-linked. In Type 2 diabetic patients, the ApoCIII concentration varies with metabolic control of the disease but does not always correlate with the triglyceride level. In various clinical studies, the level of VLDL/LDL-linked ApoCIII was correlated with the severity of the CAD score, and treatment with fibrates decreased the ApoCIII mRNA level in association with PPAR activation. Overexpression of the human ApoCIII gene in transgenic animals results in hypertriglyceridaemia, which can be corrected by overexpression of the ApoE gene. ApoCIII decreases TRL catabolism by inhibiting lipoprotein lipase activity and reducing ApoE-dependent hepatic uptake of TRL and remnants. There appears to be an interaction between ApoCIII and ApoE at the surface of the lipoprotein. Our recent study of ApoCIII levels in TRL and intermediate-density lipoprotein isolated from hyperlipidaemic Type III and IV individuals confirmed the importance of the ApoCIII/ApoE ratio in these lipoproteins.
Diabetes Metab 1998 Dec
PMID:Role of apolipoprotein CIII in triglyceride-rich lipoprotein metabolism. 993 15

The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated receptors which regulate genes involved in lipid metabolism and homeostasis. PPARalpha is preferentially expressed in the liver and PPARgamma preferentially in adipose tissue. Activation of PPARalpha leads to peroxisome proliferation in rodents and increased beta-oxidation of fatty acids. PPARgamma-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both of these PPAR receptors are potential targets for treatment of dyslipidemia in man. Studies by others using a proteomics approach have characterized the effects of PPARalpha agonists in livers from lean healthy mice. However, we wanted to map the effects of a therapeutic dose of a PPARalpha agonist in a disease model of insulin resistance and diabetes, the obese diabetic ob/ob mouse, by proteomics. Therefore, ob/ob mice, which have highly elevated levels of plasma triglycerides, glucose and insulin, were treated for one week with WY14,643 (180 micromol/kg/day), a well-characterized selective PPARalpha agonist. Plasma triglycerides, glucose and insulin levels were determined and we found significant therapeutic effects on triglycerides and glucose levels. The liver protein compositions were investigated by high-resolution two-dimensional gel electrophoresis which showed that WY14,643 produced up-regulation of at least 16 spots. These were identified by mass spectrometry and 14 spots were found to be components of the peroxisomal fatty acid metabolism. Thus, WY14,643 at a therapeutic dose, caused induction of peroxisomal fatty acid beta-oxidation in obese diabetic mice.
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PMID:A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome proliferator WY14,643. 1034 69

Transcriptional activation of the hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene at birth is critical since PEPCK appearance initiates hepatic gluconeogenesis. A delayed appearance results in hypoglycemia, while a premature appearance results in neonatal diabetes, both are incompatible with sustaining life. Experiments using transgenic mice and transfected hepatoma cells suggest that both repression and activation underlie the correct onset of hepatic PEPCK gene transcription. In transgenic mice, transgenes driven by the proximal PEPCK promoter are prematurely expressed in the fetal liver and over-expressed in the neonatal liver, indicating that sequences upstream of the proximal promoter restrain perinatal expression. In Hepa1c1c7 cells, which mimic the fetal liver, the proximal PEPCK promoter (597 bp) exhibited a 3. 5-10-fold higher activity than longer promoters. Repression of the longer promoter (2000 bp) was diminished upon deletion of the sequence spanning positions(-840) to(- 1116) which contains a PPAR/RXR recognition element. The intact 2000 bp PEPCK promoter could be markedly activated by co-transfecting the transcription factor HNF-1 together with C/EBP. It could be repressed by co-transfection with RXRalpha and adding PPARalpha relieved this inhibition.
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PMID:Repression and activation of transcription of phosphoenolpyruvate carboxykinase gene during liver development. 1047 25

The metabolic capacity of skeletal muscle plays a significant role for insulin sensitivity and the blood lipid profile. The metabolic capacity of the muscle is a function of the individual's physical activity level. This is also true for the content of type IIx muscle fibres, which is reduced and the number of capillaries, which is elevated with muscle usage. Several of these skeletal muscle features are risk factors for or linked with life style-induced diseases such as type II diabetes, hypertension, hyperlipidaemia and obesity. This central role of the skeletal muscle and its functional metabolic capacity for life style diseases highlights the importance of people maintaining daily physical activity. This article focuses on the link between the metabolic capacity of skeletal muscle and the metabolic syndrome and briefly discusses possible metabolic explanations for this relationship. An important aspect is that when skeletal muscle has a high capacity for lipid oxidation more saturated fatty acids are oxidized and more unsaturated fatty acids are built into the phospholipid fraction of the plasma membrane, giving it more fluidity and improved insulin sensitivity. Moreover, the article points at the role of these fatty acids in activating genes via the PPAR-receptor system essential for enzyme and transport proteins in the lipid metabolism.
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PMID:[Metabolic capacity of skeletal muscles and health]. 1077 58


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