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)

Thiazolidinediones (TZDs) are a novel class of insulin-sensitizing agents used in the treatment of NIDDM and are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The thiazolidinedione BRL 49653 has been shown to promote the differentiation of the HIB-1B brown preadipocyte cell line and to increase rat interscapular brown adipose tissue (BAT) mass. Given the importance of brown fat in the control of energy metabolism in rodents, this may represent an important therapeutic effect of this class of compound. To date, however, no studies examining the effects of TZDs on human brown fat have been reported. In the present study, we have measured uncoupling protein 1 (UCP-1) mRNA, a specific marker for BAT, in isolated adipocytes and subcultured preadipocytes prepared from different adult human adipose tissue depots. Consistent with previous studies of adult human whole adipose tissue, UCP-1 mRNA was detectable in isolated human adipocytes prepared from all depots studied with a rank order of perirenal, omental, and subcutaneous. BRL 49653 treatment of subcultured human pre-adipocytes prepared from all depots resulted in increased levels of UCP-1 mRNA, compared with those of the vehicle-treated cells. When exposed to BRL 49653 for 5 days, preadipocytes from the human perirenal depot accumulated lipid, and a proportion of cells showed clear mitochondrial staining for UCP-1 protein by confocal microscopy. Thus, cells of the brown fat lineage were detectable in all human adipose depots studied, and cultured human pre-adipocytes, particularly from the perirenal depot, showed a marked increase in UCP-1 expression in response to thiazolidinediones. Given the role of brown adipocytes in the enhancement of energy expenditure, promotion of brown fat adipogenesis by thiazolidinediones could contribute to the beneficial effects of these drugs on insulin resistance in humans.
Diabetes 1998 Jan
PMID:Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes. 942 89

Fat cell differentiation is a critical aspect of obesity and diabetes. Dietary fatty acids are converted to arachidonic acid, which serves as precursor of prostaglandins (PGs). PGJ2 derivatives function as activating ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor that is central to adipogenic determination. We report here that PGF2 alpha blocks adipogenesis through activation of mitogen-activated protein kinase, resulting in inhibitory phosphorylation of PPAR gamma. Both mitogen-activated protein kinase activation and PPAR gamma phosphorylation are required for the anti-adipogenic effects of PGF2 alpha. Thus, PG signals generated at a cell surface receptor regulate the program of gene expression required for adipogenesis by modulating the activity of a nuclear hormone receptor that is directly activated by other PG signals. The balance between PGF2 alpha and PGJ2 signaling may thus be central to the development of obesity and diabetes.
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PMID:Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor gamma. 944 16

The past several years have seen an explosive increase in our understanding of the transcriptional basis of adipose cell differentiation. In particular, a key role has been illustrated for PPAR-gamma, a member of the nuclear hormone receptor superfamily. PPAR-gamma has also been recently identified as the major functional receptor for the thiazolidinedione class of insulin-sensitizing drugs. This review examines the evidence that has implicated this transcription factor in the processes of adipogenesis and systemic insulin action. In addition, several models are discussed that may explain how a single protein can be involved in these related but distinct physiological actions. I also point out several important areas where our knowledge is incomplete and more research is needed. Finally, I discuss how advances in our understanding of nuclear receptor function, particularly the docking of cofactors in a ligand-dependent fashion, should lead to improved drugs that utilize the PPAR-gamma system for the treatment of insulin resistance.
Diabetes 1998 Apr
PMID:PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. 956 80

Peroxisome proliferator-activated receptors (PPARs) belongs to the nuclear hormone receptor superfamily. So far three different subtypes of PPAR (alpha, gamma, and delta (beta)) have been identified in amphibians, chicken, rodents and man. These receptors are transcription factors that control the beta-oxidation and transport pathways of fatty acids and adipocyte differentiation containing fatty acid synthesis under the modification of PPAR activation with CBP and its analogs. Thus, PPARs play an important role in lipid metabolism. Furthermore, altered fatty acid levels are associated with obesity, diabetes, hypertension and atherosclerosis, so PPARs may serve as molecular sensors in these metabolic disorders.
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PMID:[Lipid metabolism related nuclear receptor--the structure, function, expression and classification of peroxisome proliferation-activated receptor (PPAR)]. 970 44

Thiazolidinediones (TZDs) are an exciting new class of insulin-sensitizing drugs being used currently for the treatment of non-insulin-dependent diabetes mellitus. The molecular target of these compounds is thought to be the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is expressed predominantly in adipose tissue, yet a major site of TZD-responsive glucose disposal is skeletal muscle. Potential explanations for this paradox are discussed in this review.
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PMID:Mechanisms by which Thiazolidinediones Enhance Insulin Action. 1032 88

The nuclear hormone receptor PPAR gamma promotes adipogenesis and macrophage differentiation and is a primary pharmacological target in the treatment of type II diabetes. Here, we show that PPAR gamma gene knockout results in two independent lethal phases. Initially, PPAR gamma deficiency interferes with terminal differentiation of the trophoblast and placental vascularization, leading to severe myocardial thinning and death by E10.0. Supplementing PPAR gamma null embryos with wild-type placentas via aggregation with tetraploid embryos corrects the cardiac defect, implicating a previously unrecognized dependence of the developing heart on a functional placenta. A tetraploid-rescued mutant surviving to term exhibited another lethal combination of pathologies, including lipodystrophy and multiple hemorrhages. These findings both confirm and expand the current known spectrum of physiological functions regulated by PPAR gamma.
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PMID:PPAR gamma is required for placental, cardiac, and adipose tissue development. 1054 90

Peroxisome proliferator-activated receptors (PPARs) are a nuclear hormone receptor superfamily of ligand-activated transcription factors, and the PPARgamma subtype regulates adipocyte differentiation, lipid metabolism, and insulin sensitivity. There have been several reports on the relationship between the PPARgamma2 Pro12Ala genotype and obesity or diabetes in Caucasians. The objective of this study was to examine the relationship between this mutation and obesity or diabetes in Korean subjects. Two hundred and twenty-nine Korean subjects, including 111 obese subjects (body mass index, >25 kg/m2) were included in this study. One hundred and eleven subjects had normal glucose tolerance, 60 had impaired glucose tolerance, and 58 had diabetes mellitus. We evaluated these subjects for the Pro12Ala mutation in the PPARgamma gene using PCR-restriction fragment length polymorphism. Allele frequencies of the Pro12Ala missense mutation of PPARgamma2 were not different among Korean subjects with normal glucose tolerance (qAla = 0.045), those with impaired glucose tolerance (qAla = 0.033), and those with diabetes mellitus (qAla = 0.043; P > 0.05). Allele frequencies of PPARgamma2 Ala in obese subjects (qAla = 0.036) were not significantly different from those in nonobese subjects (qAla = 0.047). These results suggest that the Pro12Ala mutation in PPARgamma is not associated with either diabetes or obesity and may not be an important determinant of obesity or diabetes in Korean subjects.
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PMID:Significance of Pro12Ala mutation in peroxisome proliferator-activated receptor-gamma2 in Korean diabetic and obese subjects. 1084 55

Troglitazone and structurally related compounds (pioglitazone, rosiglitazone etc.) containing thiazolidinediones (TZD) are a novel class of antidiabetic agents which decrease blood glucose in diabetic animal models and in patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) through alleviating insulin resistance. A large body of evidence is now accumulating indicating that insulin resistance and/or resulting hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome called "syndrome X" or "insulin resistance syndrome" which includes hypertension, dislipidemia and hypercoagulation. Therefore, TZD class of insulin sensitizers seem to have therapeutic potential to improve this clustering syndrome in addition to diabetes. Moreover, it was demonstrated that the TZD class of insulin sensitizers including troglitazone bind and activate the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor. Although PPARgamma is predominantly expressed in adipose tissue, one of the target tissues for insulin, it have been subsequently found to be expressed in macrophages, vascular smooth muscle cells (VSMC), endothelial cells and several cancer cell lines. PPARgamma activation by PPARgamma agonists such as TZD class of insulin sensitizers in these cells modulates these cell functions such as the production of inflammatory cytokine by macrophages, proliferation and migration of VSMC, and growth or differentiation in cancer cells. In addition, troglitazone has potent antioxidant effect, and suppresses both L-type and receptor operated Ca2+ channel and protein kinase C. Thus since TZD class of insulin sensitizers has many kind of therapeutic effect in addition to lowering blood glucose, these agents expect to have therapeutic potential beyond diabetes.
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PMID:Troglitazone and related compounds: therapeutic potential beyond diabetes. 1106 64

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPARalpha plays a key role in lipid and glucose metabolism, inflammatory response and energy homeostasis. The aim of our study was to screen the PPARalpha gene for mutations, and to test the genetic contribution of PPARalpha in diabetes and its vascular complications. The first two non coding exons and the coding region of the PPARalpha gene were screened by single strand conformation polymorphism (SSCP) and sequencing in 74 unrelated Type 2 diabetic patients with history of coronary heart disease (CHD) (18 Caucasian and 56 Indian subjects). A total of 7 nucleotide variants were detected: two single amino acid substitutions, a silent mutation, four intron base changes. Association studies were undertaken in two populations of Type 2 diabetic patients from Pondichery and from France, to test the distribution of allelic frequencies for L162V (exon 5) and A268V (exon 7) polymorphisms. No association was found between these PPARalpha variants and diabetes or CHD. However, in the Caucasian diabetic male population with CHD, the Val162 allele carriers showed higher concentrations of total cholesterol and Apo B when compared to non-carriers (p =0.01 and p =0.005, respectively). A trend toward elevated concentrations of total cholesterol and Apo B was also observed in the Caucasian diabetic male patients without CHD carrying Val162 allele. In conclusion, it is likely that PPARalpha gene does not have a major role in diabetes and CHD in our populations, although we can not exclude a minor contribution of the PPARalpha gene to the risk of CHD associated with Type 2 diabetes through a modulation of atherogenic plasma lipids.
Diabetes Metab 2000 Nov
PMID:Mutation screening of the PPARalpha gene in type 2 diabetes associated with coronary heart disease. 1111 19

Rosiglitazone (Avandiatrade mark) is a new generation thiazolidinedione used in the treatment of Type 2 diabetes. As with other thiazolidinediones, it binds to the gamma-isoform of the peroxisome proliferator-activated receptor (PPAR), a nuclear hormone receptor. Subsequent to PPAR-gamma activation, rosiglitazone increases insulin suppression of hepatic glucose output and increases peripheral glucose uptake in the muscles, thereby improving the glycaemic state of the individual. In rodent models of obesity and Type 2 diabetes, rosiglitazone has been shown to have positive effects in the main target organs responsible for the condition, namely the liver, pancreas, skeletal muscle and adipose tissue. These studies also suggest that rosiglitazone may help in preserving renal and pancreatic function that deteriorates in chronic hyperinsulinaemia. In clinical studies, rosiglitazone has been shown to be effective, safe and well-tolerated, not only when used as monotherapy, but also when used in combination with sulphonylureas, metformin or insulin. Unlike troglitazone, rosiglitazone is not metabolised via CYP3A4 and is thus unlikely to be subject to clinically important drug interactions. In addition, no evidence of hepatotoxicity has been associated with rosiglitazone to date. Rosiglitazone should therefore be strongly considered as part of the overall management of Type 2 diabetes.
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PMID:Rosiglitazone: a new therapy for Type 2 diabetes. 1113 21


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