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)

Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs, acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.
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PMID:A futile metabolic cycle activated in adipocytes by antidiabetic agents. 1283 85

The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR). The transcriptional control of these metabolic circuits requires coordination between these metabolic receptors and other transcription factors and coregulators. Altered signaling by this subset of receptors, either through chronic ligand excess or genetic factors, may cause an imbalance in these homeostatic circuits and contribute to the pathogenesis of common metabolic diseases such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia and atherosclerosis, and gallbladder disease. Further studies should exploit the fact that many of these nuclear receptors are designed to respond to small molecules and turn them into therapeutic targets for the treatment of these disorders.
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PMID:Nuclear receptors and the control of metabolism. 1251 1

Thiazolidinediones (TZDs) form a new class of oral antidiabetic agents. They improve insulin sensitivity and reduce glycemia, lipidemia and insulinemia in patients with type 2 diabetes. Their mechanism is original, since they activate the nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARgamma), altering the expression of genes involved in glucose and lipid homeostasis. Stimulating PPARgamma improves insulin sensitivity via several mechanisms: 1) it raises the expression of GLUT4 glucose transporter; 2) it regulates release of adipocyte-derived signaling factors that affect insulin sensitivity in muscle, and 3) it contributes to a turn-over in adipose tissue, inducing the production of smaller, more insulin sensitive adipocytes. TZDs also affect free fatty acids (FFA) lipotoxicity on islets, improving pancreatic B-cell function. In addition, triglycerides and FFA levels are lowered by TZDs. Two TZDs, rosiglitazone and pioglitazone, have recently obtained the European commercial licence, but their use is restricted to the association with metformin or sulfonylureas. At the moment, they are indicated in type 2 diabetes but could be of interest in a broader array of diseases related to insulin resistance. As for side effects, rosiglitazone and pioglitazone may cause increased plasma volume, edema and dose-related weight gain. TZDs offer an attractive option in the treatment of type 2 diabetes, though it may be too soon to determine if they prevent vascular complications, as do other oral antidiabetic agents. An important issue for the future will be to assess the influence of weight gain in the long time.
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PMID:[Thiazolidinediones in type 2 diabetes. Role of peroxisome proliferator-activated receptor gamma (PPARgamma)]. 1252 53

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which upon activation with various natural and synthetic ligands, stimulates the transcription of genes responsible for growth and differentiation of adipocytes. Furthermore, PPAR gamma is the receptor for the insulin-sensitizing thiazolidinediones, which are commonly used for the treatment of type 2 diabetes. Rare inactivating mutations of the gene encoding PPAR gamma are associated with insulin resistance type 2 diabetes, and hypertension, whereas a rare gain of function mutation causes extreme obesity. A common polymorphism (Pro12Ala) of the adipose tissue-specific gamma 2 isoform is associated with increased insulin sensitivity and decreased risk of developing type 2 diabetes. These findings indicate a central role of PPAR gamma in fat cell biology and in the pathophysiology of obesity, diabetes, and insulin resistance.
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PMID:The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity. 1264 37

Thiazolidinediones are used to treat type 2 diabetes mellitus because they decrease plasma glucose, insulin, triglyceride, and fatty acid levels. Thiazolidinediones are agonists for peroxisome proliferator-activated receptor gamma, a nuclear receptor that is highly expressed in fat tissue. We identify glyceroneogenesis as a target of thiazolidinediones in cultured adipocytes and fat tissues of Wistar rats. The activation of glyceroneogenesis by thiazolidinediones occurs mainly in visceral fat, the same fat depot that is specifically implicated in the progression of obesity to type 2 diabetes. The increase in glyceroneogenesis is a result of the induction of its key enzyme, phosphoenolpyruvate carboxykinase, whose gene expression is peroxisome proliferator-activated receptor gamma-dependent in adipocytes. The main role of this metabolic pathway is to allow the re-esterification of fatty acids via a futile cycle in adipocytes, thus lowering fatty acid release into the plasma. The importance of such a fatty acid re-esterification process in the control of lipid homeostasis is highlighted by the existence of a second thiazolidinedione-induced pathway involving glycerol kinase. We show that glyceroneogenesis accounts for at least 75% of the whole thiazolidinedione effect. Because elevated plasma fatty acids promote insulin resistance, these results suggest that the glyceroneogenesis-dependent fatty acid-lowering effect of thiazolidinediones could be an essential aspect of the antidiabetic action of these drugs.
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PMID:Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells. 1264 61

Retinoid X Receptors (RXRs) consist of a family of nuclear receptors that target and regulate multiple signalling pathways. The early evolutionary emergence of RXRs in comparison to other nuclear receptors may have allowed for the development of unique properties as transcriptional regulators. Indeed, the complexity of these receptors is derived from their ability to activate transcription as homodimers or as obligate heterodimeric partners of a multitude of other nuclear receptors. In addition, RXRs can regulate gene expression in a ligand-dependent (forming permissive heterodimeric complexes) or - independent (forming non-permissive heterodimeric complexes) manner. Given that ligand binding is a critical component of RXR function, this review will focus on the ligand dependent functions of RXR. The remarkably conserved ligand binding domain of RXR is a multi-functional structure that in addition to ligand binding, serves as a homo- and heterodimeric interface, and a region to bind coactivactor and corepressor molecules. RXRs have a small ligand binding pocket and therefore bind their ligands (such as 9-cis RA) with both high affinity and specificity. In the presence of ligand, permissive RXR heterodimers bind coactivators, but nonpermissive complexes can bind coactivators or corepressors depending on the activation of the RXR's heterodimeric partner. Physiologically, the temporal and tissue specific pattern of RXRs as well as the presence of phenotypic abnormalities in receptor knockout studies (most severe in RXRa -/- animals) demonstrate the important role for these receptors both during development (morphogenesis) and in adult differentiated tissues (cell proliferation, cell differentiation, cell death). These receptors also play an important regulatory role metabolic signaling pathways (glucose, fatty acid and cholesterol metabolism), including metabolic disorders such as type 2 diabetes, hyperlipidemia and atherosclerosis. RXRs function as master regulators producing diverse physiological effects through the activation of multiple nuclear receptor complexes. RXRs represent important targets for pharmacologic interventions and therapeutic applications.
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PMID:The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death. 1275 20

By the end of this decade, it has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus. This epidemic of predominantly type 2 diabetes has largely been mediated by our shift toward a more sedentary lifestyle predisposing to obesity and insulin resistance. Affected individuals can also exhibit an array of associated undesirable traits such as hypertension, dyslipidemia, and hypercoagulability, leading to morbidity and mortality from atherosclerotic vascular disease. The coexistence of several of these traits with insulin resistance constitutes the metabolic syndrome. Accordingly, improving insulin sensitivity in this group, and thereby potentially ameliorating the excess vascular risk, is a primary goal of treatment. Recent interest has focused on the thiazolidinediones, a novel class of antidiabetic agents, which act as insulin sensitizers and, therefore, potentially target the underlying metabolic disturbance. These agents are high-affinity ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma, and a large body of in vitro and in vivo data has evolved to support their increasing clinical use. Importantly, clinical and laboratory findings in human subjects harboring natural mutations and polymorphisms within the receptor have provided additional insights. Here, we focus on the consequences of inherited variation in the human peroxisome proliferator-activated receptor gamma gene, linking this receptor to disordered glucose homeostasis, adipogenesis, lipid metabolism, and blood pressure regulation. These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome.
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PMID:The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation. 1278 36

Thiazolidinediones have recently emerged as promising antidiabetic drugs. Unlike other oral antidiabetic drugs, thiazolidinediones function to ameliorate insulin resistance, a primary factor for the development of type 2 diabetes. Thiazolidinediones are ligands of the nuclear receptor, peroxisome proliferator-activated receptor-gamma, and their antidiabetic effects appear to be mediated by activation of this receptor. The two currently marketed thiazolidinediones, rosiglitazone and pioglitazone, display similar efficacies in their glucose lowering activities, but interestingly display slightly different clinical and side effect profiles. Understanding the molecular basis for these differences will help in the development of next generation thiazolidinediones that are more efficacious and safer for the treatment of type 2 diabetes.
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PMID:Thiazolidinediones in diabetes: current status and future outlook. 1280 79

Diabetes, obesity, atherosclerosis and cancer are the principal contributors to morbidity and mortality in Western society. Emerging evidence indicates that a nuclear receptor, the peroxisome proliferator-activated receptor gamma (PPARgamma), plays a role in these pathological processes. Furthermore, modulation of receptor action in these diseases may be of therapeutic value, as exemplified by the recent introduction of the thiazolidinediones, a novel class of insulin-sensitizing agent for the treatment of type 2 diabetes mellitus. The availability of such high-affinity ligands has facilitated the study of signalling pathways through which PPARgamma regulates metabolic processes; these analyses have been complemented by the study of human subjects harbouring (naturally occurring) mutations and polymorphisms within the receptor. The latter have provided unique genetic evidence for a link between PPARgamma and mammalian glucose homeostasis, lipid metabolism and regulation of fat mass. This review highlights recent studies which have advanced our understanding of the pivotal role that this receptor plays in metabolism, with particular reference to the consequences of inherited variation in the human receptor gene.
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PMID:PPARgamma and metabolism: insights from the study of human genetic variants. 1291 47

Peroxisome proliferator-activated receptors (PPARs) participate in the molecular mechanism of pathologies with altered lipid homeostasis such as type 2 diabetes or obesity. The insulin sensitizer drug, rosiglitazone, has been shown to bind and activate PPAR-gamma1 in adipocytes and PPAR-gamma2 in hepatocytes. The identification of new molecular targets associated with fatty acid oxidation and PPAR-gamma nuclear receptor regulation in insulin resistance tissues is a key research goal. In the present study, we have used a proteomic approach to identify such targets. Lean and obese C57 Bl/6J lep/lep mice were given BRL49653, rosiglitazone, 10 mg/kg diet, by dietary admixture for 7 days. Rosiglitazone normalized the impaired glucose tolerance and dyslipidemia in lep/lep mice but had no significant effect in the lean mice. Samples of liver, white and brown adipose tissue, and muscle proteins were obtained and 100 microg of proteins was arrayed by two-dimensional gel electrophoresis. Thirty-four polypeptides were differentially expressed (p < 0.05) between lep/lep and lean mice and eleven were significantly (p < 0.05) modulated by rosiglitazone treatment of the obese mice. None of the proteins was modulated by rosiglitazone treatment of the lean mice. The identity of these differentially expressed proteins was made using tandem mass spectrometric analysis and revealed components of fatty acid and carbohydrate metabolism as well as proteins with unknown function.
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PMID:Effect of rosiglitazone on the differential expression of obesity and insulin resistance associated proteins in lep/lep mice. 1292 76


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