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 thiazolidinedione rosiglitazone maleate works primarily to improve insulin sensitivity in muscle and adipose tissue. It may have additional pharmacologic effects, however, as its main target is peroxisome proliferator-activated receptor-gamma. Data using the homeostasis model assessment and proinsulin:insulin ratio in patients with type 2 diabetes mellitus suggest that rosiglitazone may have the potential to sustain or improve beta-cell function. In these patients the drug reduces fasting plasma glucose, glycosylated hemoglobin, insulin, and C-peptide. In clinical trials, rosiglitazone monotherapy significantly reduced glycosylated hemoglobin by 1.5% compared with placebo and led to significant improvements in glycemic control when given in combination with metformin, sulfonylureas, or insulin. A dosage of 4 mg twice/day significantly reduced fasting plasma glucose levels and produced comparable reductions in glycosylated hemoglobin compared with glyburide. Rosiglitazone has a low risk of gastrointestinal side effects and hypoglycemia, reduced insulin demand, potential sparing effects on beta-cells, and favorable drug interaction profile. Adverse events of clinical significance are edema, anemia, and weight gain. Premarketing data indicate no significant difference in liver enzyme elevations for rosiglitazone, placebo, or active controls. Another drug in the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity and was removed from the market. Therefore, until long-term data are available for rosiglitazone, liver enzyme monitoring is recommended.
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PMID:A review of rosiglitazone in type 2 diabetes mellitus. 1156 Jan 98

Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance.
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PMID:Insulin resistance and insulin sensitizers. 1168 68

Great advances have been made in the management of diabetes during the past decade. Whereas only one class of oral medications (the sulfonylureas) was available for the treatment of type 2 diabetes in the early 1990s, we now have five classes of oral antidiabetic agents from which to choose. The thiazolidinedione class of medications was first introduced to the United States when troglitazone was marketed during early 1997. Rosiglitazone, approved by the FDA during the spring of 1999, was the second thiazolidinedione to be marketed in the United States. Similar to troglitazone, rosiglitazone improves insulin sensitivity in patients with type 2 diabetes by activating peroxisome proliferator-activated receptor-gamma (PPARgamma) receptors in adipose tissues, skeletal muscles, and the liver. The efficacy and safety of rosiglitazone therapy in patients with type 2 diabetes have been demonstrated in a number of clinical studies, which are summarized in this article. Selected characteristics of rosiglitazone are compared with those of pioglitazone--the other thiazolidinedione currently available in the United States. Edema of mild to moderate severity has been reported in approximately 5% of patients treated with rosiglitazone during clinical trials. Therefore, caution must be taken when this agent is administered to patients with heart failure. Rosiglitazone has also been associated with elevations of total, LDL, and HDL cholesterol during clinical trials. However, the LDL:HDL cholesterol ratio or the total:HDL cholesterol ratio has mostly been observed to be unchanged. Although liver toxicity has not been observed with rosiglitazone during clinical trials, the safety of this drug for long-term usage and in larger patient populations remains to be established in further clinical studies and in postmarketing experience.
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PMID:Rosiglitazone: an agent from the thiazolidinedione class for the treatment of type 2 diabetes. 1172 76

Troglitazone is a peroxisome proliferator-activated receptor-gamma agonist that has been shown to halt mesangium expansion in experimental models of type 2 diabetes mellitus and to act directly on rat mesangial cells. Because glutamine serves as the precursor for cellular biosynthetic processes, we asked whether troglitazone would inhibit mesangial cell glutamine metabolism under these conditions. Confluent monolayers of rat mesangial cells were incubated in RPMI medium in the presence of troglitazone or vehicle (DMSO). Troglitazone effected a dose-dependent reduction in glutamine utilization and in alanine formation, associated with a decrease in monolayer collagen-glycosaminoglycan content. Despite the reduced glutamine uptake, ammonium formation did not decrease, consistent with increased glutamate flux through the deamination pathway. Assayable activity of the alanine aminotransferase decreased by 63%, whereas assayable glutamate dehydrogenase remained unchanged. In control monolayers, the sum of ammonium plus alanine plus glutamate nitrogen released accounted for <75% of the glutamine nitrogen uptake. In troglitazone-treated monolayers, all of the glutamine nitrogen taken up could be accounted for as ammonium nitrogen released into the medium. These results are consonant with troglitazone reducing glutamine metabolism and specifically the transamination pathway in rat mesangial cells associated with a reduction in collagen-glycosaminoglycan content.
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PMID:Troglitazone inhibits glutamine metabolism in rat mesangial cells. 1173 5

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are used as cancer chemopreventative agents, their mechanism is unclear because NSAIDs have cyclooxygenase-independent actions. We investigated an alternative target for NSAIDs, peroxisome proliferator-activated receptor-gamma (PPARgamma), activation of which decreases cancer cell proliferation. NSAIDs have been shown to activate this receptor, but only at high concentrations. Here, we have examined binding of diclofenac to PPARgamma using a cis-parinaric acid displacement assay and studied the effect of diclofenac effect on PPARgamma trans-activation in a COS-1 cell reporter assay. Unexpectedly, diclofenac bound PPARgamma at therapeutic concentrations (K(i) = 700 nM) but induced only 2-fold activation of PPARgamma at a concentration of 25 microM and antagonized PPARgamma trans-activation by rosiglitazone. This antagonism was overcome with increasing rosiglitazone concentrations, indicating that diclofenac is a partial agonist. No effect of diclofenac was seen without exogenous receptor, confirming that it was working through a PPARgamma-specific mechanism. This is the first description of an NSAID that can antagonize PPARgamma. In addition, this is the first time that an NSAID has been shown to bind this receptor at clinically meaningful concentrations. The physiological relevance of these findings was tested using adipocyte differentiation and cancer cell proliferation assays. Diclofenac decreased PPARgamma-mediated adipose cell differentiation by 60% and inhibited the action of rosiglitazone on the prostate cancer cell line, DU-145, allowing a 3-fold increase in proliferation. This work shows that standard doses of diclofenac may have pharmacodynamic interactions with rosiglitazone and this has therapeutic implications, both in the management of type 2 diabetes and during cancer treatment.
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PMID:Diclofenac antagonizes peroxisome proliferator-activated receptor-gamma signaling. 1175

Several genes are implicated to be the cause for diabetes, such as genes of PPAR gamma (peroxisome proliferator-activated receptor-gamma), adiponectin, beta 3-adrenergic receptor, etc., and their polymorphisms may have significant impact on the treatment and prevention of diabetes. Detection and analysis of such susceptibility genes will provide an enormous benefit for the future tailor-made medicine of diabetes, which include choosing the most effective treatment policy for each individual and developing novel drugs based on the genetic information that are applicable for corresponding individuals. Tailor-made medicine will be an efficient tool for treatment and prevention of lifestyle diseases, especially type 2 diabetes, along with further identification of its disease-causing genes.
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PMID:[Tailor-made medicine for diabetes]. 1180 26

The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene is associated with a reduced risk of type 2 diabetes. A beneficial effect on insulin sensitivity is reported in some but not all populations. It is possible that this genetic variant produces a characteristic phenotype only against a certain genetic background. We therefore tested the hypothesis that carriers of the Ala allele of PPARgamma2 exhibit a different phenotype against the background of the Gly972Arg polymorphism in the insulin receptor substrate (IRS) 1. We determined insulin sensitivity in the four combinations defined by the absence or presence of the polymorphic allele (healthy, glucose tolerant subjects), by the oral glucose tolerance test (OGTT; using a validated index, n=318) and hyperinsulinemic clamp ( n=201). Insulin sensitivity was not or was only marginally different between Pro/Pro and X/Ala in the overall population. Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARgamma2) + X/Arg (IRS-1) than in Pro/Pro (PPARgamma2) + X/Arg (IRS-1). On the other hand, insulin sensitivity was similar in the X/Ala (PPARgamma2) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARgamma2) + Gly/Gly (IRS-1). The results were practically identical using insulin sensitivity from the clamp. In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARgamma) which was not present in the whole population or against the Gly972 (IRS-1) background. This suggests that the Ala allele of PPARgamma2 becomes particularly advantageous against the background of an additional, possibly disadvantageous genetic polymorphism. Allowing for gene-gene interaction effects may reveal novel information regarding metabolic effects of genetic variants.
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PMID:Interaction effect between common polymorphisms in PPARgamma2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity. 1212 1

Troglitazone, rosiglitazone and pioglitazone are members of the thiazolidinedione (TZD) class - antidiabetic agents that have proven efficacy in the treatment of patients with type 2 diabetes. All three agents are believed to mediate their effects via activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma). Despite this common mechanism of action, they all have unique chemical structures and receptor-binding affinities, and consequently, in addition to the class effects (probably mediated through PPAR gamma), each TZD has a unique safety profile. Side effects have been categorized as unique to individual TZDs, or common to the class of drug. Of the unique effects, the best characterized is hepatotoxicity, which has been associated specifically with troglitazone to date. Studies with rosiglitazone and pioglitazone indicate that hepatotoxicity is not a class effect. Further differences in the safety profiles of these agents arise because the oxidative metabolism for each agent occurs by distinct cytochrome pathways: troglitazone and pioglitazone involve CYP 3A4 and CYP 2C8 whereas rosiglitazone is principally metabolized by CYP 2C8. CYP 3A4 is involved in the metabolism of over 150 drugs, hence the potential for drug interactions with troglitazone and pioglitazone is much greater than with rosiglitazone. Class effects include edema, slight reductions in hemoglobin and hematocrit (due to hemodilution), weight gain and alterations in plasma lipid profiles. This article considers safety data obtained from both clinical trials and clinical practice as a means of differentiating among troglitazone, rosiglitazone and pioglitazone.
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PMID:Differentiating members of the thiazolidinedione class: a focus on safety. 1192 35

The thiazolidinediones (TZDs) or 'glitazones' are a new class of oral antidiabetic drugs that improve metabolic control in patients with type 2 diabetes through the improvement of insulin sensitivity. TZDs exert their antidiabetic effects through a mechanism that involves activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPAR gamma), a nuclear receptor. TZD-induced activation of PPAR gamma alters the transcription of several genes involved in glucose and lipid metabolism and energy balance, including those that code for lipoprotein lipase, fatty acid transporter protein, adipocyte fatty acid binding protein, fatty acyl-CoA synthase, malic enzyme, glucokinase and the GLUT4 glucose transporter. TZDs reduce insulin resistance in adipose tissue, muscle and the liver. However, PPAR gamma is predominantly expressed in adipose tissue. It is possible that the effect of TZDs on insulin resistance in muscle and liver is promoted via endocrine signalling from adipocytes. Potential signalling factors include free fatty acids (FFA) (well-known mediators of insulin resistance linked to obesity) or adipocyte-derived tumour necrosis factor-alpha (TNF-alpha), which is overexpressed in obesity and insulin resistance. Although there are still many unknowns about the mechanism of action of TZDs in type 2 diabetes, it is clear that these agents have the potential to benefit the full 'insulin resistance syndrome' associated with the disease. Therefore, TZDs may also have potential benefits on the secondary complications of type 2 diabetes, such as cardiovascular disease.
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PMID:The mode of action of thiazolidinediones. 1192 33

Phytanic acid, a metabolite of the chlorophyll molecule, is part of the human diet and is present in normal human serum at low micromolar concentrations. It was previously shown to be a ligand of the 9-cis-retinoic acid receptor and peroxisome proliferator-activated receptor (PPAR) a. PPAR agonists are widely used in the treatment of type 2 diabetes. Here, we report that phytanic acid is not only a transactivator of PPARa, but it also acts via PPARb and PPARg in CV-1 cells that have been cotransfected with the respective full-length receptor and an acyl-CoA oxidase-PPAR-responsive element-luciferase construct. We observed that, in contrast to other fatty acids, phytanic acid at physiological concentrations enhances uptake of 2-deoxy-D-glucose in rat primary hepatocytes. This result could be explained by the increase in mRNA expression of glucose transporters-1 and -2 and glucokinase, as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Compared with the PPARg-specific agonist ciglitazone, phytanic acid exerts only minor effects on the differentiation of C3H10T1/2 cells into mature adipocytes. These results clearly demonstrate that phytanic acid acts via different PPAR isoforms to modulate expression of genes involved in glucose metabolism, thus suggesting a potential role of phytanic acid in the management of insulin resistance.
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PMID:Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes. 1192 21


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