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)

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

The discovery of peroxisome proliferator-activated receptor gamma (PPARgamma) as the molecular target for antidiabetic thiazolidinediones has heralded a new era in the approach to understanding the pathophysiology of insulin resistance and its relationship to cardiovascular disease. However, the subsequent discovery of PPARgamma-dependent modulation of immune function and the cell cycle has led to a new paradigm in the approach to treating proliferative, inflammatory diseases. Moreover, PPARgamma agonists can promote apoptosis, block angiogenesis and inhibit pathological remodelling in a variety of malignant and non-malignant pathological states. These findings imply that the pharmacological modulation of this key nuclear transcription factor and its co-factors could be important tools in understanding the relationships between multigenic diseases, and pave the way to a focused interventional approach in their treatment. With the availability of the PPARgamma protein crystal structure, the ligand binding domain co-ordinates and a better knowledge of the interaction of PPARgamma with co-factor assemblies, libraries of simple synthetic organic PPARgamma ligands can be constructed. High throughput screening can identify the best candidates for targeting cellular phenotypic transition, cell cycle control, inflammation and apoptosis. Instead of single agents for single pathologies, one can envisage the development of multifunctional therapeutic agents that target the multiple cellular processes that contribute to multifactorial diseases such as diabetes, hypertension, atherosclerosis, psoriasis and other inflammatory diseases, and carcinogenesis. The considerable potential of PPARgamma ligands in the treatment of diseases other than diabetes is the subject of this review.
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PMID:Pharmacological peroxisome proliferator-activated receptorgamma ligands: emerging clinical indications beyond diabetes. 1113 30

Thiazolidinediones (TZD) improve insulin sensitivity in human as well as in different animal models of insulin resistance and Type 2 diabetes. However, no clear link to the insulin signaling events has been identified. Using differentiated 3T3-L1 adipocytes, we found that TZD rapidly and markedly increased IRS-2 gene expression. This effect was specific for PPARgamma agonists and was not seen with PPARalpha agonists. It was rapidly induced (within 4 h) and maintained throughout the observation period of 48 h. It was also concentration dependent (EC50 approximately 50 nM) and not inhibited by cycloheximide, suggesting a direct effect on the IRS-2 promoter. There was no evidence that TZD altered IRS-2 mRNA stability, supporting that the increased mRNA levels were due to an increased gene transcription. IRS-2 protein expression was increased approximately 30% after 48 h and approximately 50% after 96 h. No effects of TZD were seen on IRS-1, PKB/Akt, or GLUT4 gene expression. TZD also increased IRS-2 mRNA levels in cultured human adipose tissue. These data show the first direct link between TZD and a critical molecule in insulin's signaling cascade in both 3T3-L1 and human adipocytes, and indicate a novel mode of action of these compounds.
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PMID:Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes. 1114 9

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor gamma(2) (PPAR gamma) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family-based association. When these 6 traits were included in a multivariate analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1--2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.
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PMID:Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. 1115 5

Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, an important modulator of fatty acid oxidation. We hypothesized that increased fatty acid availability would increase the expression and activity of heart and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced diabetes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal muscle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-activated receptor-alpha (PPARalpha). Specific PPARalpha stimulation, through Wy-14643 treatment, significantly increased the expression of MCD in heart and skeletal muscle. Troglitazone, a specific PPARgamma agonist, decreased MCD expression. The sensitivity of MCD induction by fatty acids and Wy-14643 was soleus > extensor digitorum longus > heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-induced cardiac hypertrophy, in which PPARalpha expression is decreased (and fatty acid oxidation is decreased), resulted in decreased MCD mRNA and activity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.
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PMID:Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids. 1117 2

Thiazolidinediones (TZDs) are a new class of compounds that improve the insulin sensitivity in patients with non-insulin-dependent diabetes mellitus (NIDDM) as well as in rodent models of NIDDM. These compounds act as high-affinity ligands for a member of the nuclear hormone receptor superfamily PPARgamma, which has been shown to play an important role in adipocyte differentiation. The strong correlation between the antidiabetic activity of TZDs and their ability to activate PPARgamma has led to suggestions that PPARgamma or downstream regulated genes mediate the effects of TZDs. To identify novel genes that potentially mediate the effects of TZDs, we have isolated genes that are differentially expressed during thiazolidinedione-stimulated differentiation of 3T3-L1 cells. Using mRNA differential display, we have compared 3T3-L1 cells treated to differentiate in the presence of BRL49653 with untreated 3T3-L1 cells and identified Fos-related antigen 1 (Fra-1), a member of the Fos protein family, as a novel molecular target for BRL49653 action in 3T3-L1 cells. Analysis of all members of the Fos-Jun family of transcription factors showed that Fra-1 was the only member that was specifically up-regulated by BRL49653. The only other member of the Fos-Jun family expressed in differentiated 3T3-L1 cells was JunD and a complex of Fra-1 and JunD was formed on a consensus AP-1 binding element in differentiated 3T3-L1 cells, suggesting that the complex of Fra-1 and JunD may play a role in the stimulation of the differentiation process of 3T3-L1 cells observed after treatment of the cells with insulin sensitizers.
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PMID:The transcription factor Fos-related antigen 1 is induced by thiazolidinediones during differentiation of 3T3-L1 cells. 1117 52

Coronary heart disease (CHD), whose primary aetiology is atherosclerosis, is the leading cause of mortality and a major cause of morbidity in the industrialised world [1]. Serum lipoprotein levels are aetiologically related to the risk of atherosclerosis and CHD [2]. The liver and the gastrointestinal system are the major protagonists involved in regulation of lipoprotein biochemical-physiological mechanisms and the development of hypercholesterolaemia. Furthermore, specific lipoprotein receptors are being discovered as targets for pharmacological intervention to correct lipoprotein disorders. Agents that target lipoprotein regulation in the liver, gastrointestinal-biliary and atherosclerotic tissues resulting in improved serum lipoprotein levels and/or control of primary and secondary dyslipidaemic disorders including diabetes, are currently undergoing clinical trials. The most novel promising compounds, after the greatly effective newest HMG-CoA reductase inhibitors, are drugs that affect peroxisome proliferator-activated receptors, PPARalpha and PPARgamma receptors, bile acid transport mechanisms, cholesterol absorption and cholesterol acyltransferase and other biochemical targets of lipoprotein regulation. Current knowledge and ongoing trials with these agents are described here within the boundaries of investigator confidentiality agreements.
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PMID:New pharmacological agents under clinical investigation for treating disorders of lipoprotein regulation leading to atherosclerosis. 1122 51

The peroxisome proliferator-activated receptor gamma (PPARgamma) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARgamma in obesity and diabetes.
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PMID:Peroxisome proliferator-activated receptor gamma, the ultimate liaison between fat and transcription. 1124 74

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agouti expression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-gamma protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-gamma.
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PMID:Agouti regulates adipocyte transcription factors. 1124 12

The preferential channeling of different fuels to fat and changes in the transcription profile of adipose tissue and skeletal muscle are poorly understood processes involved in the pathogenesis of obesity and insulin resistance. Carbohydrate and lipid metabolism may play relevant roles in this context. Freely moving lean Zucker rats received 3- and 24-h infusions of Intralipid (Pharmacia and Upjohn, Milan, Italy) plus heparin, or saline plus heparin, to evaluate how an increase in free fatty acids (nonesterified fatty acid [NEFA]) modulates fat tissue and skeletal muscle gene expression and thus influences fuel partitioning. Glucose uptake was determined in various tissues at the end of the infusion period by means of the 2-deoxy-[1-3H]-D-glucose technique after a euglycemic-hyperinsulinemic clamp: high NEFA levels markedly decreased insulin-mediated glucose uptake in red fiber-type muscles but enhanced glucose utilization in visceral fat. Using reverse transcriptase-polymerase chain reaction and Northern blotting analyses, the mRNA expression of fatty acid translocase (FAT)/CD36, GLUT4, tumor necrosis factor (TNF)-alpha, peroxisome proliferator-activated receptor (PPAR)-gamma, leptin, uncoupling protein (UCP)-2, and UCP-3 was investigated in different fat depots and skeletal muscles before and after the study infusions. GLUT4 mRNA levels significantly decreased (by approximately 25%) in red fiber-type muscle (soleus) and increased (by approximately 45%) in visceral adipose tissue. Furthermore, there were marked increases in FAT/CD36, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 mRNA levels in the visceral fat and muscle of the treated animals in comparison with those measured in the saline-treated animals. These data suggest that the in vivo gene expression of FAT/CD36, GLUT4, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 in visceral fat and red fiber-type muscle are differently regulated by circulating lipids and that selective insulin resistance seems to favor, at least in part, a prevention of fat accumulation in tissues not primarily destined for fat storage, thus contributing to increased adiposity and the development of a prediabetic syndrome.
Diabetes 2001 Mar
PMID:Preferential channeling of energy fuels toward fat rather than muscle during high free fatty acid availability in rats. 1124 80


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