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)

Peroxisome proliferator activated receptor (PPAR) gamma is present in two isoforms generated by alternative splicing, PPAR gamma 1 and PPAR gamma 2. A Pro12Ala polymorphism in human PPAR gamma 2 moderately reduces its transcriptional activity, and thus PPAR gamma 2 is thought to be a promising candidate gene for several human disorders, including obesity and type 2 diabetes mellitus. In this report, we examined the polymorphism of the PPAR gamma 2 gene in people at high and low altitudes in Bolivia, and found a significant difference in the frequency of Ala carriers (Pro/Ala and Ala/Ala) between 153 native high-altitude Bolivian subjects (64.1%) and 288 low-altitude Bolivian subjects (37.9%). The frequency of this Ala allele in Bolivian subjects was fairly higher than that in other ethnic groups. As body mass index, however, was not associated with Pro12Ala polymorphism of the PPAR gamma 2 gene among either the high altitude Bolivians or low altitude Bolivians, Pro12Ala polymorphism of the gene has little relationship to obesity in Bolivians.
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PMID:The difference of mutation in the peroxisome proliferator activated receptor gamma2 gene among people at high altitudes and low altitudes in Bolivia. 1618 May 11

Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are insulin sensitizers, whereas PPAR alpha agonists are lipid-lowering agents in humans. Chronic treatment with PPAR gamma agonists has been shown to prevent the onset of diabetes in young Zucker diabetic fatty (ZDF) rats; however, the effects of PPAR alpha agonists have not been well characterized in this model. Here we investigated chronic efficacy of PPAR alpha and nonthiazolidinedione (nTZD) PPAR gamma agonists on the onset of diabetes in 6-wk-old male ZDF rats. Whereas treatment with the nTZD PPAR gamma agonist completely prevented development of hyperglycemia, PPAR alpha activation was associated with lowering of food intake and body weight and reductions in fed and fasting hyperglycemia, with prevention of the hyperinsulinemic peak preceding the development of hyperglycemia in ZDF rats. Both compounds improved glucose tolerance during an oral glucose tolerance test with concomitant increases in insulin response. Such improvements of insulin secretion were associated with increased islet to total pancreatic area ratio and pancreatic insulin contents. Hyperinsulinemic-euglycemic clamp studies demonstrated that nTZD PPAR gamma reduced basal endogenous glucose production and increased insulin-stimulated glucose disposal, consistent with an improved insulin action as a cause of the improved glucose homeostasis. In contrast, activation of PPAR alpha did not significantly improve glucose metabolism during the hyperinsulinemic-euglycemic clamp. In conclusion, chronic treatment of ZDF rats with a PPAR gamma agonist completely prevented the onset of diabetes by improving both insulin action and secretion, whereas PPAR alpha agonism was partially effective, primarily by improving the pancreatic islet insulin response. Unlike the PPAR gamma agonist, the PPAR alpha agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPAR alpha agonists in the prevention of type 2 diabetes mellitus.
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PMID:Peroxisome proliferator-activated receptor (PPAR)-alpha agonism prevents the onset of type 2 diabetes in Zucker diabetic fatty rats: A comparison with PPAR gamma agonism. 1672 96

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, and when activated by their ligands, they induce perixosome proliferation. Three receptors have been identified: PPAR gamma, PPAR delta, and PPAR alpha, all with different tissue expression. PPAR gamma is predominantly expressed in adipose tissue and regulates the formation of fat cells and their function. The effect of PPAR gamma activation is to enhance the action of insulin in insulin-sensitive tissue by increasing peripheral glucose disposal and decreasing hepatic glucose production. The thiazolidinediones (TZDs) are a class of medications used for treatment and possibly the prevention of type 2 diabetes, which are potent agonists for the PPAR gamma receptor. Because the thiazolidinediones target insulin resistance, these agents may improve many of the risk factors associated with obesity and insulin resistance including dyslipidemia, hypertension, impaired fibrinolysis, and atherosclerosis. The impact of the thiazolidinediones on cardiovascular mortality is currently unclear but it appears that the thiazolidinediones exert numerous non-glycemic effects that may improve cardiovascular outcomes. Several non-TZD PPAR gamma agonists and combined PPAR gamma/alpha effect on cardiovascular disease are also being evaluated. These drugs have anti-inflammatory and vascular properties and are currently the subject of numerous studies targeting the primary and secondary prevention of macrovascular disease in patients with diabetes and insulin resistance and might be developed as anti-atherogenic agents on the basis of their actions.
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PMID:Effects of PPAR gamma agonists on cardiovascular function in obese, non-diabetic patients. 1677 91

Activation of the PPAR gamma 2 gene (PPARG2) improves the action of insulin and its lipid metabolism. We examined the association between Pro12Ala polymorphism of PPARG2, type 2 diabetes mellitus (DM2), and peripheral insulin sensitivity in a population with a high intake of oleic acid. A cross-sectional, population-based study was undertaken in Pizarra, a small town in the province of Malaga in southern Spain. A total of 538 subjects, aged 18-65 y, were selected randomly from the municipal census. All subjects underwent a clinical, anthropometrical, and biochemical evaluation, including an oral glucose tolerance test and Pro12Ala polymorphism of PPARG2. Insulin resistance was measured by homeostasis model assessment. Those subjects with the Ala-12 allele had an odds ratio for impaired fasting glucose of 0.55, for impaired glucose tolerance of 0.59, and for DM2 of 0.30. The intake of monounsaturated fatty acids (MUFA) contributed to the variance of the homeostasis model assessment insulin resistance index (HOMA IR) (P = 0.04), with a 2-way interaction between the Ala-12 allele of PPARG2 and the intake of MUFA (P = 0.005). The results suggest the existence of an interaction between Pro12Ala polymorphism of PPARG2 and dietary MUFA, such that obese people with the Ala-12 allele have higher HOMA IR values, especially if their intake of MUFA is low.
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PMID:Pro12Ala polymorphism of the PPARG2 gene is associated with type 2 diabetes mellitus and peripheral insulin sensitivity in a population with a high intake of oleic acid. 1692 Aug 49

Agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) are a new class of oral drugs designed to treat insulin-resistant diabetes (i.e., type 2 diabetes). However, troglitazone, the first compound in the class approved by the US Food and Drug Administration (FDA) in 1997 was found to be hepatotoxic and was withdrawn from the market after reports of severe liver failure. The mechanism of PPAR gamma agonist-induced hepatotoxicity remains unknown. In this study, we examined the hepatotoxic effects of five PPAR gamma agonists (ciglitazone, pioglitazone, rosiglitazone, troglitazone, and JTT-501) on rat primary hepatocytes and human HepG2 cells. We also compared the gene expression profiles of rat primary hepatocytes after exposure to PPAR gamma agonists by using the Rat Genome Survey Microarray system from Applied Biosystems in order to understand the mechanisms of hepatotoxicities induced by PPARgamma agonists. Consistent with the hepatotoxicity data, our results demonstrate that the gene expression profiles affected by troglitazone and ciglitazone can be clearly distinguished from those by pioglitazone and rosiglitazone. Genes that are differentially expressed between the more toxic troglitazone/ciglitazone group and the less toxic rosiglitazone/pioglitazone group are involved in necrotic, apoptotic, and cell proliferative pathways. The five compounds were also clustered based on a set of molecular descriptors. The clustering based on chemical structural information is in good agreement with the clustering of compounds based on cytotoxicity or gene expression data, indicating a strong relationship between chemical structure and biological endpoints. Our work suggests that microarray analysis together with toxicological observations can be used to rank drugs for hepatotoxicity and to evaluate the safety of new compounds.
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PMID:Differences in hepatotoxicity and gene expression profiles by anti-diabetic PPAR gamma agonists on rat primary hepatocytes and human HepG2 cells. 1703 37

Monocytes and macrophages play a key role in the progression of atheromatous changes. The peroxisome proliferator-activated receptor gamma (PPAR gamma) can limit macroangiopathy through the control of cytokine transcription. The objectives of this study were to examine the influence of PPAR gamma and its agonist (rosiglitazone) on the TNFalpha, IL-6, IL-8 and IL-10 gene expression in monocytes of patients with diabetic macroangiopathy and to analyse obtained results in context of selected atherogenic factors ant direct indicators of endothelial lesion. TNFalpha, IL-6, IL-8, IL-10 and PPAR gamma gene expression was assessed in peripheral blood monocytes in 45 patients with type 2 diabetes before and following 22 weeks of rosiglitazone therapy (real-time PCR [Applied Biosystems]). As indicators of endothelial lesion, concentration of thrombomodulin (immunoassay [Diagnostica Stago]) and amount of circulating blood endothelial cells (immunofluorescence method with MoAb CLB-HEC19) were determined. Following rosiglitazone therapy, a statistically significant downward tendency of TNFalpha (p=0.026) and IL-8 (p=0.008) gene expression was noted. Before and following rosiglitazone treatment, PPAR gamma, IL-6 and IL-10 gene expression was undetectable in studied monocytes in vivo. In conclusion, TNFalpha and IL-8 play an important role in monocyte atherogenic activity. Rosiglitazone reduces monocyte proinflammatory readiness by influencing the expression of selected atherogenic cytokines (PPAR gamma-independent pathway).
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PMID:Stimulation of the peroxisome proliferator-activated receptor gamma (PPAR gamma) and the expression of selected blood monocyte cytokine genes in diabetic macroangiopathy. 1714 Dec 46

Genes play an important role in the development of diabetes mellitus. Type 2 diabetes is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility. Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce the disorder. Only a minority of cases of type 2 diabetes are caused by single gene defects and one example is maturity onset diabetes of the young (MODY). Till date knowledge of the genetics of type 2 diabetes is limited. Consistent with the complex web of physiologic defects in type 2 diabetes, the genetics of the disorder involves a large number of susceptibility genes, each with a relatively small effect. In this article, the studies on genetics of diabetes in Asian Indians are reviewed. As Asian Indians have an increased susceptibility to diabetes and have increased insulin resistance, they are a unique population for carrying out genetic studies. There appears to be certain genes which predispose Indians to diabetes while other genes (for example Pro 12 Ala polymorphism of PPAR gamma gene) which afford protection against diabetes and insulin resistance to Caucasians, do not appear to protect Indians. Further studies are needed to unravel the genetics of diabetes in South Asians .
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PMID:Genetic predisposition to type 2 diabetes among Asian Indians. 1749 55

Insulin resistance is a common finding in diabetes mellitus, and may serve as a measure of efficacy of therapies for diabetes mellitus: exercise, exogenous insulin, sulfonylureas, and PPAR gamma agonists, and as a possible marker for risk for developing type II diabetes mellitus. The purpose of our study was to compare one measure of insulin resistance, the QUICKI method, which is a calculation of the inverse of the sum of the log of fasting serum glucose plus the log of fasting insulin level, with the observational measure of fasting serum insulin levels. We studied 79 African-American and Caribbean Black patients in an inner-city hospital-based internal medicine practice, 37 of them with type 2 diabetes mellitus and 42 controls. We found that most controls fell within manufacturers proposed reference range for fasting insulin levels. However, about 5% were appreciably above the range, suggesting insulin resistance, despite euglycemia. Among our diabetics there were two subpopulations: those with elevated fasting insulin levels and those with normal or deficient insulin levels. Only about 30% had elevated fasting insulin levels; however, by the QUICKI method, 54% showed insulin resistance. These findings suggest that QUICKI might be more sensitive measure of insulin resistance, while elevated fasting insulin levels may be more specific.
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PMID:Fasting insulin levels as a measure of insulin resistance in American blacks. 1768 9

Peroxisome proliferators-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR gamma 2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro12Ala polymorphism of PPAR gamma 2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case-control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro12Ala polymorphism in PPAR gamma 2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro12Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P < 0.001). In this study, no association is seen between the Pro12Ala polymorphism in PPAR gamma 2 gene and the type 2 diabetes in Qatar.
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PMID:Lack of association between the Pro12Ala polymorphism of the PPAR-gamma 2 gene and type 2 diabetes mellitus in the Qatari consanguineous population. 1780 73

Dyslipidemia and intramuscular accumulation of fatty acid metabolites are increasingly recognized as core features of obesity and type 2 diabetes. Emerging evidence suggests that normal physiological adaptations to a heavy lipid load depend on the coordinated actions of broad transcriptional regulators such as the peroxisome proliferator activated receptors (PPARs) and PPAR gamma coactivator 1 alpha (PGC1 alpha). The application of transcriptomics and targeted metabolic profiling tools based on mass spectrometry has led to our finding that lipid-induced insulin resistance is a condition in which upregulation of PPAR-targeted genes and high rates of beta-oxidation are not supported by a commensurate upregulation of tricarboxylic acid (TCA) cycle activity. In contrast, exercise training enhances mitochondrial performance, favoring tighter coupling between beta-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high-fat diet. The exercise-activated transcriptional coactivator, PGC1 alpha, plays a key role in coordinating metabolic flux through these 2 intersecting metabolic pathways, and its suppression by overfeeding may contribute to diet-induced mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from a mitochondrial disconnect between beta-oxidation and TCA cycle activity. Understanding of this "disconnect" and its molecular basis may lead to new therapeutic approaches to combatting metabolic disease.
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PMID:Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease. 1805 12


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