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 "thrifty" genotype and phenotype that save energy are detrimental to the health of people living in affluent societies. Individual differences in energy metabolism are caused primarily by single nucleotide polymorphisms (SNPs), some of which promote the development of obesity/type 2 diabetes mellitus. In this review, four major questions are addressed: (1) Why did regional differences in energy metabolism develop during evolution? (2) How do genes respond to starvation and affluence? (3) Which SNPs correspond to the hypothetical "thrifty genes"? (4) How can we cope with disease susceptibility caused by the "thrifty" SNPs? We examined mtDNA and genes for energy metabolism in people who live in several parts of Asia and the Pacific islands. We included 14 genes, and the SNP frequencies of PPAR gamma 2, LEPR, and UCP3-p and some other genes differ significantly between Mongoloids and Caucasoids. These differences in SNPs may have been caused by natural selection depending on the types of agriculture practiced in different regions. Interventions to counteract the adverse effects of "thrifty" SNPs have been partially effective.
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PMID:Single nucleotide polymorphisms of thrifty genes for energy metabolism: evolutionary origins and prospects for intervention to prevent obesity-related diseases. 1215 Sep 34

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. Since PPARs appear to be closely involved in the regulation of dietary fat storage and catabolism, they have been established as an important target for the treatment of type 2 diabetes and other disorders associated with the high intake of dietary fat. Thiazolidinediones (TZDs) were the first class of compounds to be identified as PPAR gamma-ligands, constituting a new class of antidiabetic drugs that have recently been introduced as therapeutic agents for the treatment of type 2 diabetes mellitus by acting as insulin sensitizers. These compounds improve insulin resistance by increasing cell sensitivity to insulin. In fact, PPAR gamma agonists increase peripheral insulin sensitivity by increasing the transcription of genes, which, in turn, increase glucose uptake, also improving insulin-stimulated glucose disposal in muscle. PPAR gamma agonists increase insulin signaling, reduce circulating levels of free fatty acids and stimulate adipocyte differentiation, thus favoring the formation of smaller, more insulin-sensitive adipocytes. TZDs have been proven effective in different experimental models to evaluate their effectiveness as an antidiabetic agent, and the involvement of PPAR gamma in the pharmacological effects of these compounds has been supported by studies showing an excellent correlation between the hypoglycemic action of these drugs and their affinity for PPAR gamma. Despite this evidence, the site of action and the molecular mechanism of TZDs remain unclear. The aim of the present article was to review and discuss the most relevant pharmacological studies performed in the search for establishing the mechanism of action of antidiabetic TZDs and related compounds acting as PPAR gamma agonists, as well as to summarize those representative experimental approaches currently used to evaluate PPAR gamma agonists as therapeutic agents for the treatment of insulin-resistant type 2 diabetes mellitus.
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PMID:Experimental approaches to study PPAR gamma agonists as antidiabetic drugs. 1250 Apr 31

Resistin is a cysteine-rich protein postulated to be a molecular link between obesity and type 2 diabetes. The aim of this study was to investigate the role of PPAR gamma in the regulation of resistin expression in human primary macrophages. Fluorescent real-time PCR (Taqman) analysis of resistin expression across a range of human tissues showed that resistin is highly expressed in bone marrow compared to other tissues. Taqman analysis and Western blotting showed that rosiglitazone decreased resistin expression at both the mRNA and protein levels in human primary monocyte-derived macrophages in vitro. Resistin expression was reduced by up to 80% after exposure to 100 nM rosiglitazone for 96 h. Bioinformatics analysis of the genomic sequence upstream of the resistin coding sequence identified several putative PPAR response elements of which one was shown to bind PPAR gamma using electrophoretic mobility shift assays. Our data support a direct role for PPAR gamma in the regulation of resistin expression.
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PMID:Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. 1250 8

New agents are being developed to address the underlying endocrinopathies and metabolic disturbances of type 2 diabetes. Stimulants of the nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) are being identified to selectively improve insulin actions, and dual agonists of PPAR gamma and PPAR alpha are being evaluated for enhanced control of hyperglycemia and dyslipidemia. Novel activators of insulin receptor phosphorylation and inhibitors of receptor dephosphorylation are offering encouraging leads for new agents. Analogues of glucagon-like peptide-1 that increase glucose-induced insulin secretion may additionally increase beta-cell neogenesis from progenitor duct cells. The amylin analogue pramlintide, which suppresses glucagon secretion and reduces weight, is advancing in clinical trial. Direct stimulants of glucose utilization and partial inhibitors of gluconeogenesis are providing useful new drug templates. Thus, new pharmacologic approaches are emerging to treat the multiple lesions of type 2 diabetes.
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PMID:New pharmacologic agents for diabetes. 1264 7

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

Obesity, i.e. an excess of white adipose tissue (WAT), predisposes to the development of type 2 diabetes and cardiovascular disease. Brown adipose tissue is present in rodents but not in adult humans. It expresses uncoupling protein 1 (UCP1) that allows dissipation of energy as heat. Peroxisome proliferator-activated receptor gamma (PPAR gamma) and PPAR gamma coactivator 1 alpha (PGC-1 alpha) activate mouse UCP1 gene transcription. We show here that human PGC-1 alpha induced the activation of the human UCP1 promoter by PPAR gamma. Adenovirus-mediated expression of human PGC-1 alpha increased the expression of UCP1, respiratory chain proteins, and fatty acid oxidation enzymes in human subcutaneous white adipocytes. Changes in the expression of other genes were also consistent with brown adipocyte mRNA expression profile. PGC-1 alpha increased the palmitate oxidation rate by fat cells. Human white adipocytes can therefore acquire typical features of brown fat cells. The PPAR gamma agonist rosiglitazone potentiated the effect of PGC-1 alpha on UCP1 expression and fatty acid oxidation. Hence, PGC-1 alpha is able to direct human WAT PPAR gamma toward a transcriptional program linked to energy dissipation. However, the response of typical white adipocyte targets to rosiglitazone treatment was not altered by PGC-1 alpha. UCP1 mRNA induction was shown in vivo by injection of the PGC-1 alpha adenovirus in mouse white fat. Alteration of energy balance through an increased utilization of fat in WAT may be a conceivable strategy for the treatment of obesity.
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PMID:Acquirement of brown fat cell features by human white adipocytes. 1280 71

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR gamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPAR gamma-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.
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PMID:Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. 1283 13

Both type 2 diabetes and hypertension are multifactorial diseases. Several lines of evidence suggested that common genetic factors contribute to both conditions. Genes responsible for obesity and insulin resistance are candidates for common genetic factors. Among candidate genes are genes encoding glycogen synthase, beta 3-adrenergic receptor, glycogen-associated regulatory subunit of protein phosphatase-1, peroxisome proliferator--activated receptor-gamma (PPAR gamma), leptin and adiponectin. In addition, recent genome scans mapped loci linked to type 2 diabetes, hypertension and/or metabolic syndrome. Identification of genes responsible for both type 2 diabetes and hypertension will increase our understanding of molecular mechanisms of these conditions and facilitate the development of effective methods for prevention and intervention of diabetes and hypertension as well as metabolic syndrome.
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PMID:[Genetic susceptibility to diabetes and hypertension]. 1287 70

Both metformin and thiazolidinedione derivatives(TZDs) improve insulin resistance, a major pathogenesis of type 2 diabetes, and decrease blood glucose levels without stimulating insulin secretion. Metformin inhibits glucose output from the liver, while TZDs increase glucose utilization in the peripheral tissues. In addition, there has been indicated that these agents ameliorate metabolic syndrome beyond glucose-level lowering. Molecular targets of these agents have recently been revealed; AMP-activated protein kinase (AMPK) for metformin and adiponectin, while PPAR gamma for TZDs which induce gene expression of adipocyte glycerol kinase and adiponectin. Insulin-sensitizing agents are clinically useful for obese diabetic patients with insulin resistance. However, periodical examinations are necessary to avoid serious adverse effects such as lactic acidosis, although rare, by metformin and liver injury by TZDs.
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PMID:[Insulin-sensitizing agents: metformin and thiazolidinedione derivatives]. 1287 89

The PPAR gamma agonists, thiazolidinediones (TZDs), have anti-inflammatory properties as well as increasing insulin sensitivity. This has widened their therapeutic scope to treat inflammatory diseases such as atherosclerosis in addition to Type 2 Diabetes. TZDs are known to reduce monocyte/macrophage expression of Matrix metalloproteinase (MMP)-9, which is implicated in atherosclerotic plaque destabilization. This study aims to identify other metalloproteinase genes of the ADAM (A Disintegin And Metalloproteinase) and ADAMTS families that are regulated by PPAR gamma or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis. The synthetic PPAR gamma agonist, GW7845, and the natural agonist 15d-PGJ2, suppressed PMA stimulated MMP-9 in human monocyte-like cells (THP-1) only in the presence of 9-cis-retinoic acid. Quantitative Real-Time PCR showed that this reduction was regulated at the mRNA level. Expression of ADAMs 8, 9, and 17 were increased, and ADAM15 was decreased by stimulation of THP-1 with PMA, although these ADAMs were not regulated by PPAR gamma or RXR agonists. PMA-induced ADAM28 expression was further enhanced by the addition of 9-cis-retinoic acid. ADAMTS4, implicated in rheumatoid arthritis, was expressed in THP-1 cells, and significantly increased after 24 h of PMA stimulation. ADAMTS4 expression was suppressed by both PPAR gamma and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the PPAR gamma antagonist, GW9662, suggests that PPAR gamma plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that PPAR gamma and RXR agonists have complex effects on monocyte metalloproteinase expression, which may have implications for therapeutic strategies.
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PMID:Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid. 1453 4


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