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)

Increased nitric oxide (NO) synthesis has been proposed to participate in the generation of insulin resistance in adipose and muscle tissues. Therefore, we examined the potential rate-limiting role of tetrahydrobiopterin (BH4) in cytokine-induced NO synthesis, and the effect of peroxisome proliferator activated receptor-gamma (PPARgamma) activation using the insulin-sensitizer rosiglitazone on cytokine-induced BH4 synthesis in 3T3-L1 adipocytes. Our data indicate that modulated availability of the mandatory nitric oxide synthase (NOS) cofactor BH4 affected cytokine-induced NO generation. Semiquantitative linear range reverse transcription polymerase chain reaction (RT-PCR) analysis demonstrated that rosiglitazone not only reduced inducible nitric oxide synthase (iNOS) mRNA transcription, but also guanosine triphosphate cyclohydrolase (GTPCH), the rate-limiting and controlling step of BH4 synthesis. Accordingly, intracellular BH4 concentration was reduced by 45% following rosiglitazone treatment. Furthermore, we observed a transient inhibitory effect of natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PJ2) on cytokine-mediated iNOS and GTPCH induction. Thus, the inhibition of cytokine-induced NO synthesis by rosiglitazone is at least in part attributable to reduced availability of BH4, the synthesis of which might represent a potential new target in the treatment of type 2 diabetes and insulin resistance.
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PMID:Diminished production of nitric oxide synthase cofactor tetrahydrobiopterin by rosiglitazone in adipocytes. 1256 86

Previous studies indicate that endothelial nitric oxide synthase (eNOS) function is impaired in diabetes as a result of increased vascular generation of reactive oxygen species. We hypothesized that eNOS gene therapy would augment NO. bioavailability and protect against hepatic ischemia-reperfusion (I-R) injury in type 2 diabetes mellitus. We developed a transgenic (Tg) diabetic mouse in which eNOS is systemically overexpressed. We also examined the effects of hepatic eNOS adenovirus therapy in diabetic mice. Diabetic (db/db) and nondiabetic mice were subjected to hepatic I-R injury. In nondiabetic mice, genetic overexpression of eNOS (both eNOS-Tg and eNOS adenovirus) resulted in hepatoprotection. In contrast, hepatic I-R injury was significantly increased in the db/db eNOS-Tg mouse, as serum alanine aminotransaminase (ALT) levels were increased by 3.3-fold compared with diabetic controls. Similarly, eNOS adenovirus treatment resulted in a 3.2-fold increase in serum ALT levels as compared with diabetic controls. We determined that hepatic eNOS was dysfunctional in the db/db mouse and increased genetic expression of eNOS resulted in greater production of peroxynitrite. Treatment with the eNOS cofactor tetrahydrobiopterin (BH4) or the BH4 precursor sepiapterin resulted in a significant decrease in serum ALT levels following I-R injury. We present clear examples of the protective and injurious nature of NO. therapy in I-R. Our data indicate that eNOS exists in an "uncoupled" state in the setting of diabetes and that "recoupling" of the eNOS enzyme with cofactor therapy is beneficial.
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PMID:eNOS gene therapy exacerbates hepatic ischemia-reperfusion injury in diabetes: a role for eNOS uncoupling. 1676 64

Endothelial nitric oxide synthase (eNOS) dysfunction induces insulin resistance and glucose intolerance. Tetrahydrobiopterin (BH4) is an essential cofactor of eNOS that regulates eNOS activity. In the diabetic state, BH4 is oxidized to 7,8-dihydrobiopterin, which leads to eNOS dysfunction owing to eNOS uncoupling. The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice. Single administration of BH4 lowered fasting blood glucose levels in wild-type mice with streptozotocin (STZ)-induced diabetes and alleviated eNOS dysfunction by increasing eNOS dimerization in the liver of these mice. Liver has a critical role in glucose-lowering effects of BH4 through suppression of hepatic gluconeogenesis. BH4 activated AMP kinase (AMPK), and the suppressing effect of BH4 on gluconeogenesis was AMPK-dependent. In addition, the glucose-lowering effect and activation of AMPK by BH4 did not appear in mice with STZ-induced diabetes lacking eNOS. Consecutive administration of BH4 in ob/ob mice ameliorated glucose intolerance and insulin resistance. Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes.
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PMID:Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase-dependent manner in diabetic mice. 2364 19