Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are two approaches to identify diabetes-susceptibility genes. One approach is to isolate and characterize genes expressed in the beta-cell and in insulin target tissues whose mutation or altered expression may contribute to the development of diabetes mellitus. Another approach is to clone a diabetes-susceptibility gene by a reverse genetic strategy. The first step for this strategy is to identify a DNA polymorphism that is linked to the disease locus. Using the strategy of the first approach, several candidate genes were examined. Among these genes, the mutation of insulin genes and insulin receptor genes was found in the patient with diabetes. By cDNA cloning or PCR-direct sequencing methods, we identified several mutations in the insulin receptor genes of four insulin-resistant diabetic patients. At least two mutants of insulin receptor genes were expressed in Chinese hamster ovary cells and these mutated receptors showed impaired ability to transduce insulin action in these cultured cells. The expression of these mutant genes in animals such as transgenic mice will be indispensable to establish the relationship between the gene mutation and the abnormality found in the patient. Using the strategy of the second approach, Bell et al. recently reported that the gene responsible for MODY (maturity-onset diabetes of the young) is tightly linked to the adenosine deaminase gene on chromosome 20q. However, this strategy will not be applicable for identification of diabetes-susceptibility genes of NIDDM, since this disorder is likely to be genetically heterogenous, with mutations in several different genes able to cause hyperglycemia, and this heterogeneity could confound the linkage analysis.
 ...
PMID:[Diabetes mellitus and molecular biology]. 177 65

Endogenous adenosine enhances the insulin sensitivity of isolated rat adipocytes. We studied whether this effect was related to an ability of adenosine to alter the activation of insulin receptor kinase by insulin. It was found that depletion of endogenous adenosine by adenosine deaminase treatment decreases insulin's ability to activate the receptor kinase at submaximal insulin concentrations. This occurred without changes in insulin binding. At 4 ng/ml insulin, adenosine deaminase decreased insulin activation of insulin receptor kinase by 25%, a reduction that equalled the effect of adenosine deaminase on insulin stimulation of 2-deoxyglucose transport. The effects of adenosine deaminase on both insulin activation of insulin receptor kinase and insulin stimulation of 2-deoxyglucose transport were reversed by the addition of N6-phenylisopropyl-adenosine, a nonhydrolyzable adenosine analog. Our data are consistent with the view that adenosine modulates the coupling of insulin binding to biological actions of insulin at or before the level of activation of insulin receptor kinase.
 ...
PMID:Adenosine modulates insulin activation of insulin receptor kinase in intact rat adipocytes. 355 35

Insulin action and insulin binding in isolated rat fat cells incubated with adenosine or adenosine deaminase were studied. Adenosine enhanced the effects of insulin on glucose transport and glucose metabolism. The nucleoside shifted the concentration-response curves of insulin-stimulated D-[3-3H]glucose incorporation into total lipids, and of D-[U-14C]glucose conversion to fatty acids to smaller insulin concentrations. In addition, the maximal response of the fatty acid synthesis was increased. Insulin sensitivity and maximal response to insulin of the glucose transport system, as assessed by the rate of uptake of 2-deoxyglucose and 3-O-methylglucose, were increased by adenosine. The adenosine derivative N6-phenylisopropyladenosine similarly enhanced deoxyglucose transport in the presence of insulin. However, insulin binding was not affected by adenosine. The results suggest that adenosine modulates insulin action at a step distal from the insulin receptor, and before, or at, the glucose transport system.
 ...
PMID:Modulation of insulin sensitivity by adenosine. Effects on glucose transport, lipid synthesis, and insulin receptors of the adipocyte. 675 15

Deficient insulin signaling is a key event mediating diabetic glomerulopathy. Additionally, diabetic kidney disease has been related to increased levels of adenosine. Therefore, we tested a link between insulin deficiency and dysregulated activity of the equilibrative nucleoside transporters (ENTs) responsible for controlling extracellular levels of adenosine. In ex vivo glomeruli, high D-glucose decreased nucleoside uptake mediated by ENT1 and ENT2 transporters, resulting in augmented extracellular levels of adenosine. This condition was reversed by exposure to insulin. Particularly, insulin through insulin receptor/PI3K pathway markedly upregulated ENT2 uptake activity to restores the extracellular basal level of adenosine. Using primary cultured rat podocytes as a cellular model, we found insulin was able to increase ENT2 maximal velocity of transport. Also, PI3K activity was necessary to maintain ENT2 protein levels in the long term. In glomeruli of streptozotocin-induced diabetic rats, insulin deficiency leads to decreased activity of ENT2 and chronically increased extracellular levels of adenosine. Treatment of diabetic rats with adenosine deaminase attenuated both the glomerular loss of nephrin and proteinuria. In conclusion, we evidenced ENT2 as a target of insulin signaling and sensitive to dysregulation in diabetes, leading to chronically increased extracellular adenosine levels and thereby setting conditions conducive to kidney injury.
 ...
PMID:Deficient Insulin-mediated Upregulation of the Equilibrative Nucleoside Transporter 2 Contributes to Chronically Increased Adenosine in Diabetic Glomerulopathy. 3213 71