| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T87875 | ||||
| Target Name | mRNA of Glucagon receptor | ||||
| Target Type | Clinical Trial |
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| Action against Disease Model | ISIS 325568 | ISIS 325568, is a second generation antisense drug that inhibits the body's ability to produce the excessive amounts of glucose. ISIS 325568 inhibits the expression of GCGR leading to a reduction in the ability of glucagon to produce glucose and cancelling out a lack of sensitivity to insulin. | Drug Info | ||
| The Effect of Target Knockout, Knockdown or Genetic Variations | We compared pertinent clinical and metabolic parameters in glucagon receptor-null (Gcgr(-/-)) mice and wild-type (Gcgr(+/+)) controls after equivalent destruction of beta-cells.Gcgr(+/+) mice became hyperglycemic (>500 mg/dL), hyperketonemic, polyuric, and cachectic and had to be killed after 6 weeks. Despite comparable |??cell destruction in Gcgr(-/-) mice, none of the foregoing clinical or laboratory manifestations of diabetes appeared. There was marked |?-cell hyperplasia and hyperglucagonemia (~1,200 pg/mL), but hepatic phosphorylated cAMP response element binding protein and phosphoenolpyruvate carboxykinase mRNA were profoundly reduced compared with Gcgr(+/+) mice with diabetes--evidence that glucagon action had been effectively blocked. Fasting glucose levels and oral and intraperitoneal glucose tolerance tests were normal. Both fasting and nonfasting free fatty acid levels and nonfasting beta-hydroxy butyrate levels were lower.We conclude that blocking glucagon action prevents the deadly metabolic and clinical derangements of type 1 diabetic mice. | ||||
| References | |||||
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