It has been suggested that it may be possible to utilize the recently developed and more readily available beta cell lines as an alternative to islets or whole pancreas for transplantation therapy of diabetes. We recently reported that stable transfection and overexpression of the calcium binding protein calbindin in the rat beta cell line RIN 1046-38 results in a marked increase in insulin mRNA (greater than 20 fold for most clones) as well as insulin content, release and transcription. These studies provided direct evidence for a role for calbindin in beta cell function which may have therapeutic relevance. However, RIN cells have little or no responsiveness to glucose. For transplantation therapy, it will be important to utilize beta cells with functions approximating normal beta cells. Thus we propose in this exploratory grant to further examine the role of calbindin in the beta cell using beta-HC cells which respond to glucose and other secretagogues. Specifically, beta-HC cells will be examined for the effect of calbindin on basal insulin mRNA, on basal insulin content, release and transcription, and on the response to secretagogues. In addition we will also determine whether calbindin, which has been reported to protect against apoptotic death of a number of different cells, can protect against cytokine and streptozotocin (STZ) induced destruction of rat beta cells. Possible mechanisms involved in a protective effect of calbindin will be examined, including inhibition of stimulation of nitric oxide production and inhibition of calpain or interleukin 1-beta-converting enzyme protease activity. These findings would have therapeutic implications for the prevention of beta cell destruction which could have important application to beta cell transplantation.
|Effective start/end date||9/30/98 → 9/29/02|
- National Institute of Diabetes and Digestive and Kidney Diseases
- Cell Biology
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