Grants and Contracts Details
Description
The beta cells of the pancreas produce and secrete insulin in response to increasing blood
glucose levels and this process is essential for maintaining normal glucose homeostasis. Defects in
insulin production and secretion result in type 1 as well as type 2 diabetes. Although, three beta-cell
specific transcription factors (Pdx-1, MafA, and NeuroDi) have been implicated in glucose regulation
of insulin production, the exact molecular mechanisms by which glucose modulates the function of
these transcription factors remain unknown. The long-term goal of this research is to gain a detailed
understanding of the mechanisms and pathways leading to glucose induction of insulin gene
expression via modulation of the transcription factors Pdx-1, MafA, and NeuroDi. Our previous
findings suggest that glucose regulates the function of the these transcription factors by different
mechanisms and pathways to ensure a tight control of insulin gene expression in pancreatic beta
cells. Based on our preliminary data, we hypothesize that glucose regulates insulin gene
expression by 1) influencing the interaction of Pdx-1 with other transcriptional regulators; 2)
controlling MafA expression via 0-linked GlcNAc modification of proteins; and 3) regulating
the nucleo-cytoplasmic shuttling of NeuroDi.
We propose to test this hypothesis in cultured pancreatic beta cell lines as well as isolated
pancreatic islets using various biochemical, molecular, and cell biological, and immunological
techniques to identify the critical pathways and players involved in glucose regulation of beta-cell
specific transcription factors. The information obtained from our studies will be instrumental in the
design of new therapies to treat and prevent diabetes, associated with defects in insulin production.
Status | Finished |
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Effective start/end date | 9/1/10 → 8/31/13 |
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