NEW YORK (Reuters Health) - Polypyrimidine tract-binding protein (PTB) promotes rapid biogenesis of insulin secretory granules and may, therefore, represent a therapeutic target in type 2 diabetes, according to a new report. In vivo, downregulation of PTB resulted in depletion of insulin secretory granules from insulinoma cells.
Sustained glucose stimulation depletes pancreatic beta cells of their pool of insulin secretory granules, the authors explain, and the factors promoting their quick restoration are unknown.
Dr. Michele Solimena from University of Technology Dresden, Dresden, Germany and colleagues investigated the role of PTB in the biogenesis of insulin secretory granules. Their findings are reported in the February 22nd advance online publication of Nature Cell Biology.
Early experiments demonstrated that stabilization of the mRNA of ICA512, a receptor-tyrosine-phosphatase-like protein associated with insulin secretory granules, could partially account for the rapid glucose-dependent stimulation of the synthesis of ICA512.
Later, the report indicates, cytosolic PTB was found to bind to and stabilize the 3'-untranslated region of ICA512 mRNA and to promote the expression and translation of mRNAs of other glucose-regulated proteins.
The depletion of insulin secretory granules resulting from PTB downregulation led to a reduction of cell insulin content by 69% and a decrease in secreted insulin of 48%.
Prolonged glucose stimulation appeared to result in translocation of PTB from the nucleus to the cytosol, the researchers note, in a pattern suggestive of targeting to the endoplasmic reticulum.
“Our research does not yet have direct clinical implications,” Dr. Solimena told Reuters Health. “The discovery of a novel pathway responsible for the rapid production of insulin and all other components required for its regulated secretion could open, however, new prospects for the treatment of type 2 diabetes.”
“We are currently investigating whether activation of PTB depends on its phosphorylation,” Dr. Solimena said. “To this aim we are using various pharmacological agents that are known to modulate the activity of different phosphorylating enzymes. We are also generating transgenic mice in which the expression of PTB in pancreatic beta cells can be regulated. This approach will allow us to test further the role of PTB in the biogenesis of secretory granules in animals.”
“It would be especially interesting to determine whether PTB or still to be identified factors involved in PTB activation represent susceptibility genes for type 2 diabetes,” Dr. Solimena concluded.
Source: Nat Cell Biol 2004. [ Google search on this article ]
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