The microRNA miR-375 regulates myotrophin, a protein involved in the final stages of insulin secretion from pancreatic islet cells, according to a publication in
The results suggest miR-375 as a possible new avenue for diabetes treatment, according to lead author Markus Stoffel, from Rockefeller University in New York. Of possibly greater immediate significance is a growing belief that microRNAs play other important roles in the pancreas, he said.
"We took an unbiased approach and cloned all of the microRNAs from a pancreatic beta cell line," Stoffel told
To determine their functionality, the team overexpressed the microRNAs or inhibited endogenous microRNAs in beta cells and studied the effects on glucose-induced insulin secretion. miR-375 had a marked effect, leading the group to examine its underlying molecular mechanism, said Stoffel.
"They saw subtle but significant effects of either depleting the microRNA or overexpressing it," explained Victor R. Ambrose, professor of genetics at Dartmouth Medical School in New Hampshire, who was not involved in the study. The team determined targets for miR-375 computationally, he said, and pinpointed myotrophin, a protein known to be involved in neuronal secretion, which the team showed to be involved in exocytosis—the final stage of insulin secretion.
Knocking out myotrophin directly using small inhibitory RNAs (siRNAs) mimicked the effect of overexpression of the microRNA, Ambrose said. "They got some pretty good evidence and support for an in vivo role for miR-375, probably in regulation of myotrophin levels, and thereby influencing the response of pancreatic islet cells to glucose."
The microRNA control of myotrophin at the late stages of insulin secretion was most likely to be a fail-safe protection mechanism, according to Stoffel. "We are much more at risk from hypersecreting than hyposecreting insulin," he said. "If we just secreted a little bit too little insulin, we would just run around with high glucose levels and we wouldn't even notice—and that's what's happening in type II diabetes."
The potential for therapeutic intervention raised by the discovery is clear, according to Maria Fatima Gebauer Hernandez, a group leader at the Center for Genomic Regulation in Barcelona. "You could try to eliminate miR-375 function to increase insulin secretion," she said. "At least, you have a way to increase the last step of insulin production to some extent."
"It's not that this makes a black-and-white effect, just a level you can increase," said Gebauer, who was not involved in the study.
Stoffel was also guarded in his speculations about the significance of the discovery. "One has to be careful, because a defect in exocytosis is not believed to be the primary defect in insulin secretion in type II diabetes," he said. The results were just a beginning, reporting only a function on insulin secretion. "And that's in a differentiated beta cell. Now, we know nothing about the role of the microRNAs in development, in growth, or in cell death of the beta cell. We have good reasons to believe that they have more functions that may also be important. We are studying this now."
"I just want to be careful and not say, yes, yes, this is going to be a treatment in a few years or so," Stoffel added.