Protein found that could lead to diabetes treatment

Scientists have linked a protein to regulation of the body’s use of the sugar glucose. In the process, they illustrated the protein’s potential as a target for new drugs to treat diabetes and obesity.

Removing the gene for the protein, Par-1b/MARK2, produced a line of mice that were lean, hypersensitive to insulin and resisted weight gain even on a high-fat diet.

Scientists recently published their results online in Proceedings of the National Academy of Sciences.

“Medically speaking, this is the reverse of type 2 diabetes,” said lead author Jonathan Hurov, Ph.D., who earned a doctorate from the School of Medicine and is a postdoctoral researcher in Boston. “Type 2 diabetics are insulin resistant, and these mice are the opposite of that. If we can find a way to block the activity of this protein in diabetics or the obese, we may be able to improve their prognosis.”

Par-1b/MARK2 belongs to a family of proteins known as kinases. Because of the wide variety of functions performed by kinases, Hurov said, scientists already have experience designing compounds to inhibit them.

The finding surprised Hurov and his doctoral mentor, Helen Piwnica-Worms, Ph.D., professor of cell biology and anatomy. They had been looking at the protein for its potential role in other processes.

“This protein initially came to scientists’ attentions as a contributor to cellular polarity — processes that place different features on a particular side of a cell,” said Piwnica-Worms, a Howard Hughes Medical Institute investigator. “We had seen evidence in the test tube that it might be linked to cell cycle regulation, which we study for the insights it offers into the origins of cancers.”

When mice missing the gene for Par-1b/MARK2 were unusually thin, Hurov began a series of tests of their metabolism, eventually discovering that they were hypersensitive to insulin.

He also found evidence suggesting that the changes were linked to the way fat tissues in the mice responded to insulin.

“Fat, muscles and the liver all respond to insulin, but fat tissues seemed to be the source of increased insulin sensitivity in these mice,” he said.

“We’re going to follow up by knocking out the gene selectively in these individual tissue types to see if the changes are really coming just from fat or if there’s cross talk between the different tissues that contributes to the differences,” Hurov said.