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Regenerating insulin-producing cells with zinc could tackle the underlying cause of diabetes

2018-12-28

Most current diabetes treatments, from insulin injections to newer GLP-1 agonists, don’t solve the underlying cause of the disease. The ability to regenerate insulin-producing cells in the pancreas would do the job, but that has so far proven to be an elusive target. A team of Stanford University scientists is now searching for a solution in a common nutrient: zinc.

As it turns out, insulin-producing beta cells have a particularly strong taste for zinc. The researchers are leveraging that affinity to zinc as a way to guide regenerative medicine towards the cells.  

Diabetes happens when the body can’t produce enough insulin, so the study’s senior author, Stanford University endocrinologist Justin Annes, M.D., Ph.D., has been trying to develop drugs that can help regenerate insulin-producing beta cells. His team did find such a candidate recently in a known cancer drug, JNK inhibitor CC-401.

According to Annes’ recent study published in the journal Endocrinology, CC-401 induced beta-cell replication in vitro and in rodents. However, there was one major problem: The drug’s mechanism of action also increased the expression of many genes that are normally suppressed. That touch off an uncontrolled replication of off-target cells, which could cause serious side effects.

So Annes turned his attention to zinc. Scientists know that beta cells take in about 1,000 times more zinc than surrounding cells, and that trait has been used to help scientists visually identify beta cells in pancreatic tissues. That means zinc holds potential as a “lighthouse” for beta-cell regenerative drug, Annes figured.

With help from medicinal chemists, Annes’ team came up with a strategy based on a well-established technique known as chelation, which is generally used to treat lead and mercury poisoning. Chelation involves a drug that clumps with the metals, which can then be excreted from the body.

The Stanford team used a zinc-chelating agent that can accumulate in beta cells and linked it with a beta-cell regenerating therapy. They showed that in rat cells the combo helped the beta cells replicate about 250% more than other cell types. Studies in human cells returned a smaller yet still significant 130% advantage, the team reported in the journal Cell Chemical Biology.

Various ideas for regenerating beta cells are being explored by other scientists as potential treatments or even cures for diabetes. AstraZeneca and Ionis are investigating the use of antisense oligonucleotides in beta cells to silence genes that disrupt insulin production, for example. And scientists at the University of Miami have recently found a source of pancreatic stem cells that can turn into—and therefore replenish—beta cells.

The Stanford team still has a long way to go to prove that their zinc-chelating approach can deliver regenerative therapy. “This is the first demonstration of a selectively delivered replication molecule in beta cells,” said Annes in a statement. One challenge is that zinc is found in cells throughout the body, so there's a risk that the treatment will find its way to other organs, causing side effects. The researchers plan to work on improving the beta-cell selectivity of the technique in the hopes of further developing it to treat diabetes.


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